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Wang SW, Wang C, Cheng YM, Hsieh TH, Wang CC, Kao JH. Liver and atherosclerotic risk of alcohol consumption in patients with metabolic dysfunction-associated Steatotic Liver Disease. Atherosclerosis 2025; 403:119161. [PMID: 40090036 DOI: 10.1016/j.atherosclerosis.2025.119161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 03/18/2025]
Abstract
BACKGROUND/PURPOSE A new disease name, "Steatotic Liver Disease (SLD)" was proposed in 2023. Within this algorithm, combined metabolic and alcoholic liver disease (MetALD) was named as a new specific subgroup. The clinical profiles and outcomes of MetALD patients are unknown. METHODS Participants from Taiwan Biobank database after exclusion those with positive for HBsAg, anti-HCV, and former drinkers were selected. MASLD was diagnosed if having hepatic steatosis on ultrasound plus at least one of cardiometabolic criteria. Increased or moderate alcohol intake was defined as continuous drinkers with alcohol consumption exceeding 210 g for men and 140 g for women weekly or below the levels, respectively. The fibrosis 4 (FIB-4) score was used to assess the severity of liver fibrosis, and carotid plaques on duplex ultrasound were employed to diagnose atherosclerosis. RESULTS In a total of 18,160 (mean age 55.28 ± 10.41; 33.2 % males) participants, there were 7316 (40.3 %) MASLD patients and 209 (1.2 %) MetALD patients. The participants with MetALD were younger and male predominant. After propensity score matching for age and gender, MetALD patients had higher AST, GGT, fatty liver index (FLI), and FIB-4 score and tended to have a higher proportion of carotid plaques than MASLD patients. Among MASLD patients, those with moderate alcohol intake had higher values of GGT, FLI, and FIB-4 score and a higher proportion of carotid plaques than those with no or social alcohol intake. CONCLUSIONS MetALD patients have a higher risk of liver injury than those with MASLD. Moreover, moderatet alcohol intake also increases the risk of liver injury and atherosclerotic in MASLD patients, suggesting MASLD patients should refrain from alcohol intake.
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Affiliation(s)
- Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, Taiwan
| | - Ching Wang
- National Yang Ming Chiao Tung University, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Wang SW, Wang C, Cheng YM, Chen CY, Hsieh TH, Wang CC, Kao JH. Genetic predisposition of metabolic dysfunction-associated steatotic liver disease: a population-based genome-wide association study. Hepatol Int 2025; 19:415-427. [PMID: 39755997 DOI: 10.1007/s12072-024-10769-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/06/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND/PURPOSE Although metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed to replace the diagnosis of non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria since 2023, the genetic predisposition of MASLD remains to be explored. METHODS Participants with data of genome-wide association studies (GWAS) in the Taiwan Biobank database were collected. Patients with missing data, positive for HBsAg, anti-HCV, and alcohol drinking history were excluded. MASLD was defined if having hepatic steatosis on ultrasound, plus at least one of cardiometabolic criteria. The Taiwan biobank used two genetic chips during the period of data collection: Taiwan biobank version 1 (TWBv1) as the initial chip and TWBv2 specifically designed for the Taiwanese population. TWBv2 was used as test group and TWBv1 as validation group. NAFLD fibrosis score (NFS) was used to assess the degree of liver fibrosis, and carotid plaques on duplex ultrasound were employed for the diagnosis of atherosclerosis. RESULTS In a total of 16,407 (mean age 55.35 ± 10.41; 29.6% males) participants, 6722 (41.0%) had MASLD. Eleven single-nucleotide polymorphisms (SNP) were identified to be associated with MASLD. Their functions were exonic in two and intronic in nine. They were related to the PNALA3, and SAMM50 genes located on chromosome 22. The linkage disequilibrium showed a high correlation with each other. Four SNPs of PNALA3 and SAMM50 genes had increased risk of MASLD and higher levels of AST/ALT. In addition, there was no association of these two genes with glucose metabolism, but better lipid profiles in SAMM50. CONCLUSIONS This large GWAS study indicates that eleven SNPs of PNPLA3 and SAMM50 genes predispose the development of MASLD in Taiwanese population.
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Affiliation(s)
- Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan
| | - Ching Wang
- National Yang Ming Chiao Tung University, Hsinchu City, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Chun-Yi Chen
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, 289 Jianguo Rd., Xindian Area, New Taipei City, 23142, Taiwan.
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Tang Z, Ku PW, Xia Y, Chen LJ, Zhang Y. Preexisting multimorbidity predicts greater mortality risks related to long-term PM 2.5 exposure. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 368:125762. [PMID: 39880353 DOI: 10.1016/j.envpol.2025.125762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/17/2025] [Accepted: 01/26/2025] [Indexed: 01/31/2025]
Abstract
Long-term health risk assessments related to ambient fine particulate matter (PM2.5) exposure have been more limited to general population but not towards individuals suffering from multimorbidity. While both multimorbidity and PM2.5 are independently linked to elevated mortality risk, their combined effects and interactions remain practically unexplored. A cross-cohort analysis was undertaken on data from 3 prospective cohorts, initially enrolling 869038 adults aged ≥18 years followed up during 2005-2022. Multimorbidity was identified at baseline surveys through a list of nine common chronic conditions. Cox proportional hazards models were utilized to quantify the associations of long-term PM2.5 exposure with all-cause, cardiovascular, and respiratory mortality among individuals with and without multimorbidity. Joint effects and interactions between baseline multimorbidity and PM2.5 level on the additive and multiplicative scales were examined. Risk differences of PM2.5-induced mortality were analyzed stratified by number of chronic conditions and multimorbidity patterns. Subgroup and sensitivity analyses were carried out to evaluate the consistency of the findings. Among 713119 eligible participants for primary analysis, 65490 prevalent cases of multimorbidity were identified at baseline over a median follow-up of 12.2 years. Compared to individuals without multimorbidity, associations of PM2.5 exposure with all-cause and cardiovascular mortality were more prominent among multimorbidity individuals (P <0.05 for heterogeneity). Our analysis unveiled a significant additive interaction between PM2.5 level and preexisting multimorbidity status, yielding estimated attributable proportions of 11.7%-17.8% and excess risks of 31.1%-72.6% for different mortality outcomes. Sex subgroup and sensitivity analyses consistently produced similar results. This large-scale multicohort analysis demonstrated markedly stronger associations between PM2.5 levels and risks of all-cause and cardiovascular mortality in multimorbidity populations compared to those without multimorbidity. PM2.5 exposure and preexisting multimorbidity showed synergistic effects in triggering mortality events, wherein the joint risks were intensified with elevated PM2.5 levels and an increased number of chronic conditions.
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Affiliation(s)
- Ziqing Tang
- Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Po-Wen Ku
- Graduate Institute of Sports and Health Management, National Chung Hsing University, 402, Taichung, Taiwan; Department of Behavioral Science and Health, University College London, London, UK
| | - Yang Xia
- Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Li-Jung Chen
- Department of Exercise Health Science, National Taiwan University of Sport, No. 16, Sec. 1, Shuangshi Rd., North Dist., Taichung City, 404, Taiwan; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, SE5 8AF, UK.
| | - Yunquan Zhang
- Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Public Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
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Hsu WH, Geng JH, Wu PY, Huang JC, Kuo CH, Chen SC. Metabolic syndrome is associated with gastroesophageal reflux disease in a large Taiwanese population study. Int J Med Sci 2025; 22:1555-1561. [PMID: 40093807 PMCID: PMC11905277 DOI: 10.7150/ijms.109616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 02/19/2025] [Indexed: 03/19/2025] Open
Abstract
Gastroesophageal reflux disease (GERD) and metabolic syndrome (MetS) have emerged as prominent health issues in past decades. This study aimed to evaluate whether the presence of MetS and its constituent factors was associated with a higher likelihood of GERD in a large cohort of Taiwanese adults. MetS and its components were defined according to the modified National Cholesterol Education Program Expert Panel and Adult Treatment Panel III for Asians, and the presence of GERD was assessed using standardized interviews and questionnaires. Of 121,583 participants from the Taiwan biobank, 16,664 (13.7%) were diagnosed with GERD and 27,441 (22.6%) were diagnosed with MetS. After multivariable analysis, the participants with MetS (odds ratio [OR] = 1.079), abdominal obesity (OR = 1.094), hypertriglyceridemia (OR = 1.085), and low high-density lipoprotein cholesterol (OR = 1.073) (all p < 0.001) were significantly associated with GERD, but high blood pressure and hyperglycemia were not. Furthermore, there was a trend of a stepwise increase in the rate of GERD in accordance with the number of MetS components. Participants with 3 components (vs. 0; OR = 1.093; p = 0.002), 4 components (vs. 0; OR = 1.108; p = 0.005), and 5 components (vs. 0; OR = 1.137; p = 0.029) were significantly associated with GERD. Our results suggest that MetS may be associated with the development of GERD in the Taiwanese population.
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Affiliation(s)
- Wen-Hung Hsu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Jiun-Hung Geng
- Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Yu Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Jiun-Chi Huang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Chao-Hung Kuo
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Lee SY, Huang SM, Hung CT, Fang SC. The Relationship Between Psychological Distress and Sleep Quality Among Middle-Aged and Older Adults: The Moderating Effect of Gender. J Nurs Res 2025; 33:e372. [PMID: 39787132 DOI: 10.1097/jnr.0000000000000655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Symptoms of psychological distress such as depression and anxiety as well as gender are known to be associated with sleep quality in middle-aged and older adults. However, little is known about the effect on sleep quality of interactions among these factors. PURPOSE This study was developed to investigate the moderating effect of gender on the relationship between psychological distress and sleep quality in middle-aged and older adults. METHODS A cross-sectional design, secondary data analysis of data on 5,590 individuals aged ≥ 45 years from the Taiwan Biobank database (2009-2018) was used. In this database, psychological distress was assessed using the Patient Health Questionnaire-4, and sleep quality was assessed using a self-report, one-question scale. Demographic data and health-related variables were evaluated as potential confounding factors. A hierarchical regression was conducted to examine the moderating effect of gender on the relationship between psychological distress and sleep quality after adjusting for potential confounders. RESULTS The participants with severe psychological distress were found to have a lower mean quality of sleep than those without ( p < .01), and males returned a better mean quality of sleep score than females ( p < .01). Moreover, a significant interaction effect between psychological distress and gender on sleep quality score was found ( b = 0.123, SE = 0.022, p = .03). In terms of participants with severe psychological distress, males reported significantly poorer sleep quality than females. CONCLUSIONS The findings provide evidence that gender moderates the relationship between sleep quality and psychological distress. Also, in terms of individuals with severe psychological distress, males reported worse sleep quality than women, indicating psychological distress impacts sleep quality in men more than women. Nurses should be aware of these findings when working with clinical professionals to tailor gender-specific education interventions to improve sleep quality and psychological health.
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Affiliation(s)
- Szu-Ying Lee
- Department of Nursing, MacKay Medical College, New Taipei City, Taiwan
| | - Sheng-Miauh Huang
- Department of Nursing, MacKay Medical College, New Taipei City, Taiwan
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Wang SW, Chang YW, Wang C, Cheng YM, Hsieh TH, Wang CC, Kao JH. Clinical profiles and their interaction of concurrent metabolic associated steatotic liver disease and hepatitis B virus infection. World J Hepatol 2024; 16:1429-1440. [DOI: 10.4254/wjh.v16.i12.1429] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/23/2024] [Accepted: 07/30/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND A new nomenclature of metabolic associated steatotic liver disease (MASLD) was proposed in 2023, thus expanding the diagnostic name of “MASLD combined with other etiologies”.
AIM To investigate the clinical profiles of patients with concurrent MASLD and chronic hepatitis B virus (HBV) infection.
METHODS This study included participants from the Taiwan Bio-bank. The diagnostic criteria of MASLD encompassed hepatic steatosis and any cardio-metabolic risk factors. Positive hepatitis B surface antigen was considered indicative of chronic HBV infection. Dual etiology was defined as MASLD combined with chronic HBV infection (MASLD-HBV). Fibrosis 4 (FIB-4) score determined the severity of liver fibrosis, and atherosclerosis was diagnosed by the presence of carotid plaques on duplex ultrasound.
RESULTS In a total of 18980 participants (mean age, 55.18 ± 10.35 years; males, 30.42%), there were 7654 (40.3%) MASLD patients and 2128 (11.2%) HBV carriers. After propensity score matching for age and gender, HBV carriers had a lower percentage of MASLD than healthy controls. Those with dual etiology had higher aspartate aminotransferase, alanine aminotransferase (ALT), and FIB-4 levels, but lower gamma glutamyl transferase (GGT) levels than MASLD patients. In contrast, those with dual etiology had higher ALT and GGT levels, but lower FIB-4 than “HBV alone” patients. The risk of atherosclerosis was similar among these three groups.
CONCLUSION MASLD-HBV patients have worse liver fibrosis severity than MASLD patients, but better liver fibrosis stage than “HBV alone” patients, suggesting a complex interaction between MASLD and chronic HBV infection.
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Affiliation(s)
- Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Taipei 235, Taiwan
| | - Yu-Wen Chang
- Department of Gastroenterology and Hepatology, Taipei Tzu Chi Hospital, Taipei 231, Taiwan
| | - Ching Wang
- Department of Education, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung’s Taichung MetroHarbor Hospital, Taichung 43503, Taiwan
| | | | - Chia-Chi Wang
- Department of Hepatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan
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Cheng YM, Hsieh TH, Wang SW, Wang CC, Kao JH. Metabolic associated steatotic liver disease misses fewer high-risk patients than metabolic associated fatty liver disease. Clin Exp Hepatol 2024; 10:249-256. [PMID: 40290523 PMCID: PMC12022616 DOI: 10.5114/ceh.2024.145429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/24/2024] [Indexed: 04/30/2025] Open
Abstract
Aim of the study Metabolic associated steatotic liver disease (MASLD) was proposed to replace non-alcoholic fatty liver disease (NAFLD) in 2023. It has different diagnostic criteria from metabolic associated fatty liver disease (MAFLD). The comparison between the two disease names and diagnostic criteria deserves investigation. Material and methods We recruited participants from the Taiwan Bio-bank database. NAFLD was diagnosed based on the presence of hepatic steatosis after excluding chronic hepatitis B or C virus infection, chronic drinkers, or other known liver diseases. According to the presence of cardiometabolic criteria, NAFLD is divided into two groups: MASLD and cryptogenic steatotic liver disease (SLD). The "missing" group was defined as those patients who met the diagnostic criteria for MASLD but not for MAFLD. Cryptogenic SLD was used as the control group. We used the NAFLD fibrosis score (NFS) as an indicator for liver fibrosis. Results This study included 17,595 participants, among whom 7,274 (41.3%) had MASLD, and 6,905 had pure MAFLD, defined as MAFLD having no other causes of liver diseases. The cryptogenic SLD group consisted of 264 (1.5%) patients, while the "missing" group had 369 patients. There were no differences in metabolic parameters, liver markers and the percentage of carotid plaques between these two groups. When comparing the "missing" group to the control group, the "missing" group had higher NFS and a higher proportion of carotid plaques. Conclusions In this large, population-based study, is not advisable to exclude the "missing" group having higher risk of liver fibrosis and atherosclerosis than controls. MASLD misses fewer high-risk patients than pure MAFLD for replacing NAFLD.
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Affiliation(s)
| | | | - Shan-Wen Wang
- Taipei Medical University-Shuang Ho Hospital, Taiwan
| | | | - Jia-Horng Kao
- National Taiwan University Hospital, Taiwan
- National Taiwan University College of Medicine, Taiwan
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Shen HC, Pan MH, Huang CJ, Yeh HY, Yang HI, Lin YH, Huang CC, Lee KC, Yang YY, Hou MC. Multiple genetic polymorphisms are associated with the risk of metabolic syndrome, fatty liver, and airflow limitation: A Taiwan Biobank study. Gene 2024; 927:148660. [PMID: 38866261 DOI: 10.1016/j.gene.2024.148660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/30/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024]
Abstract
BACKGROUND Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases. METHODS In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations. RESULTS MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1). CONCLUSIONS MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation.
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Affiliation(s)
- Hsiao-Chin Shen
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chih-Jen Huang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hsiao-Yun Yeh
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yi-Hsuan Lin
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chang Huang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taiwan
| | - Kuei-Chuan Lee
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ying-Ying Yang
- Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Ming-Chih Hou
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
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Lu JH, Tsai CC, Lee JI, Lin CY, Huang SP, Geng JH, Kuo CH, Chen SC. Vegetarian Diet Reduced Gastroesophageal Reflux Disease in a Nationwide Longitudinal Survey in Taiwan. Nutrients 2024; 16:3712. [PMID: 39519544 PMCID: PMC11547424 DOI: 10.3390/nu16213712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND/OBJECTIVES This large, longitudinal follow-up cohort study aimed to explore how being a vegetarian and related factors impacted the incident gastroesophageal reflux disease (GERD) in a comprehensive Taiwanese cohort. METHODS The study cohort was enrolled from the Taiwan Biobank. Vegetarian status, duration of being a vegetarian, type of vegetarian diet, and whether or not the participants had GERD were recorded from self-reported surveys. Associations between vegetarian status, duration, and type of diet with incident GERD were analyzed with multivariate logistic regression with adjustments for confounding variables. RESULTS After excluding participants with pre-existing GERD, we included 23,714 participants into the study. Multivariable analysis showed that vegetarian status (current vs. never; hazard ratio [HR], 0.697; 95% confidence interval [CI], 0.546 to 0.889; p = 0.004) was significantly inversely associated with incident GERD; conversely, ever being a vegetarian was not associated (p = 0.489). In addition, those who had been a vegetarian for 6 years or more had 0.72 times lower risk of GERD compared to those who had never been a vegetarian (HR, 0.717; 95% CI 0.558 to 0.922, p = 0.009). No significant differences were observed regarding the type of vegetarian diet with incident GERD. CONCLUSIONS The results showed that following a vegetarian diet was an independent protective factor for incident GERD, with a significant protective effect observed in those who adhered to a vegetarian diet for at least 6 years. Future research is warranted to explore the underlying mechanisms and whether adopting a vegetarian diet can decrease the incidence of GERD.
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Affiliation(s)
- Jyun-Han Lu
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Chun-Chi Tsai
- Health Management and Occupational Safety and Health Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812015, Taiwan;
| | - Jia-In Lee
- Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Chih-Yi Lin
- Administration Management Center, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812015, Taiwan;
| | - Shu-Pin Huang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Jiun-Hung Geng
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812015, Taiwan
| | - Chao-Hung Kuo
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812015, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Szu-Chia Chen
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 812015, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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10
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Wang SW, Hsieh TH, Cheng YM, Wang CC, Kao JH. Liver and atherosclerotic risks of patients with cryptogenic steatotic liver disease. Hepatol Int 2024; 18:943-951. [PMID: 38227142 DOI: 10.1007/s12072-023-10624-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 12/01/2023] [Indexed: 01/17/2024]
Abstract
BACKGROUND AND AIMS In 2023, a new nomenclature of "metabolic associated steatotic liver disease" (MASLD) has emerged by incorporating cardio-metabolic criteria to redefine "non-alcoholic fatty liver disease" (NAFLD). Among steatotic liver disease (SLD), those having no known causes and without any one of cardio-metabolic criteria are deemed to have cryptogenic SLD. This study aims to compare the liver and atherosclerotic risks between MASLD and cryptogenic SLD patients. APPROACH We analyzed participants with liver ultrasound data from the Taiwan Bio-Bank cohort, excluding those with positive HBsAg, positive anti-HCV, or "frequent drinker". MASLD involves hepatic steatosis and any of five cardiometabolic risk factors, whereas cryptogenic SLD features hepatic steatosis without these risk factors. Liver fibrosis severity was assessed by using NAFLD fibrosis score (NFS), while atherosclerosis was determined by carotid plaques on duplex ultrasound. RESULTS Among 17,595 subjects (age 55.47 ± 10.41; males 31.8%), 7538 participants (42.8%) had SLD, comprising 96.5% of MASLD and 3.5% of cryptogenic SLD. Cryptogenic SLD patients are younger and had a lower percentage of male than those with MASLD. After propensity score matching for age and sex, patients with cryptogenic SLD exhibited milder glucose and lipid profiles, fewer carotid plaques, lower liver steatosis, inflammation, and fibrosis markers than those with MASLD. CONCLUSIONS In this large population-based study, cryptogenic SLD, the excluded group, occupy only 3.5% in NAFLD patients. It has lower liver and atherosclerotic risks than MASLD, supporting its exclusion from NAFLD and justifying the rationale for the new disease name and diagnostic criteria of MASLD.
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Affiliation(s)
- Shao-Wen Wang
- Department of Education, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, New Taipei City and Hualien, Taiwan.
- Medical Department, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, 289 Jianguo Rd., Xindian Area, New Taipei City, 23142, Taiwan.
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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11
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Lai EY, Huang YT. Identifying pleiotropic genes via the composite test amidst the complexity of polygenic traits. Brief Bioinform 2024; 25:bbae327. [PMID: 39007593 PMCID: PMC11247409 DOI: 10.1093/bib/bbae327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/29/2024] [Accepted: 06/24/2024] [Indexed: 07/16/2024] Open
Abstract
Identifying the causal relationship between genotype and phenotype is essential to expanding our understanding of the gene regulatory network spanning the molecular level to perceptible traits. A pleiotropic gene can act as a central hub in the network, influencing multiple outcomes. Identifying such a gene involves testing under a composite null hypothesis where the gene is associated with, at most, one trait. Traditional methods such as meta-analyses of top-hit $P$-values and sequential testing of multiple traits have been proposed, but these methods fail to consider the background of genome-wide signals. Since Huang's composite test produces uniformly distributed $P$-values for genome-wide variants under the composite null, we propose a gene-level pleiotropy test that entails combining the aforementioned method with the aggregated Cauchy association test. A polygenic trait involves multiple genes with different functions to co-regulate mechanisms. We show that polygenicity should be considered when identifying pleiotropic genes; otherwise, the associations polygenic traits initiate will give rise to false positives. In this study, we constructed gene-trait functional modules using the results of the proposed pleiotropy tests. Our analysis suite was implemented as an R package PGCtest. We demonstrated the proposed method with an application study of the Taiwan Biobank database and identified functional modules comprising specific genes and their co-regulated traits.
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Affiliation(s)
- En-Yu Lai
- Institute of Statistical Science, Academia Sinica, No.128, Academia Road, Section 2, Nankang, Taipei 11529, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, No.128, Academia Road, Section 2, Nankang, Taipei 11529, Taiwan
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12
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Lin CC, Geng JH, Wu PY, Huang JC, Hu HM, Chen SC, Kuo CH. Sex difference in the associations among risk factors with gastroesophageal reflux disease in a large Taiwanese population study. BMC Gastroenterol 2024; 24:165. [PMID: 38750425 PMCID: PMC11095001 DOI: 10.1186/s12876-024-03254-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 05/02/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Gastroesophageal reflux disease (GERD) is a common global health issue. Previous studies have revealed a higher prevalence of GERD in females than in males, however few studies have investigated sex differences in the risk factors associated with GERD. Therefore, the aim of this population-based study was to examine sex differences in the risk factors for GERD in a large cohort of over 120,000 Taiwanese participants. METHODS We enrolled 121,583 participants (male: 43,698; female: 77,885; mean age 49.9 ± 11.0 years) from the Taiwan Biobank. The presence of GERD was ascertained using self-reported questionnaires. Sex differences in the risk factors associated with GERD were examined using multivariable logistic regression analysis. RESULTS The overall prevalence of GERD was 13.7%, including 13.0% in the male participants and 14.1% in the female participants (p < 0.001). Multivariable analysis showed that older age, hypertension, smoking history, alcohol history, low fasting glucose, and low uric acid were significantly associated with GERD in the male participants. In the female participants, older age, diabetes, hypertension, smoking history, alcohol history, low systolic blood pressure, low fasting glucose, high hemoglobin, high total cholesterol, low high-density lipoprotein cholesterol (HDL-C), low low-density lipoprotein cholesterol, and low uric acid were significantly associated with GERD. Significant interactions were found between sex and age (p < 0.001), diabetes (p < 0.001), smoking history (p < 0.001), fasting glucose (p = 0.002), triglycerides (p = 0.001), HDL-C (p = 0.001), and estimated glomerular filtration rate (p = 0.002) on GERD. CONCLUSIONS Our results showed a higher prevalence of GERD among females compared to males. Furthermore, sex differences were identified in the risk factors associated with GERD, and older age, diabetes, smoking history, and low HDL-C were more closely related to GERD in females than in males.
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Affiliation(s)
- Chien-Chieh Lin
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Jiun-Hung Geng
- Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 812, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Pei-Yu Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482, Shan-Ming Rd., Siaogang Dist., Kaohsiung, 812, Taiwan R.O.C
- Department of Internal Medicine, Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan, Republic of China
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Jiun-Chi Huang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482, Shan-Ming Rd., Siaogang Dist., Kaohsiung, 812, Taiwan R.O.C
- Department of Internal Medicine, Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan, Republic of China
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Huang-Ming Hu
- Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482, Shan-Ming Rd., Siaogang Dist., Kaohsiung, 812, Taiwan R.O.C..
- Department of Internal Medicine, Division of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan, Republic of China.
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
| | - Chao-Hung Kuo
- Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482, Shan-Ming Rd., Siaogang Dist., Kaohsiung, 812, Taiwan R.O.C..
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
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13
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Chiu CT, Lee JI, Lu CC, Huang SP, Chen SC, Geng JH. The association between body mass index and osteoporosis in a Taiwanese population: a cross-sectional and longitudinal study. Sci Rep 2024; 14:8509. [PMID: 38605101 PMCID: PMC11009266 DOI: 10.1038/s41598-024-59159-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024] Open
Abstract
This study investigates the correlation between body mass index (BMI) and osteoporosis utilizing data from the Taiwan Biobank. Initially, a comprehensive analysis of 119,009 participants enrolled from 2008 to 2019 was conducted to assess the association between BMI and osteoporosis prevalence. Subsequently, a longitudinal cohort of 24,507 participants, initially free from osteoporosis, underwent regular follow-ups every 2-4 years to analyze the risk of osteoporosis development, which was a subset of the main cohort. Participants were categorized into four BMI groups: underweight (BMI < 18.5 kg/m2), normal weight (18.5 kg/m2 ≤ BMI < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 27 kg/m2), and obese groups (BMI ≥ 27 kg/m2). A T-score ≤ - 2.5 standard deviations below that of a young adult was defined as osteoporosis. Overall, 556 (14.1%), 5332 (9.1%), 2600 (8.1%) and 1620 (6.7%) of the participants in the underweight, normal weight, overweight and obese groups, respectively, had osteoporosis. A higher prevalence of osteoporosis was noted in the underweight group compared with the normal weight group (odds ratio [OR], 2.20; 95% confidence interval [95% CI], 1.99 to 2.43; p value < 0.001) in multivariable binary logistic regression analysis. Furthermore, in the longitudinal cohort during a mean follow-up of 47 months, incident osteoporosis was found in 61 (9%), 881 (7.2%), 401 (5.8%) and 213 (4.6%) participants in the underweight, normal weight, overweight and obese groups, respectively. Multivariable Cox proportional hazards analysis revealed that the risk of incident osteoporosis was higher in the underweight group than in the normal weight group (hazard ratio [HR], 1.63; 95% CI 1.26 to 2.12; p value < 0.001). Our results suggest that BMI is associated with both the prevalence and the incidence of osteoporosis. In addition, underweight is an independent risk factor for developing osteoporosis. These findings highlight the importance of maintaining normal weight for optimal bone health.
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Affiliation(s)
- Chao-Tse Chiu
- Department of Orthopaedics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
- Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-In Lee
- Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Chang Lu
- Department of Orthopaedics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
- Department of Orthopaedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Pin Huang
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, 807, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Institute of Medical Science and Technology, College of Medicine, National Sun Yat-Sen University, Kaohsiung, 804, Taiwan
| | - Szu-Chia Chen
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospita, l, Kaohsiung Medical University, 812, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Jiun-Hung Geng
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, 807, Kaohsiung, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Urology, Kaohsiung Municipal Siaogang Hospital, No. 482, Shanming Rd, Xiaogang District, Kaohsiung, 812, Taiwan.
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14
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Cheng KL, Wang SW, Cheng YM, Hsieh TH, Wang CC, Kao JH. Prevalence and clinical outcomes in subtypes of metabolic associated fatty liver disease. J Formos Med Assoc 2024; 123:36-44. [PMID: 37491179 DOI: 10.1016/j.jfma.2023.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/09/2023] [Accepted: 07/12/2023] [Indexed: 07/27/2023] Open
Abstract
BACKGROUND/PURPOSE In 2020, metabolic Associated Fatty Liver Disease (MAFLD) was proposed to replace non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria. The prevalence and clinical outcomes of MAFLD subtypes remained unclear. METHODS The participants from Taiwan bio-bank cohort were included. MAFLD was defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, diabetes mellitus (DM), or metabolic dysfunction. The patients with positive HBsAg or anti-HCV were considered as chronic HBV or HCV infection. NAFLD fibrosis score (NFS) > 0.676 plus fibrosis 4 (FIB-4) score > 2.67 was defined as advanced liver fibrosis. Atherosclerosis was diagnosed as having carotid plaques on duplex ultrasounds. The clinical outcomes were assessed among four subtypes of MAFLD including DM, obesity, chronic HBV infection, and chronic HCV infection. RESULTS A total of 21,885 participants (mean age 55.34 ± 10.31; 35.69% males) were included in the final analysis. Among them, 38.83% were diagnosed with MAFLD. The prevalence of MAFLD was 66.95% in DM patients, 65.07% in obese participants, 33.74% in chronic HBV patients, and 30.23% in chronic HCV patients. Logistic regression analysis showed that the subtypes of DM and chronic HCV infection were associated with an increased risk of advanced liver fibrosis in MAFLD patients. Additionally, the subtypes of DM and lean were associated with an increased risk of atherosclerosis, but a decreased risk of atherosclerosis in the subtype of chronic HBV infection. CONCLUSION This population-based study proves the concept that subtypes of MAFLD can help risk stratification of clinical outcomes.
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Affiliation(s)
- Kun-Lin Cheng
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Shao-Wen Wang
- Department of Gastroenterology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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15
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Chen PS, Lee NC, Sung CJ, Liu YW, Weng WC, Fan PC, Lee WT, Chien YH, Wu CS, Sung YF, Tsai MC, Lee YC, Hsueh HW, Fan SMY, Wu MC, Li H, Chen HY, Lin HI, Ou-Yang CH, Hwuh WL, Lin CH. Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5. Mov Disord 2023; 38:2217-2229. [PMID: 37752895 DOI: 10.1002/mds.29604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/15/2023] [Accepted: 08/29/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Pin-Shiuan Chen
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Chieh-Ju Sung
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Wen Liu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Chin Weng
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Pi-Chuan Fan
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Wang-Tso Lee
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Yin-Hsiu Chien
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Chao-Szu Wu
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Yueh-Feng Sung
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ming-Chen Tsai
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Chung Lee
- Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsueh-Wen Hsueh
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Sabrina Mai-Yi Fan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Meng-Chen Wu
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsun Li
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Huan-Yun Chen
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Han-I Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Hsin Ou-Yang
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wuh-Liang Hwuh
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Liu TY, Liao CC, Chang YS, Chen YC, Chen HD, Lai IL, Peng CY, Chung CC, Chou YP, Tsai FJ, Jeng LB, Chang JG. Identification of 13 Novel Loci in a Genome-Wide Association Study on Taiwanese with Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:16417. [PMID: 38003606 PMCID: PMC10671380 DOI: 10.3390/ijms242216417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Liver cancer is caused by complex interactions among genetic factors, viral infection, alcohol abuse, and metabolic diseases. We conducted a genome-wide association study and polygenic risk score (PRS) model in Taiwan, employing a nonspecific etiology approach, to identify genetic risk factors for hepatocellular carcinoma (HCC). Our analysis of 2836 HCC cases and 134,549 controls revealed 13 novel associated loci such as the FAM66C gene, noncoding genes, liver-fibrosis-related genes, metabolism-related genes, and HCC-related pathway genes. We incorporated the results from the UK Biobank and Japanese database into our study for meta-analysis to validate our findings. We also identified specific subtypes of the major histocompatibility complex that influence both viral infection and HCC progression. Using this data, we developed a PRS to predict HCC risk in the general population, patients with HCC, and HCC-affected families. The PRS demonstrated higher risk scores in families with multiple HCCs and other cancer cases. This study presents a novel approach to HCC risk analysis, identifies seven new genes associated with HCC development, and introduces a reproducible PRS model for risk assessment.
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Affiliation(s)
- Ting-Yuan Liu
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
| | - Chi-Chou Liao
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
| | - Ya-Sian Chang
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
| | - Yu-Chia Chen
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
- Million-Person Precision Medicine Initiative, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
| | - Hong-Da Chen
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
- Department of Laboratory Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - I-Lu Lai
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
| | - Cheng-Yuan Peng
- Department of Internal Medicine, Section of Hepatobiliary Tract, China Medical University Hospital, Taichung 40447, Taiwan;
| | - Chin-Chun Chung
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
| | - Yu-Pao Chou
- Center for Precision Medicine and Epigenome Research Center, China Medical University Hospital, Taichung 40447, Taiwan; (T.-Y.L.); (C.-C.L.); (Y.-S.C.); (Y.-C.C.); (H.-D.C.); (I.-L.L.); (C.-C.C.); (Y.-P.C.)
| | - Fuu-Jen Tsai
- Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
- Division of Pediatric Genetics, Children’s Hospital of China Medical University, Taichung 40447, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan
| | - Long-Bin Jeng
- Department of Surgery, Section of Hepatobiliary Tract, China Medical University Hospital, Taichung 40447, Taiwan;
| | - Jan-Gowth Chang
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 41354, Taiwan
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan
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Tsai PS, Cheng YM, Wang CC, Kao JH. The impact of concomitant hepatitis C virus infection on liver and cardiovascular risks in patients with metabolic-associated fatty liver disease. Eur J Gastroenterol Hepatol 2023; 35:1278-1283. [PMID: 37773778 DOI: 10.1097/meg.0000000000002558] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/01/2023]
Abstract
BACKGROUND Chronic hepatitis C virus (HCV)-infected patients with hepatic steatosis are excluded from the diagnosis of nonalcoholic fatty liver disease (NAFLD). The new name and diagnostic criteria of metabolic-associated fatty liver disease (MAFLD) were proposed in 2020 to replace the original term NAFLD. The clinical outcome of MAFLD patients with concomitant chronic HCV infection requires further investigation. METHODS The participants from Taiwan bio-bank cohort were included. MAFLD is defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, type 2 diabetes, or metabolic dysfunction. The patients with positive anti-HCV were considered chronic HCV infections. The severity of liver fibrosis was determined using the fibrosis-4 index and NAFLD fibrosis score (NFS). The risk of cardiovascular disease (CVD) was assessed using intima-media thickness (IMT) or plaques of carotid duplex ultrasound. RESULTS A total of 18 907 participants (age 55.79 ± 10.42; males 31.9%) were included for final analysis. The prevalence of MAFLD and chronic HCV infections were 39.2% and 2.6%, respectively. According to the status of MAFLD and chronic HCV infection, they were distributed to four groups: 'dual etiology group', 'MAFLD alone', 'HCV alone', and healthy controls. Compared with the 'MAFLD alone' group, the 'dual etiology' group had a lower frequency of the male sex, reduced levels of serum triglyceride, total cholesterol, and LDL; but overall older age, a higher percentage of hypertension history. In addition, they had higher levels of serum aspartate aminotransferase, fibrosis-4 index, and NFS; but no difference in levels of alanine aminotransferase, gamma-glutamyl transferase, fatty liver index, IMT, and the percentage of carotid plaques. Using binary logistic regression, chronic HCV infection was associated with more severe liver fibrosis, but not with carotid plaques in MAFLD patients. CONCLUSION MAFLD patients with concomitant HCV infection, a specific phenotype of MAFLD may include a higher risk of advanced liver fibrosis, but a similar risk of atherosclerotic cardiovascular disease compared to those without.
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Affiliation(s)
- Pei-Shan Tsai
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien
| | - Yu-Ming Cheng
- Department of Gastroenterology and Hepatology, Tung's Taichung MetroHarbor Hospital, Taichung
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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Wu MC, Chang YY, Lan MY, Chen YF, Tai CH, Chen SJ, Lin CH. Blood neurofilament light chain as a surrogate marker for dystonia. Eur J Neurol 2023; 30:3098-3104. [PMID: 37422850 DOI: 10.1111/ene.15972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/15/2023] [Accepted: 07/04/2023] [Indexed: 07/11/2023]
Abstract
BACKGROUND AND PURPOSE Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia. METHOD We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single-molecule array. RESULTS Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole-exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores. CONCLUSION Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.
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Affiliation(s)
- Meng-Chen Wu
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Yee Chang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ying-Fa Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chun-Hwei Tai
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Szu-Ju Chen
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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Cheng YM, Hsieh TH, Wang CC, Kao JH. Impact of HBV infection on clinical outcomes in patients with metabolic dysfunction-associated fatty liver disease. JHEP Rep 2023; 5:100836. [PMID: 37600956 PMCID: PMC10432217 DOI: 10.1016/j.jhepr.2023.100836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 05/28/2023] [Accepted: 06/05/2023] [Indexed: 08/22/2023] Open
Abstract
Background & Aims The new name and diagnostic criteria of metabolic-associated fatty liver disease (MAFLD) was proposed in 2020. Although chronic HBV infection has protective effects on lipid profiles and hepatic steatosis, the impact of chronic HBV infection on clinical outcomes of MAFLD requires further investigation. Methods The participants from a Taiwan bio-bank cohort were included. MAFLD is defined as the presence of hepatic steatosis plus any of the following three conditions: overweight/obesity, type 2 diabetes mellitus, and metabolic dysfunction. The patients with positive glycated haemoglobin were considered as having chronic HBV infection. Atherosclerosis was determined as having carotid plaques on duplex ultrasound. Advanced liver fibrosis was defined as Fibrosis-4 >2.67. Based on the status of MAFLD and HBV infection, the participants were distributed into four groups: 'dual aetiology', 'MAFLD alone', 'HBV alone', and 'healthy controls'. Results A total of 20,460 participants (age 55.51 ± 10.37; males 32.67%) were included for final analysis. The prevalence of MAFLD and chronic HBV infections were 38.8% and 10.3%, respectively. According to univariate analysis, 'HBV alone' group had lower levels of glycated haemoglobin, lipid profiles, and intima media thickness than healthy controls. The 'dual aetiology' group had lower levels of triglycerides, cholesterol, γ-glutamyl transferase, intima media thickness, and percentage of carotid plaques than 'MAFLD alone' group. Using binary logistic regression, chronic HBV infection increased the overall risk of advanced liver fibrosis; and had a lower probability of carotid plaques in MAFLD patients, but not in those without MAFLD. Conclusions The large population-based study revealed chronic HBV infection increases the overall risk of liver fibrosis, but protects from atherosclerosis in patients with MAFLD. Impact and implications Patients with metabolic-associated fatty liver disease can also be coinfected with chronic HBV. Concomitant HBV infection increases the overall risk of liver fibrosis, but protects from atherosclerosis in patients with MAFLD.
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Affiliation(s)
- Yu-Ming Cheng
- Tung’s Taichung MetroHarbor Hospital, Taichung, Taiwan
| | - Tsung-Han Hsieh
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan
| | - Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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A novel C19orf12 frameshift mutation in a MPAN pedigree impairs mitochondrial function and connectivity leading to neurodegeneration. Parkinsonism Relat Disord 2023; 109:105353. [PMID: 36863113 DOI: 10.1016/j.parkreldis.2023.105353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/12/2023] [Accepted: 02/25/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Mitochondrial membrane protein‒associated neurodegeneration (MPAN) is a rare genetic disease characterized by progressive neurodegeneration with brain iron accumulations combined with neuronal α-synuclein and tau aggregations. Mutations in C19orf12 have been associated with both autosomal recessive and autosomal dominant inheritance patterns of MPAN. METHODS We present clinical features and functional evidence from a Taiwanese family with autosomal dominant MPAN caused by a novel heterozygous frameshift and nonsense mutation in C19orf12, c273_274 insA (p.P92Tfs*9). To verify the pathogenicity of the identified variant, we examined the mitochondrial function, morphology, protein aggregation, neuronal apoptosis, and RNA interactome in p.P92Tfs*9 mutant knock-in SH-SY5Y cells created with CRISPR-Cas9 technology. RESULTS Clinically, the patients with the C19orf12 p.P92Tfs*9 mutation presented with generalized dystonia, retrocollis, cerebellar ataxia, and cognitive decline, starting in their mid-20s. The identified novel frameshift mutation is located in the evolutionarily conserved region of the last exon of C19orf12. In vitro studies revealed that the p.P92Tfs*9 variant is associated with impaired mitochondrial function, reduced ATP production, aberrant mitochondria interconnectivity and ultrastructure. Increased neuronal α-synuclein and tau aggregations, and apoptosis were observed under conditions of mitochondrial stress. Transcriptomic analysis revealed that the expression of genes in clusters related to mitochondrial fission, lipid metabolism, and iron homeostasis pathways was altered in the C19orf12 p.P92Tfs*9 mutant cells compared to control cells. CONCLUSION Our findings provide clinical, genetic, and mechanistic insight revealing a novel heterozygous C19orf12 frameshift mutation to be a cause of autosomal dominant MPAN, further strengthening the importance of mitochondrial dysfunction in the pathogenesis of MPAN.
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21
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Hsieh MS, Kao HL, Huang WC, Wang SY, Lin SY, Chu PY, Pan CC, Chou TY, Ho HL, Yeh YC. Constant p.L424H Mutation in GTF2I in Micronodular Thymomas With Lymphoid Stroma: Evidence Supporting Close Relationship With Type A and AB Thymomas. Mod Pathol 2023; 36:100008. [PMID: 36853782 DOI: 10.1016/j.modpat.2022.100008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/22/2022] [Accepted: 09/19/2022] [Indexed: 01/11/2023]
Abstract
Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.
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Affiliation(s)
- Min-Shu Hsieh
- Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hua-Lin Kao
- Department of Pathology and Laboratory Medicine, Taipei Medical University Hospital, Taipei City, Taiwan
| | - Wen-Chang Huang
- Department of Pathology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
| | - Shu-Ying Wang
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shin-Ying Lin
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ping-Yuan Chu
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chin-Chen Pan
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Teh-Ying Chou
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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22
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Cheng YM, Wang CC, Kao JH. Metabolic associated fatty liver disease better identifying patients at risk of liver and cardiovascular complications. Hepatol Int 2022; 17:350-356. [PMID: 36471232 DOI: 10.1007/s12072-022-10449-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/04/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND/PURPOSE A nomenclature of "metabolic associated fatty liver disease" (MAFLD) with a new definition was proposed in 2020 instead of the previous "non-alcoholic fatty liver disease" (NAFLD). Whether it better coheres with the clinical demand remains controversial. METHODS The participants with fatty liver on ultrasonography in Taiwan bio-bank cohorts were included. MAFLD is defined as the presence of fatty liver, plus any of the following three conditions: overweight/obesity, type 2 diabetes mellitus (DM), or metabolic dysfunction. The severity of liver fibrosis was determined using fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS). The risk of atherosclerotic cardiovascular disease was assessed using intima-media thickness (IMT) or plaques of carotid duplex ultrasound. RESULTS A total of 9,719 subjects (ages 55.9 ± 10.8; males 42.6%) were distributed among 4 groups: "overlapping group", "MAFLD only", "NAFLD only", and "neither fatty liver disease (FLD)" with the percentages of 79.7, 12, 7.1, and 1.2%, respectively. Compared with NAFLD patients, MAFLD patients had a greater percentage of males, higher levels of BMI, waist circumference, HbA1c, and triglyceride. In addition, they had higher levels of serum ALT, AST, GGT, fatty liver index (FLI), NFS, and IMT, but no difference in FIB-4 index and the percentage of carotid plaques. To note, "MAFLD only group" had greater levels of AST, ALT, GGT, FLI, FIB-4, NFS, IMT and a higher percentage of carotid plaques than the "NAFLD only group". CONCLUSION The grand, population-based study showed MAFLD with new diagnostic criteria to aid in identifying a greater number of high-risk patients of metabolic, liver, and cardiovascular complications, suggesting MAFLD may be a better nomenclature than NAFLD in clinical practice.
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Mechanism and modeling of human disease-associated near-exon intronic variants that perturb RNA splicing. Nat Struct Mol Biol 2022; 29:1043-1055. [PMID: 36303034 DOI: 10.1038/s41594-022-00844-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 08/23/2022] [Indexed: 12/24/2022]
Abstract
It is estimated that 10%-30% of disease-associated genetic variants affect splicing. Splicing variants may generate deleteriously altered gene product and are potential therapeutic targets. However, systematic diagnosis or prediction of splicing variants is yet to be established, especially for the near-exon intronic splice region. The major challenge lies in the redundant and ill-defined branch sites and other splicing motifs therein. Here, we carried out unbiased massively parallel splicing assays on 5,307 disease-associated variants that overlapped with branch sites and collected 5,884 variants across the 5' splice region. We found that strong splice sites and exonic features preserve splicing from intronic sequence variation. Whereas the splice-altering mechanism of the 3' intronic variants is complex, that of the 5' is mainly splice-site destruction. Statistical learning combined with these molecular features allows precise prediction of altered splicing from an intronic variant. This statistical model provides the identity and ranking of biological features that determine splicing, which serves as transferable knowledge and out-performs the benchmarking predictive tool. Moreover, we demonstrated that intronic splicing variants may associate with disease risks in the human population. Our study elucidates the mechanism of splicing response of intronic variants, which classify disease-associated splicing variants for the promise of precision medicine.
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Brayne C, Moffitt TE. The limitations of large-scale volunteer databases to address inequalities and global challenges in health and aging. NATURE AGING 2022; 2:775-783. [PMID: 37118500 PMCID: PMC10154032 DOI: 10.1038/s43587-022-00277-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/02/2022] [Indexed: 04/30/2023]
Abstract
Large-scale volunteer databanks (LSVD) have emerged from the recognized value of cohorts, attracting substantial funding and promising great scientific value. A major focus is their size, with the implicit and sometimes explicit assumption that large size (thus power) creates generalizability. We contend that this is open to challenge. In the context of aging and age-related disease research, LSVD typically have limitations such as healthy volunteer, white ethnicity and high-education biases, and they omit early and late life stages critical for understanding aging. Their outputs are heavily focused on biomedical pathways of single chronic diseases. LSVD outputs increasingly dominate the funding and the publication landscapes. This Perspective discusses LSVD limitations and calls for more transparent reporting in LSVD research, as well as a greater reflection on the value of LSVD in relation to resources consumed. We invite funders and researchers to examine whether LSVD do actually contribute knowledge needed for our acute global health challenges including inequalities.
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Affiliation(s)
- Carol Brayne
- Cambridge Public Health, University of Cambridge, Cambridge, UK.
| | - Terrie E Moffitt
- Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
- Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK
- Promenta Centre, University of Oslo, Oslo, Norway
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25
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Chang Y, Chao D, Chung C, Chou Y, Chang C, Lin C, Chu H, Chen H, Liu T, Juan Y, Chang S, Chang J. Cancer carrier screening in the general population using whole-genome sequencing. Cancer Med 2022; 12:1972-1983. [PMID: 35861108 PMCID: PMC9883534 DOI: 10.1002/cam4.5034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Cancer is a major cause of death, and its early identification and intervention have potential for clinical actionability and benefits for human health. The studies using whole-genome sequencing (WGS) and large samples analysis of cancer-related genes have been rarely done. METHODS We performed WGS to explore germline mutations in coding and non-coding areas of cancer-related genes and non-coding driver genes and regulatory areas. Structural variants (SVs) was also analyzed. We used several tools and a subgrouping method to analyze the variants in 1491 healthy participants. Moreover, 275 cancer-related genes sequencing was carried out in 125 cancer patients. RESULTS The incidence of familial cancer in the Taiwanese general population is 8.79% (131/1491). Cancer carrier rate of cancer-related genes is about 7.04% (105/1491) for pathogenic/likely pathogenic variants (P/LP) on ClinVar database only, and 28.24% (421/1491) for P/LP and loss of function variants. The carrier frequencies of cancer-related genes P/LP on ClinVar database were as follows: 8.40% (11/131), 7.11% (28/394), and 6.83% (66/966) in FC, 1MC, and nMC, respectively. The SVs and non-coding driver gene variants are uncommon. There are 1.54% (23/1491) of actionable cancer genes in American College of Medical Genetics and Genomics (ACMG), and the germline mutation rate of 275 cancer-related genes is 7.2% (9/125) in cancer patients including 4.0% (5/125) of actionable cancer genes in ACMG. After analyzing the frequencies of P/LP variants on GJB2 and SLC25A13 genes, we suggest that these two genes may not be cancer-related genes and need be re-evaluated. CONCLUSIONS WGS analysis can completely detect germline mutations in cancer carriers. This study use subgrouping approach for samples provides a strategy to study whether a gene or variant is a cancer-related gene or variant in the future studies.
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Affiliation(s)
- Ya‐Sian Chang
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
- School of MedicineChina Medical UniversityTaichungTaiwan
| | - Dy‐San Chao
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
| | - Chin‐Chun Chung
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
| | - Yu‐Pao Chou
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
| | - Chieh‐Min Chang
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
| | - Chia‐Li Lin
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
| | - Hou‐Wei Chu
- Institute of Biomedical Sciences|Academia SinicaTaipeiTaiwan
| | - Hon‐Da Chen
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
| | - Ting‐Yuan Liu
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
| | - Yu‐Hsuan Juan
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
| | - Shun‐Jen Chang
- Department of Kinesiology, Health and Leisure StudiesNational University of KaohsiungKaohsiungTaiwan
| | - Jan‐Gowth Chang
- Center for Precision MedicineChina Medical University HospitalTaichungTaiwan
- Epigenome Research CenterChina Medical University HospitalTaichungTaiwan
- Department of Laboratory MedicineChina Medical University HospitalTaichungTaiwan
- School of MedicineChina Medical UniversityTaichungTaiwan
- Department of Bioinformatics and Medical EngineeringAsia UniversityTaichungTaiwan
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Hamamoto R, Takasawa K, Machino H, Kobayashi K, Takahashi S, Bolatkan A, Shinkai N, Sakai A, Aoyama R, Yamada M, Asada K, Komatsu M, Okamoto K, Kameoka H, Kaneko S. Application of non-negative matrix factorization in oncology: one approach for establishing precision medicine. Brief Bioinform 2022; 23:bbac246. [PMID: 35788277 PMCID: PMC9294421 DOI: 10.1093/bib/bbac246] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/06/2022] [Accepted: 05/25/2022] [Indexed: 12/19/2022] Open
Abstract
The increase in the expectations of artificial intelligence (AI) technology has led to machine learning technology being actively used in the medical field. Non-negative matrix factorization (NMF) is a machine learning technique used for image analysis, speech recognition, and language processing; recently, it is being applied to medical research. Precision medicine, wherein important information is extracted from large-scale medical data to provide optimal medical care for every individual, is considered important in medical policies globally, and the application of machine learning techniques to this end is being handled in several ways. NMF is also introduced differently because of the characteristics of its algorithms. In this review, the importance of NMF in the field of medicine, with a focus on the field of oncology, is described by explaining the mathematical science of NMF and the characteristics of the algorithm, providing examples of how NMF can be used to establish precision medicine, and presenting the challenges of NMF. Finally, the direction regarding the effective use of NMF in the field of oncology is also discussed.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Rina Aoyama
- Showa University Graduate School of Medicine School of Medicine
| | | | - Ken Asada
- RIKEN Center for Advanced Intelligence Project
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Auwerx C, Sadler MC, Reymond A, Kutalik Z. From pharmacogenetics to pharmaco-omics: Milestones and future directions. HGG ADVANCES 2022; 3:100100. [PMID: 35373152 PMCID: PMC8971318 DOI: 10.1016/j.xhgg.2022.100100] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
The origins of pharmacogenetics date back to the 1950s, when it was established that inter-individual differences in drug response are partially determined by genetic factors. Since then, pharmacogenetics has grown into its own field, motivated by the translation of identified gene-drug interactions into therapeutic applications. Despite numerous challenges ahead, our understanding of the human pharmacogenetic landscape has greatly improved thanks to the integration of tools originating from disciplines as diverse as biochemistry, molecular biology, statistics, and computer sciences. In this review, we discuss past, present, and future developments of pharmacogenetics methodology, focusing on three milestones: how early research established the genetic basis of drug responses, how technological progress made it possible to assess the full extent of pharmacological variants, and how multi-dimensional omics datasets can improve the identification, functional validation, and mechanistic understanding of the interplay between genes and drugs. We outline novel strategies to repurpose and integrate molecular and clinical data originating from biobanks to gain insights analogous to those obtained from randomized controlled trials. Emphasizing the importance of increased diversity, we envision future directions for the field that should pave the way to the clinical implementation of pharmacogenetics.
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Affiliation(s)
- Chiara Auwerx
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Marie C. Sadler
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
| | - Alexandre Reymond
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Zoltán Kutalik
- Department of Computational Biology, University of Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- University Center for Primary Care and Public Health, Lausanne, Switzerland
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Wang YF, Liao YC, Tzeng YS, Chen SP, Lirng JF, Fuh JL, Chen WT, Lai KL, Lee YC, Wang SJ. Mutation screening and association analysis of NOTCH3 p.R544C in patients with migraine with or without aura. Cephalalgia 2022; 42:888-898. [PMID: 35302383 DOI: 10.1177/03331024221080891] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The role of the NOTCH3 p.R544C variant, the predominant variant of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in multiple East Asian regions, in migraine is unknown. METHODS Migraine patients (n = 2,884) (2,279F/605M, mean age 38.8 ± 11.7 years), including 324 (11.2%) with migraine with aura, were prospectively enrolled by headache specialists according to the International Classification of Headache Disorders criteria. These patients and 3,502 population controls free of stroke, dementia, and headache were genotyped for NOTCH3 p.R544C by TaqMan genotyping assay or Axiom Genome-Wide TWB 2.0 Array. Clinical manifestations and brain magnetic resonance images were examined and compared between migraine patients with and without NOTCH3 p.R544C. RESULTS Thirty-two migraine patients (1.1%) and 36 controls (1.0%) harbored the p.R544C variant, and the percentages were comparable among migraine patients without and with aura, and controls (1.2%, vs. 0.6% vs. 1.0%, p = 0.625). Overall, migraine patients with and without the p.R544C variant had similar percentages of migraine with aura, headache characteristics, frequencies and disabilities. However, those with p.R544C were less likely to have pulsatile headaches (50.0% vs. 68.2%, p = 0.028), and more likely to have moderate to severe white matter hyperintensities in the external capsule (18.8% vs. 1.2%, p = 0.006) and anterior temporal lobe (12.5% vs. 0%, p = 0.008). CONCLUSIONS Our findings suggest that NOTCH3 p.R544C does not increase the risk of migraine with aura, or migraine as a whole, and generally does not alter clinical manifestations of migraine. The role of NOTCH3 variants, as well as potential influences from ethnicity or modifier genes, in migraine needs to be further clarified.
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Affiliation(s)
- Yen-Feng Wang
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Chu Liao
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Shiang Tzeng
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shih-Pin Chen
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jiing-Feng Lirng
- College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jong-Ling Fuh
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Ta Chen
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kuan-Lin Lai
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Chung Lee
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shuu-Jiun Wang
- Department of Neurology, Neurological Institute, 46615Taipei Veterans General Hospital, Taipei Veterans General Hospital, Taipei, Taiwan.,College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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29
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Wu MC, Chang YY, Lan MY, Chen YF, Tai CH, Lin YF, Tsai SF, Chen PL, Lin CH. A Clinical and Integrated Genetic Study of Isolated and Combined Dystonia in Taiwan. J Mol Diagn 2022; 24:262-273. [PMID: 35041927 DOI: 10.1016/j.jmoldx.2021.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/05/2021] [Accepted: 12/03/2021] [Indexed: 10/19/2022] Open
Abstract
Dystonia is a clinically and genetically heterogeneous movement disorder. However, genetic causes of dystonia remain largely unknown in Asian subjects. To address this, we applied an integrated two-step approach that included gene dosage analysis and a next-generation sequencing panel containing 72 known genes causative for dystonia and related movement disorders to 318 Taiwanese patients with isolated or combined dystonia. Whole-genome sequencing was performed for one multiplex family with no known causative variant. The panel confirmed the genetic diagnosis in 40 probands (12.6%). A genetic diagnosis was more likely with juvenile onset compared with adult onset (24.2% vs 10.8%; P = 0.03) and those with combined features, especially with myoclonus, compared with isolated dystonia (35.3% vs 10.5%; P = 0.004). The most common causative genes were SGCE followed by GCH1, TH, CACNA1B, PRRT2, MR1, CIZ1, PLA2G6, and PRKN. Genetic causes were identified from single cases in TOR1A, TUBB4A, THAP1, ATP1A3, ANO3, GNAL, KMT2B, SLC6A3, ADCY5, CYP27A1, PANK2, C19orf12, and SPG11. The whole-genome sequencing analysis identified a novel intragenic deletion in OPHN1 in a multiplex family with X-linked dystonia and intellectual delay. Our findings delineate the genetic architecture and clinical spectrum of dystonia-causing pathogenic variants in an Asian population.
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Affiliation(s)
- Meng-Chen Wu
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Yee Chang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Ying-Fa Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chun-Hwei Tai
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Feng Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Shih-Feng Tsai
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Pei-Lung Chen
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
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Betel Nut Chewing Is Associated with the Risk of Kidney Stone Disease. J Pers Med 2022; 12:jpm12020126. [PMID: 35207614 PMCID: PMC8879579 DOI: 10.3390/jpm12020126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/19/2021] [Accepted: 12/30/2021] [Indexed: 02/05/2023] Open
Abstract
(1) Background: Betel nut chewing injures bodily health. Although, the relationship between betel nut chewing and kidney stone disease (KSD) is unknown. (2) Methods: We analyzed 43,636 men from Taiwan Biobank. We divided them into two groups on the status of betel nut chewing, the never-chewer and ever-chewer groups. Self-reported diagnosed KSD was defined as the subject’s medical history of KSD in the questionnaire. Logistic regression was used to analyze the association of betel nut chewing and the risk of KSD. (3) Results: The mean age of subjects in the present study was 50 years, and 16% were ever-chewers. KSD was observed in 3759 (10.3%) and 894 (12.6%) participants in the group of never-chewer and ever-chewer groups, respectively. Higher risk of KSD was found in participants with betel nut chewing compared with to without betel nut chewing (odds ratio (OR), 1.094; 95% confidence interval (95% CI), 1.001 to 1.196). Furthermore, the daily amounts of betel nut chewing >30 quids was associated with a more than 1.5-fold increase (OR, 1.571; 95% CI, 1.186 to 2.079) in the odds of KSD; (4) Conclusions: Our study suggests that betel nut chewing is associated with the risk of KSD and warrants further attention to this problem.
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Liu Z, Huang CJ, Huang YH, Pan MH, Lee MH, Yu KJ, Pfeiffer RM, Viard M, Yuki Y, Gao X, Carrington M, Chen CJ, Hildesheim A, Yang HI, REVEAL-HBV Study Group. HLA Zygosity Increases Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. J Infect Dis 2021; 224:1796-1805. [PMID: 33852009 PMCID: PMC9633721 DOI: 10.1093/infdis/jiab207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Diversity in the HLA genes might be associated with disease outcomes-the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS We utilized DNA from > 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus. RESULTS Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend = 1.18 × 10-7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend = .031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio = 1.40; 95% confidence interval, 1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control. CONCLUSIONS Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC.
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Affiliation(s)
- Zhiwei Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Chih-Jen Huang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yu-Han Huang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Mei-Hung Pan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Mathias Viard
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Yuko Yuki
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Xiaojiang Gao
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mary Carrington
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Allan Hildesheim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Wang CY, Tang YA, Lee IW, Chang FM, Chien CW, Pan HA, Sun HS. Development and validation of an expanded targeted sequencing panel for non-invasive prenatal diagnosis of sporadic skeletal dysplasia. BMC Med Genomics 2021; 14:212. [PMID: 34789231 PMCID: PMC8600686 DOI: 10.1186/s12920-021-01063-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 08/20/2021] [Indexed: 11/22/2022] Open
Abstract
Background Skeletal dysplasia (SD) is one of the most common inherited neonatal disorders worldwide, where the recurrent pathogenic mutations in the FGFR2, FGFR3, COL1A1, COL1A2 and COL2A1 genes are frequently reported in both non-lethal and lethal SD. The traditional prenatal diagnosis of SD using ultrasonography suffers from lower accuracy and performed at latter gestational stage. Therefore, it remains in desperate need of precise and accurate prenatal diagnosis of SD in early pregnancy. With the advancements of next-generation sequencing (NGS) technology and bioinformatics analysis, it is feasible to develop a NGS-based assay to detect genetic defects in association with SD in the early pregnancy. Methods An ampliseq-based targeted sequencing panel was designed to cover 87 recurrent hotspots reported in 11 common dominant SD and run on both Ion Proton and NextSeq550 instruments. Thirty-six cell-free and 23 genomic DNAs were used for assay developed. Spike-in DNA prepared from standard sample harboring known mutation and normal sample were also employed to validate the established SD workflow. Overall performances of coverage, uniformity, and on-target rate, and the detecting limitations on percentage of fetal fraction and read depth were evaluated. Results The established targeted-seq workflow enables a single-tube multiplex PCR for library construction and shows high amplification efficiency and robust reproducibility on both Ion Proton and NextSeq550 platforms. The workflow reaches 100% coverage and both uniformity and on-target rate are > 96%, indicating a high quality assay. Using spike-in DNA with different percentage of known FGFR3 mutation (c.1138 G > A), the targeted-seq workflow demonstrated the ability to detect low-frequency variant of 2.5% accurately. Finally, we obtained 100% sensitivity and 100% specificity in detecting target mutations using established SD panel. Conclusions An expanded panel for rapid and cost-effective genetic detection of SD has been developed. The established targeted-seq workflow shows high accuracy to detect both germline and low-frequency variants. In addition, the workflow is flexible to be conducted in the majority of the NGS instruments and ready for routine clinical application. Taken together, we believe the established panel provides a promising diagnostic or therapeutic strategy for prenatal genetic testing of SD in routine clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-021-01063-1.
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Affiliation(s)
- Ching-Yuan Wang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan.,Center for Genomic Medicine, Innovation Headquarters, National Cheng Kung University, Tainan, Taiwan
| | - Yen-An Tang
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan.,Center for Genomic Medicine, Innovation Headquarters, National Cheng Kung University, Tainan, Taiwan
| | - I-Wen Lee
- FMC Fetal Medicine Center, Tainan, Taiwan
| | | | - Chun-Wei Chien
- Center for Genomic Medicine, Innovation Headquarters, National Cheng Kung University, Tainan, Taiwan
| | | | - H Sunny Sun
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan, 70101, Taiwan. .,Center for Genomic Medicine, Innovation Headquarters, National Cheng Kung University, Tainan, Taiwan.
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NyuWa Genome resource: A deep whole-genome sequencing-based variation profile and reference panel for the Chinese population. Cell Rep 2021; 37:110017. [PMID: 34788621 DOI: 10.1016/j.celrep.2021.110017] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 05/04/2021] [Accepted: 10/28/2021] [Indexed: 01/07/2023] Open
Abstract
The lack of haplotype reference panels and whole-genome sequencing resources specific to the Chinese population has greatly hindered genetic studies in the world's largest population. Here, we present the NyuWa genome resource, based on deep (26.2×) sequencing of 2,999 Chinese individuals, and construct a NyuWa reference panel of 5,804 haplotypes and 19.3 million variants, which is a high-quality publicly available Chinese population-specific reference panel with thousands of samples. Compared with other panels, the NyuWa reference panel reduces the Han Chinese imputation error rate by a margin ranging from 30% to 51%. Population structure and imputation simulation tests support the applicability of one integrated reference panel for northern and southern Chinese. In addition, a total of 22,504 loss-of-function variants in coding and noncoding genes are identified, including 11,493 novel variants. These results highlight the value of the NyuWa genome resource in facilitating genetic research in Chinese and Asian populations.
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Lee WH, Wu DW, Chen YC, Liu YH, Liao WS, Chen SC, Hung CH, Kuo CH, Su HM. Association of Pulmonary Function Decline over Time with Longitudinal Change of Glycated Hemoglobin in Participants without Diabetes Mellitus. J Pers Med 2021; 11:jpm11100994. [PMID: 34683134 PMCID: PMC8537814 DOI: 10.3390/jpm11100994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 09/20/2021] [Accepted: 09/29/2021] [Indexed: 01/13/2023] Open
Abstract
Pulmonary damage and function impairment were frequently noted in patients with diabetes mellitus (DM). However, the relationship between lung function and glycemic status in non-DM subjects was not well-known. Here, we evaluated the association of longitudinal changes of lung function parameters with longitudinal changes of glycated hemoglobin (HbA1c) in non-DM participants. The study enrolled participants without prior type 2 DM, hypertension, and chronic obstructive pulmonary disease (COPD) from the Taiwan Biobank database. Laboratory profiles and pulmonary function parameters, including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), were examined at baseline and follow-up. Finally, 7055 participants were selected in this study. During a mean 3.9-year follow-up, FVC and FEV1 were significantly decreased over time (both p < 0.001). In the multivariable analysis, the baseline (unstandardized coefficient β = −0.032, p < 0.001) and longitudinal change (unstandardized coefficient β = −0.025, p = 0.026) of FVC were negatively associated with the baseline and longitudinal change of HbA1c, respectively. Additionally, the longitudinal change of FVC was negatively associated with the risk of newly diagnosed type 2 DM (p = 0.018). During a mean 3.9-year follow-up, our present study, including participants without type 2 DM, hypertension, and COPD, demonstrated that the baseline and longitudinal change of FVC were negatively and respectively correlated with the baseline and longitudinal change of HbA1c. Furthermore, compared to those without new-onset DM, participants with new-onset DM had a more pronounced decline of FVC over time.
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Affiliation(s)
- Wen-Hsien Lee
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Da-Wei Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Ying-Chih Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Yi-Hsueh Liu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Wei-Sheng Liao
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Chih-Hsing Hung
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Chao-Hung Kuo
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
| | - Ho-Ming Su
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan; (W.-H.L.); (D.-W.W.); (Y.-C.C.); (Y.-H.L.); (W.-S.L.); (S.-C.C.); (C.-H.H.); (C.-H.K.)
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, 482 Shan-Ming Rd., Hsiao-Kang Dist., Kaohsiung 812, Taiwan
- Correspondence: ; Tel.: +886-7-8036783-3441; Fax: +886-7-8063346
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Chen HY, Hsu CL, Lin HY, Lin YF, Tsai SF, Ho YJ, Li YR, Tsai JW, Teng SC, Lin CH. Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48). J Biomed Sci 2021; 28:65. [PMID: 34565360 PMCID: PMC8466936 DOI: 10.1186/s12929-021-00763-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 09/23/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort. METHODS We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron-exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated. RESULTS We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein's activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development. CONCLUSIONS Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.
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Affiliation(s)
- Huan-Yun Chen
- Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Han-Yi Lin
- Department of Neurology, National Taiwan University Hospital, Number 7, Chung-Shan South Road, Taipei, 10051, Taiwan
| | - Yung-Feng Lin
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.,Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Shih-Feng Tsai
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.,Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Yu-Jung Ho
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Ye-Ru Li
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Jin-Wu Tsai
- Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.,Brain Research Center, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan
| | - Shu-Chun Teng
- Department of Microbiology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10051, Taiwan. .,Center of Precision Medicine, National Taiwan University, Taipei, Taiwan.
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Number 7, Chung-Shan South Road, Taipei, 10051, Taiwan.
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Wu CH, Hsieh CS, Chang YC, Huang CC, Yeh HT, Hou MF, Chung YC, Tu SH, Chang KJ, Chattopadhyay A, Lai LC, Lu TP, Li YH, Tsai MH, Chuang EY. Differential whole-genome doubling and homologous recombination deficiencies across breast cancer subtypes from the Taiwanese population. Commun Biol 2021; 4:1052. [PMID: 34504292 PMCID: PMC8429690 DOI: 10.1038/s42003-021-02597-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 08/05/2021] [Indexed: 12/11/2022] Open
Abstract
Whole-genome doubling (WGD) is an early macro-evolutionary event in tumorigenesis, involving the doubling of an entire chromosome complement. However, its impact on breast cancer subtypes remains unclear. Here, we performed a comprehensive and quantitative analysis of WGD and its influence on breast cancer subtypes in patients from Taiwan and consequently highlight the genomic association between WGD and homologous recombination deficiency (HRD). A higher manifestation of WGD was reported in triple-negative breast cancer, conferring high chromosomal instability (CIN), while HER2 + tumors exhibited early WGD events, with widely varied CIN levels, compared to luminal-type tumors. An association of higher activity of de novo indel signature 2 with WGD and HRD in Taiwanese breast cancer patients was reported. A control test between WGD and pseudo non-WGD samples was further employed to support this finding. The study provides a better comprehension of tumorigenesis in breast cancer subtypes, thus assisting in personalized treatment. Wu, Hsieh et al. analyze Taiwanese breast cancer patient samples using whole-exome sequencing to examine the heterogeneity and homogeneity in the timing and dependencies of somatic aberrations across disease subtypes. The authors focus on somatic alterations and related features that correlate with whole genome doubling, including homologous recombination deficiencies.
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Affiliation(s)
- Chia-Hsin Wu
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Chia-Shan Hsieh
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan
| | | | - Chi-Cheng Huang
- Comprehensive Breast Health Center, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsien-Tang Yeh
- Department of Surgery, Lotung Poh-Ai Hospital, Yilan County, Taiwan
| | - Ming-Feng Hou
- Division of Breast Surgery, Department of Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yuan-Chiang Chung
- Department of Breast Surgery, Dajia Branch, Kuang Tien General Hospital, Taichung, Taiwan
| | - Shih-Hsin Tu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - King-Jen Chang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Amrita Chattopadhyay
- Bioinformatics and Biostatistics Core, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
| | - Liang-Chuan Lai
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzu-Pin Lu
- Department of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yung-Hua Li
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Mong-Hsun Tsai
- Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
| | - Eric Y Chuang
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan. .,Bioinformatics and Biostatistics Core, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan. .,Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan. .,Master Program for Biomedical Engineering, China Medical University, Taichung, Taiwan.
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Secondhand smoke increases the risk of developing kidney stone disease. Sci Rep 2021; 11:17694. [PMID: 34489505 PMCID: PMC8421344 DOI: 10.1038/s41598-021-97254-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/23/2021] [Indexed: 12/23/2022] Open
Abstract
Research indicates smoking increases the risk of various kidney diseases, although the risk of developing kidney stone disease in non-smokers exposed to secondhand smoke is unknown. This study analyzed a total of 19,430 never-smokers with no history of kidney stone disease who participated in the Taiwan Biobank from 2008 to 2019. They were divided into two groups by secondhand smoke exposure; no exposure and exposure groups; the mean age of participants was 51 years, and 81% were women. Incident kidney stone development was observed in 352 (2.0%) and 50 (3.3%) participants in the no exposure and exposure groups during a mean follow-up of 47 months. The odds ratio (OR) of incident kidney stone was significantly higher in the exposure group than the no exposure group [OR, 1.64; 95% confidence interval (95% CI) 1.21 to 2.23]. Participants with > 1.2 h per week exposure were associated with almost twofold risk of developing kidney stones compared with no exposure (OR, 1.92; 95% CI 1.29 to 2.86). Our study suggests that secondhand smoke is a risk factor for development of kidney stones and supports the need for a prospective evaluation of this finding.
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Determinants of Longitudinal Change of Glycated Hemoglobin in a Large Non-Diabetic Population. J Pers Med 2021; 11:jpm11070648. [PMID: 34357115 PMCID: PMC8307008 DOI: 10.3390/jpm11070648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/23/2021] [Accepted: 07/07/2021] [Indexed: 11/23/2022] Open
Abstract
Although many cross-section studies have assessed the determinants of glycated hemoglobin (HbA1c), there have been limited studies designed to evaluate the temporal correlates of HbA1c in non-diabetic patients. This study aimed to identify the major determinants of longitudinal change of HbA1c in non-diabetic patients. This study included subjects from the 104,451 participants enrolled between 2012 and 2018 in the Taiwan Biobank. We only included participants with complete data at baseline and follow-up (n = 27,209). Patients with diabetes at baseline or follow-up (n = 3983) were excluded. Finally, 23,226 participants without diabetes at baseline and follow-up were selected in this study. △Parameters was defined as the difference between the measurement baseline and follow-up. Multivariable linear regression analysis was used to identify the major determinants of HbA1c longitudinal change (△HbA1c). During a mean 3.8 year follow-up, after multivariable analysis, new-onset hypertension (coefficient β: 0.014, p < 0.001), high △heart rate (coefficient β: 0.020, p = 0.002), high △BMI (coefficient β: 0.171, p = 0.028), high △fasting glucose (coefficient β: 0.107, p < 0.001), low △creatinine (coefficient β: −0.042, p < 0.001), high △total cholesterol (coefficient β: 0.040, p < 0.001), high △hemoglobin (coefficient β: 0.062, p < 0.001), high △GPT (coefficient β: 0.041, p = 0.001), and low △albumin (coefficient β: −0.070, p < 0.001) were significantly associated with high △HbA1c. In non-diabetic population, strategies to decrease the development of new-onset hypertension, resting heart rate, body mass index, fasting glucose, total cholesterol, and GPT and increase serum albumin level might be helpful in slowing the longitudinal change of HbA1c. In addition, increased hemoglobin and decreased serum creatinine over time also had an impact on the HbA1c elevation over time in non-diabetic population.
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Evolutionary Trajectories and Genomic Divergence in Localized Breast Cancers after Ipsilateral Breast Tumor Recurrence. Cancers (Basel) 2021; 13:cancers13081821. [PMID: 33920370 PMCID: PMC8069481 DOI: 10.3390/cancers13081821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 12/30/2022] Open
Abstract
Simple Summary Ipsilateral breast tumor relapse (IBTR) occurs in 5–10% of localized breast cancers (BCs) within 10 years of incidence, despite proper treatment of the primary lesion. However, the clinical consequences of evolutionary trajectories of BC cells and their impact on IBTR remain poorly understood. Here, we conducted a longitudinal genomic analysis of 10 matched localized BC patients with IBTR. Overall, we identified the differences in homologous recombination deficiency, chromosomal instability, and somatic mutation drivers between primary and relapsed lesions. Our analyses highlighted three clonal architectures that shape by distinct mutagenic processes and subclonal diversification during relapse progression. Finally, this study provided a framework, which integrated actionable biomarkers with clonal architectures, towards improvement of future treatment decisions. Abstract The evolutionary trajectories that drive clinical and therapeutic consequences in localized breast cancers (BCs) with ipsilateral breast tumor relapse (IBTR) remain largely unknown. Analyses of longitudinal paired whole-exome sequencing data from 10 localized BC patients with IBTR reveal that, compared to primary breast tumors, homologous recombination (HR) deficiency, inactivation of the HR pathway, chromosomal instability, and somatic driver mutations are more frequent. Furthermore, three major models of evolution in IBTR are summarized, through which relative contributions of mutational signatures shift, and the subclonal diversity expansions are shown. Optimal treatment regimens are suggested by the clinically relevant molecular features, such as HR deficiency (20%) or specific alterations (30%) with sensitivity to available FDA-approved drugs. Finally, a rationale for the development of the therapeutic management framework is provided. This study sheds light on the complicated evolution patterns in IBTR and has significant clinical implications for future improvement of treatment decisions.
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Cell lineage-specific methylome and genome alterations in gout. Aging (Albany NY) 2021; 13:3843-3865. [PMID: 33493135 PMCID: PMC7906142 DOI: 10.18632/aging.202353] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/05/2020] [Indexed: 12/14/2022]
Abstract
In this study, we examined data from 69 gout patients and 1,455 non-gout controls using a MethylationEPIC BeadChip assay and Illumina HiSeq platform to identify lineage-specific epigenetic alterations and associated genetic factors that contributed to gouty inflammation. Cell lineage-specific differentially methylated sites were identified using CellDMC after adjusting for sex, age, alcohol drinking, smoking status, and smoking history (total pack-years). Different cell lineages displayed distinct differential methylation. Ingenuity Pathway Analysis and NetworkAnalyst indicated that many differential methylated sites were associated with interleukin-1β expression in monocytes. On the UCSC Genome Browser and WashU Epigenome Browser, metabolic trait, cis-methylation quantitative trait loci, genetic, and functional annotation analyses identified nine methylation loci located in interleukin-1β-regulating genes (PRKCZ, CIDEC, VDAC1, CPT1A, BIRC2, BRCA1, STK11, and NLRP12) that were associated specifically with gouty inflammation. All nine sites mapped to active regulatory elements in monocytes. MoLoTool and ReMap analyses indicated that the nine methylation loci overlapped with binding sites of several transcription factors that regulated interleukin-1β production and gouty inflammation. Decreases in PRKCZ and STK11 methylation were also associated with higher numbers of first-degree relatives who also had gout. The gouty-inflammation specific methylome and genome alterations could potentially aid in the identification of novel therapeutic targets.
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Chiu TH, Huang YC, Chiu H, Wu PY, Chiou HYC, Huang JC, Chen SC. Comparison of Various Obesity-Related Indices for Identification of Metabolic Syndrome: A Population-Based Study from Taiwan Biobank. Diagnostics (Basel) 2020; 10:diagnostics10121081. [PMID: 33322810 PMCID: PMC7763700 DOI: 10.3390/diagnostics10121081] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 12/09/2020] [Accepted: 12/09/2020] [Indexed: 12/20/2022] Open
Abstract
This study aimed to evaluate the performance of 11 obesity-related indices, including body mass index (BMI), waist circumference, waist-to-height ratio, waist–hip ratio, a body shape index, abdominal volume index, body adiposity index, body roundness index, conicity index, visceral adiposity index (VAI), and triglyceride glucose (TyG) index, in identifying metabolic syndrome (MetS) in adults. The information of 5000 participants was obtained from the Taiwan Biobank. Logistic regression analyses were performed to determine the associations between MetS and obesity-related indices with odds ratio (ORs). The predictive performance of the indices to identify MetS was compared using receiver operating characteristic (ROC) curves and areas under curves (AUCs). Multivariate-adjusted logistic regression showed that the ORs for MetS increased across the quartiles of each index. ROC curves analysis demonstrated that TyG index had the greatest AUC in men (AUC = 0.850) and women (AUC = 0.890). Furthermore, VAI had the greatest AUC in men (AUC = 0.867) and women (AUC = 0.925) aged 30−50 years, while TyG index had the greatest AUC in men (AUC = 0.849) and women (AUC = 0.854) aged 51−70 years. Among the studied obesity-related indices, TyG index and VAI exhibited the best performance for identifying MetS in adults. TyG index and VAI may be the relevant indices to assess MetS in clinical practice.
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Affiliation(s)
- Tai-Hua Chiu
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (T.-H.C.); (H.C.)
| | - Ya-Chin Huang
- Department of Preventive Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan;
- Department of Occupational & Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hsuan Chiu
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan; (T.-H.C.); (H.C.)
| | - Pei-Yu Wu
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan; (P.-Y.W.); (S.-C.C.)
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Hsin-Ying Clair Chiou
- Teaching and Research Center of Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan;
| | - Jiun-Chi Huang
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan; (P.-Y.W.); (S.-C.C.)
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: ; Tel.: +886-7-8036783 (ext. 3441)
| | - Szu-Chia Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung Medical University, Kaohsiung 812, Taiwan; (P.-Y.W.); (S.-C.C.)
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Huang WC, Huang HT, Chen PY, Wang WC, Ko TM, Shrestha S, Yang CD, Tai CS, Chiew MY, Chou YP, Hu YF, Huang HD. SVAD: A genetic database curates non-ischemic sudden cardiac death-associated variants. PLoS One 2020; 15:e0237731. [PMID: 32813752 PMCID: PMC7437891 DOI: 10.1371/journal.pone.0237731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/31/2020] [Indexed: 11/19/2022] Open
Abstract
Sudden cardiac death (SCD) is an important cause of mortality worldwide. It accounts for approximately half of all deaths from cardiovascular disease. While coronary artery disease and acute myocardial infarction account for the majority of SCD in the elderly population, inherited cardiac diseases (inherited CDs) comprise a substantial proportion of younger SCD victims with a significant genetic component. Currently, the use of next-generation sequencing enables the rapid analysis to investigate relationships between genetic variants and inherited CDs causing SCD. Genetic contribution to risk has been considered an alternate predictor of SCD. In the past years, large numbers of SCD susceptibility variants were reported, but these results are scattered in numerous publications. Here, we present the SCD-associated Variants Annotation Database (SVAD) to facilitate the interpretation of variants and to meet the needs of data integration. SVAD contains data from a broad screening of scientific literature. It was constructed to provide a comprehensive collection of genetic variants along with integrated information regarding their effects. At present, SVAD has accumulated 2,292 entries within 1,239 variants by manually surveying pertinent literature, and approximately one-third of the collected variants are pathogenic/likely-pathogenic following the ACMG guidelines. To the best of our knowledge, SVAD is the most comprehensive database that can provide integrated information on the associated variants in various types of inherited CDs. SVAD represents a valuable source of variant information based on scientific literature and benefits clinicians and researchers, and it is now available on http://svad.mbc.nctu.edu.tw/.
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Affiliation(s)
- Wei-Chih Huang
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Hsin-Tzu Huang
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Industrial Development Graduate Program of College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Po-Yuan Chen
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Wei-Chi Wang
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Tai-Ming Ko
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, R.O.C
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C
| | - Sirjana Shrestha
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Chi-Dung Yang
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, China
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China
| | - Chun-San Tai
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
- Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Men-Yee Chiew
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Yu-Pao Chou
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan, R.O.C
| | - Yu-Feng Hu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
- Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C
- * E-mail: (HDH); (YFH)
| | - Hsien-Da Huang
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, China
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, China
- * E-mail: (HDH); (YFH)
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Tang YA, Wang LY, Chang CM, Lee IW, Tsai WH, Sun HS. Novel Compound Heterozygous Mutations in CRTAP Cause Rare Autosomal Recessive Osteogenesis Imperfecta. Front Genet 2020; 11:897. [PMID: 32922437 PMCID: PMC7457090 DOI: 10.3389/fgene.2020.00897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 07/20/2020] [Indexed: 11/28/2022] Open
Abstract
Whole-exome sequencing (WES) has advantages over the traditional molecular test by screening 20,000 genes simultaneously and has become an invaluable tool for genetic diagnosis in clinical practice. Here, we reported a family with a child and a fetus presenting undiagnosed skeletal dysplasia phenotypes, while the parents were asymptomatic. WES was applied to the parents and affected fetus to identify the genetic cause of the phenotypes. We identified novel compound heterozygous mutations consisting of a single-nucleotide variant (SNV) and a large deletion in the CRTAP gene (NM_006371.4:c.1153-3C > G/hg19 chr3:g.32398837_34210906del). Genetic alterations of CRTAP are known to cause osteogenesis imperfecta (OI) in an autosomal recessive manner. Further examination of the proband’s elder sibling who was diagnosed as OI after birth found that she shares the inherited compound heterozygous mutations of CRTAP; thus, the findings support the disease-causing role of CRTAP mutations. Through the in vitro molecular test and in silico analysis, the deleterious effects of the splicing-altering SNV in CRTAP (c.1153-3C > G) on gene product were confirmed. Collectively, our WES-based pathogenic variant discovery pipeline identifies the SNVs and copy number variation to delineate the genetic cause on the proband affected with OI. The data not only extend the knowledge of mutation spectrum in patients with skeletal dysplasia but also demonstrate that WES holds great promise for genetic screening of rare diseases in clinical settings.
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Affiliation(s)
- Yen-An Tang
- Center for Genomic Medicine, Research and Service Headquarter, National Cheng Kung University, Tainan, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Lin-Yen Wang
- Division of Hematology Oncology, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan.,Department of Childhood Education and Nursery, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chiao-May Chang
- Center for Genomic Medicine, Research and Service Headquarter, National Cheng Kung University, Tainan, Taiwan
| | - I-Wen Lee
- FMC Fetal Medicine Center, Tainan, Taiwan
| | - Wen-Hui Tsai
- Division of Genetics and Metabolism, Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan.,Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan, Taiwan
| | - H Sunny Sun
- Center for Genomic Medicine, Research and Service Headquarter, National Cheng Kung University, Tainan, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Gallego-Bartolomé J. DNA methylation in plants: mechanisms and tools for targeted manipulation. THE NEW PHYTOLOGIST 2020; 227:38-44. [PMID: 32159848 DOI: 10.1111/nph.16529] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 02/19/2020] [Indexed: 05/23/2023]
Abstract
DNA methylation is an epigenetic mark that regulates multiple processes, such as gene expression and genome stability. Mutants and pharmacological treatments have been instrumental in the study of this mark in plants, although their genome-wide effect complicates the direct association between changes in methylation and a particular phenotype. A variety of tools that allow locus-specific manipulation of DNA methylation can be used to assess its direct role in specific processes, as well as to create novel epialleles. Recently, new tools that recruit the methylation machinery directly to target loci through programmable DNA-binding proteins have expanded the tool kit available to researchers. This review provides an overview of DNA methylation in plants and discusses the tools that have recently been developed for its manipulation.
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Affiliation(s)
- Javier Gallego-Bartolomé
- Instituto de Biología Molecular y Celular de Plantas (IBMCP), CSIC-Universidad Politécnica de Valencia, 46011, Valencia, Spain
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Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout. Int J Mol Sci 2020; 21:ijms21134702. [PMID: 32630231 PMCID: PMC7369819 DOI: 10.3390/ijms21134702] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/23/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023] Open
Abstract
Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1β production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (PGGT1B, INSIG1, ANGPTL2, JNK1, UBAP1, and RAPTOR) were novel genes in the field of gout. One (CNTN5) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1β production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.
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Lin E, Lin CH, Lane HY. Precision Psychiatry Applications with Pharmacogenomics: Artificial Intelligence and Machine Learning Approaches. Int J Mol Sci 2020; 21:969. [PMID: 32024055 PMCID: PMC7037937 DOI: 10.3390/ijms21030969] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 01/25/2020] [Accepted: 01/30/2020] [Indexed: 12/22/2022] Open
Abstract
A growing body of evidence now suggests that precision psychiatry, an interdisciplinary field of psychiatry, precision medicine, and pharmacogenomics, serves as an indispensable foundation of medical practices by offering the accurate medication with the accurate dose at the accurate time to patients with psychiatric disorders. In light of the latest advancements in artificial intelligence and machine learning techniques, numerous biomarkers and genetic loci associated with psychiatric diseases and relevant treatments are being discovered in precision psychiatry research by employing neuroimaging and multi-omics. In this review, we focus on the latest developments for precision psychiatry research using artificial intelligence and machine learning approaches, such as deep learning and neural network algorithms, together with multi-omics and neuroimaging data. Firstly, we review precision psychiatry and pharmacogenomics studies that leverage various artificial intelligence and machine learning techniques to assess treatment prediction, prognosis prediction, diagnosis prediction, and the detection of potential biomarkers. In addition, we describe potential biomarkers and genetic loci that have been discovered to be associated with psychiatric diseases and relevant treatments. Moreover, we outline the limitations in regard to the previous precision psychiatry and pharmacogenomics studies. Finally, we present a discussion of directions and challenges for future research.
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Affiliation(s)
- Eugene Lin
- Department of Biostatistics, University of Washington, Seattle, WA 98195, USA;
- Department of Electrical & Computer Engineering, University of Washington, Seattle, WA 98195, USA
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
| | - Chieh-Hsin Lin
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- School of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsien-Yuan Lane
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan
- Department of Psychiatry, China Medical University Hospital, Taichung 40402, Taiwan
- Brain Disease Research Center, China Medical University Hospital, Taichung 40402, Taiwan
- Department of Psychology, College of Medical and Health Sciences, Asia University, Taichung 41354, Taiwan
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Rivera DR, Gokhale MN, Reynolds MW, Andrews EB, Chun D, Haynes K, Jonsson‐Funk ML, Lynch KE, Lund JL, Strongman H, Bhullar H, Raman SR. Linking electronic health data in pharmacoepidemiology: Appropriateness and feasibility. Pharmacoepidemiol Drug Saf 2020; 29:18-29. [DOI: 10.1002/pds.4918] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/23/2019] [Accepted: 10/16/2019] [Indexed: 11/06/2022]
Affiliation(s)
| | | | | | | | - Danielle Chun
- University of North Carolina Gillings School of Public Health Chapel Hill North Carolina
| | | | | | | | - Jennifer L. Lund
- University of North Carolina Gillings School of Public Health Chapel Hill North Carolina
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Gao Y, Zhang C, Yuan L, Ling Y, Wang X, Liu C, Pan Y, Zhang X, Ma X, Wang Y, Lu Y, Yuan K, Ye W, Qian J, Chang H, Cao R, Yang X, Ma L, Ju Y, Dai L, Tang Y, The Han100K Initiative, Zhang G, Xu S. PGG.Han: the Han Chinese genome database and analysis platform. Nucleic Acids Res 2020; 48:D971-D976. [PMID: 31584086 PMCID: PMC6943055 DOI: 10.1093/nar/gkz829] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/11/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
As the largest ethnic group in the world, the Han Chinese population is nonetheless underrepresented in global efforts to catalogue the genomic variability of natural populations. Here, we developed the PGG.Han, a population genome database to serve as the central repository for the genomic data of the Han Chinese Genome Initiative (Phase I). In its current version, the PGG.Han archives whole-genome sequences or high-density genome-wide single-nucleotide variants (SNVs) of 114 783 Han Chinese individuals (a.k.a. the Han100K), representing geographical sub-populations covering 33 of the 34 administrative divisions of China, as well as Singapore. The PGG.Han provides: (i) an interactive interface for visualization of the fine-scale genetic structure of the Han Chinese population; (ii) genome-wide allele frequencies of hierarchical sub-populations; (iii) ancestry inference for individual samples and controlling population stratification based on nested ancestry informative markers (AIMs) panels; (iv) population-structure-aware shared control data for genotype-phenotype association studies (e.g. GWASs) and (v) a Han-Chinese-specific reference panel for genotype imputation. Computational tools are implemented into the PGG.Han, and an online user-friendly interface is provided for data analysis and results visualization. The PGG.Han database is freely accessible via http://www.pgghan.org or https://www.hanchinesegenomes.org.
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Affiliation(s)
- Yang Gao
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Chao Zhang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Liyun Yuan
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - YunChao Ling
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaoji Wang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chang Liu
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuwen Pan
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaoxi Zhang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xixian Ma
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuchen Wang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yan Lu
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
| | - Kai Yuan
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Wei Ye
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jiaqiang Qian
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Huidan Chang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ruifang Cao
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiao Yang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Ling Ma
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuanhu Ju
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Long Dai
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuanyuan Tang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | | | - Guoqing Zhang
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Shuhua Xu
- Key Laboratory of Computational Biology, Bio-Med Big Data Center, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- Collaborative Innovation Center of Genetics and Development, Shanghai 200438, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
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Abstract
Antimicrobial susceptibility testing (AST) technologies help to accelerate the initiation of targeted antimicrobial therapy for patients with infections and could potentially extend the lifespan of current narrow-spectrum antimicrobials. Although conceptually new and rapid AST technologies have been described, including new phenotyping methods, digital imaging and genomic approaches, there is no single major, or broadly accepted, technological breakthrough that leads the field of rapid AST platform development. This might be owing to several barriers that prevent the timely development and implementation of novel and rapid AST platforms in health-care settings. In this Consensus Statement, we explore such barriers, which include the utility of new methods, the complex process of validating new technology against reference methods beyond the proof-of-concept phase, the legal and regulatory landscapes, costs, the uptake of new tools, reagent stability, optimization of target product profiles, difficulties conducting clinical trials and issues relating to quality and quality control, and present possible solutions. This Consensus Statement presents the barriers that currently prevent the timely development and implementation of novel and rapid antimicrobial susceptibility testing platforms, including the costs involved, uptake of new tools, legal and regulatory aspects, difficulties conducting clinical trials and quality control, and presents possible solutions.
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Smaïl-Tabbone M, Rance B. Contributions from the 2018 Literature on Bioinformatics and Translational Informatics. Yearb Med Inform 2019; 28:190-193. [PMID: 31419831 PMCID: PMC6697500 DOI: 10.1055/s-0039-1677945] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Objectives
: To summarize recent research and select the best papers published in 2018 in the field of Bioinformatics and Translational Informatics (BTI) for the corresponding section of the International Medical Informatics Association (IMIA) Yearbook.
Methods
: A literature review was performed for retrieving from PubMed papers indexed with keywords and free terms related to BTI. Independent review allowed the two section editors to select a list of 14 candidate best papers which were subsequently peer-reviewed. A final consensus meeting gathering the whole IMIA Yearbook editorial committee was organized to finally decide on the selection of the best papers.
Results
: Among the 636 retrieved papers published in 2018 in the various subareas of BTI, the review process selected four best papers. The first paper presents a computational method to identify molecular markers for targeted treatment of acute myeloid leukemia using multi-omics data (genome-wide gene expression profiles) and in vitro sensitivity to 160 chemotherapy drugs. The second paper describes a deep neural network approach to predict the survival of patients suffering from glioma on the basis of digitalised pathology images and genomics biomarkers. The authors of the third paper adopt a pan-cancer approach to take benefit of multi-omics data for drug repurposing. The fourth paper presents a graph-based semi-supervised method to accurate phenotype classification applied to ovarian cancer.
Conclusions
: Thanks to the normalization of open data and open science practices, research in BTI continues to develop and mature. Noteworthy achievements are sophisticated applications of leading edge machine-learning methods dedicated to personalized medicine.
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Affiliation(s)
- Malika Smaïl-Tabbone
- Loria UMR 7503, Université de Lorraine, CNRS, Inria Nancy Grand-Est, Nancy, France
| | - Bastien Rance
- HEGP, AP-HP; Université Paris Descartes, Université de Paris; UMRS 1138 Centre de Recherche des Cordeliers INSERM, Paris, France
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