|
1
|
Bayram S, Ülger Y. Association of PNPLA3 rs738409 C > G and rs2896019 T > G Polymorphisms with Nonalcoholic Fatty Liver Disease in a Turkish Population from Adıyaman Province. Genet Test Mol Biomarkers 2025; 29:63-73. [PMID: 40101239 DOI: 10.1089/gtmb.2024.0481] [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] [Indexed: 03/20/2025] Open
Abstract
Objectives: The purpose of this study was to investigate the effect of patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G and rs2896019 T > G polymorphisms on genetic susceptibility to nonalcoholic fatty liver disease (NAFLD) in a Turkish population from Adıyaman province, located in the Southeast Anatolia Region of Turkey. Materials and Methods: This hospital-based molecular epidemiological case-control study analyzed the PNPLA3 rs738409 C > G and rs2896019 T > G polymorphisms in 335 NAFLD cases and 410 healthy controls. Genotype frequencies were determined using real-time polymerase chain reaction with the TaqMan assay. The association with NAFLD susceptibility was evaluated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using an unconditional logistic regression model. Results: We found that the PNPLA3 rs738409 C > G (CC vs. GG: OR = 1.90, 95% CI = 1.05-3.44) and rs2896019 T > G (TT vs. GG: OR = 3.24, 95% CI = 1.44-7.27) polymorphisms were linked to an increased risk of NAFLD in almost all genetic models (p < 0.05). In addition, the PNPLA3 Grs738409/Grs2896019 haplotype was associated with NAFLD development (p < 0.05). Significant differences in alanine aminotransferase and aspartate aminotransferase enzyme levels were observed across the genotypes of these polymorphisms (p < 0.05). Conclusion: This is the first study on PNPLA3 single nucleotide polymorphisms (SNPs) and NAFLD in the Turkish population of Adıyaman Province, Southeast Anatolia. Our findings suggest that the PNPLA3 rs738409 C > G and rs2896019 T > G polymorphisms, along with their haplotypes, may influence NAFLD susceptibility. Further independent studies with larger sample sizes and diverse populations are needed to confirm these results.
Collapse
Affiliation(s)
- Süleyman Bayram
- Faculty of Health Sciences, Department of Public Health Nursing, Adıyaman University, Adıyaman, Turkey
| | - Yakup Ülger
- Faculty of Medicine, Department of Gastroenterology, Çukurova University, Adana, Turkey
| |
Collapse
|
|
2
|
Spitz L, Saadiq S, Shokar NK, Zuckerman MJ, Casner NA, Valenzuela R, Salinas JJ. Characterization of an At-Risk Population for Nonalcoholic Fatty Liver Disease (NAFLD) in a Primary Care Setting Along the U.S.-Mexico Border. J Transcult Nurs 2025; 36:92-102. [PMID: 39189342 PMCID: PMC11645848 DOI: 10.1177/10436596241271265] [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] [Indexed: 08/28/2024] Open
Abstract
INTRODUCTION This study aimed to determine the burden of suspected nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) in a predominantly Hispanic patient population and explore the utility of the American Gastroenterological Association's NAFLD Clinical Care Pathway (CCP). METHODOLOGY Electronic medical records (n = 223) were used to divide patients into risk groups based on the amount of metabolic risk factors they presented, diabetic status, or if they presented other liver diseases. Fribosis-4 (FIB-4) scores were used to determine the risk for advanced fibrosis. RESULTS Most patients (83.8%) were considered at risk for NAFLD based on CCP criteria, and about a third of patients (33.2%) were found to be at indeterminate (n = 60; 26.9%) or high risk (n = 14; 6.3%) for advanced fibrosis. Most indeterminate-risk patients (78.3%) were not referred for liver imaging. DISCUSSION This study demonstrates the potential of the CCP as a corrective tool that could help to better identify and screen patients at risk for NAFLD.
Collapse
Affiliation(s)
- Lindsay Spitz
- Texas Tech University Health Sciences Center, El Paso, USA
| | - Stefan Saadiq
- Texas Tech University Health Sciences Center, El Paso, USA
| | | | | | | | | | | |
Collapse
|
|
3
|
Lu CW, Chou TJ, Wu TY, Lee YH, Yang HJ, Huang KC. PNPLA3 and SAMM50 variants are associated with lean nonalcoholic fatty liver disease in Asian population. Ann Hepatol 2024; 30:101761. [PMID: 39638042 DOI: 10.1016/j.aohep.2024.101761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 08/02/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION AND OBJECTIVES Lean adults with nonalcoholic fatty liver disease (NAFLD) have a higher risk of metabolic syndrome than lean controls. The study aimed to investigate the clinical and genetic features of lean NAFLD which remain unclear in Asian populations. MATERIALS AND METHODS This was a genetic cohort study conducted in the HAVO Health Exam Clinic in 2020-2021 in Taiwan. Adults with a body mass index less than 24 kg/m2 were enrolled. Fatty liver was defined by ultrasonography. The candidate gene approach was based on the library of the NHGRI-EBI website. After removing duplication and nonsignificant variants, rs738409 in the PNPLA3 gene and rs3761472 in the SAMM50 gene were chosen. Multiple logistic regression models and receiver operating characteristic (ROC) curves were used. RESULTS A total of 1652 lean controls and 602 lean NAFLD patients were enrolled. The average age was 43.8 ± 11.5 years. Lean NAFLD subjects were older and had a higher percentage of metabolic syndrome (case vs. control: 10.5 % vs. 1.5 %). The GG genotypes of PNPLA3 rs12483959 (OR: 3.06; 95% CI: 2.15-4.37) and SAMM50 rs3761472 (OR: 2.90; 95% CI: 2.04-4.14) had a higher risk of fatty liver after adjusting for BMI and metabolic syndrome. The areas under the ROC curve for PNPLA3 rs738409 and SAMM50 rs3761472 in the detection of lean NAFLD were 0.859 (95%CI: 0.841, 0.877) and 0.860 (95%CI: 0.843, 0.877), respectively. CONCLUSIONS PNPLA3 rs738409 and SAMM50 rs3761472 gene polymorphisms are associated with a higher risk of fatty liver in lean individuals independent of BMI and metabolic syndrome in Asian populations.
Collapse
Affiliation(s)
- Chia-Wen Lu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzu-Jung Chou
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Family Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Tsan-Yu Wu
- Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Hsuan Lee
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Jen Yang
- Min-Sheng General Hospital, Taoyuan, Taiwan; Share Hope Medicine Co., Ltd., Taoyuan, Taiwan
| | - Kuo-Chin Huang
- Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Family Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Family Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan.
| |
Collapse
|
|
4
|
Garcia IS, Silva-Vignato B, Cesar ASM, Petrini J, da Silva VH, Morosini NS, Goes CP, Afonso J, da Silva TR, Lima BD, Clemente LG, Regitano LCDA, Mourão GB, Coutinho LL. Novel putative causal mutations associated with fat traits in Nellore cattle uncovered by eQTLs located in open chromatin regions. Sci Rep 2024; 14:10094. [PMID: 38698200 PMCID: PMC11066111 DOI: 10.1038/s41598-024-60703-5] [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: 10/19/2023] [Accepted: 04/26/2024] [Indexed: 05/05/2024] Open
Abstract
Intramuscular fat (IMF) and backfat thickness (BFT) are critical economic traits impacting meat quality. However, the genetic variants controlling these traits need to be better understood. To advance knowledge in this area, we integrated RNA-seq and single nucleotide polymorphisms (SNPs) identified in genomic and transcriptomic data to generate a linkage disequilibrium filtered panel of 553,581 variants. Expression quantitative trait loci (eQTL) analysis revealed 36,916 cis-eQTLs and 14,408 trans-eQTLs. Association analysis resulted in three eQTLs associated with BFT and 24 with IMF. Functional enrichment analysis of genes regulated by these 27 eQTLs revealed noteworthy pathways that can play a fundamental role in lipid metabolism and fat deposition, such as immune response, cytoskeleton remodeling, iron transport, and phospholipid metabolism. We next used ATAC-Seq assay to identify and overlap eQTL and open chromatin regions. Six eQTLs were in regulatory regions, four in predicted insulators and possible CCCTC-binding factor DNA binding sites, one in an active enhancer region, and the last in a low signal region. Our results provided novel insights into the transcriptional regulation of IMF and BFT, unraveling putative regulatory variants.
Collapse
Affiliation(s)
- Ingrid Soares Garcia
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Bárbara Silva-Vignato
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Aline Silva Mello Cesar
- Department of Agroindustry, Food and Nutrition, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Juliana Petrini
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Vinicius Henrique da Silva
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Natália Silva Morosini
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Carolina Purcell Goes
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | | | - Thaís Ribeiro da Silva
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Beatriz Delcarme Lima
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Luan Gaspar Clemente
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | | | - Gerson Barreto Mourão
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil
| | - Luiz Lehmann Coutinho
- Department of Animal Science, College of Agriculture "Luiz de Queiroz", University of São Paulo, Piracicaba, SP, Brazil.
| |
Collapse
|
|
5
|
Lee Y, Cho EJ, Choe EK, Kwak MS, Yang JI, Oh SW, Yim JY, Chung GE. Genome-wide association study of metabolic dysfunction-associated fatty liver disease in a Korean population. Sci Rep 2024; 14:9753. [PMID: 38679617 PMCID: PMC11056367 DOI: 10.1038/s41598-024-60152-0] [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: 07/14/2023] [Accepted: 04/19/2024] [Indexed: 05/01/2024] Open
Abstract
Genome-wide association studies have identified several genetic variants associated with nonalcoholic fatty liver disease. To emphasize metabolic abnormalities in fatty liver, metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been introduced; thus, we aimed to investigate single-nucleotide polymorphisms related to MAFLD and its subtypes. A genome-wide association study was performed to identify genetic factors related to MAFLD. We used a Korean population-based sample of 2282 subjects with MAFLD and a control group of 4669. We replicated the results in a validation sample which included 639 patients with MAFLD and 1578 controls. Additionally, we categorized participants into three groups, no MAFLD, metabolic dysfunction (MD)-MAFLD, and overweight/obese-MAFLD. After adjusting for age, sex, and principal component scores, rs738409 [risk allele G] and rs3810622 [risk allele T], located in the PNPLA3 gene, showed significant associations with MAFLD (P-values, discovery set = 1.60 × 10-15 and 4.84 × 10-10; odds ratios, 1.365 and 1.284, validation set = 1.39 × 10-4, and 7.15 × 10-4, odds ratios, 1.299 and 1.264, respectively). An additional SNP rs59148799 [risk allele G] located in the GATAD2A gene showed a significant association with MAFLD (P-values, discovery set = 2.08 × 10-8 and validation set = 0.034, odds ratios, 1.387 and 1.250). rs738409 was significantly associated with MAFLD subtypes ([overweight/obese-MAFLD; odds ratio (95% confidence interval), P-values, 1.515 (1.351-1.700), 1.43 × 10-12 and MD-MAFLD: 1.300 (1.191-1.416), 2.90 × 10-9]. There was a significant relationship between rs3810622 and overweight/obese-MAFLD and MD-MAFLD [odds ratios (95% confidence interval), P-values, 1.418 (1.258, 1.600), 1.21 × 10-8 and 1.225 (1.122, 1.340), 7.06 × 10-6, respectively]; the statistical significance remained in the validation set. PNPLA3 was significantly associated with MAFLD and MAFLD subtypes in the Korean population. These results indicate that genetic factors play an important role in the pathogenesis of MAFLD.
Collapse
Affiliation(s)
- Young Lee
- Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea
- Department of Applied Statistics, Chung-Ang University, Seoul, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Kyung Choe
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Min-Sun Kwak
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Jong In Yang
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Seung-Won Oh
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
- Department of Family Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Yoon Yim
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea
| | - Goh Eun Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Department of Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea.
| |
Collapse
|
|
6
|
Heidari-Ezzati S, Moeinian P, Ahmadian-Nejad B, Maghbbouli F, Abbasi S, Zahedi M, Afkhami H, Shadab A, Sajedi N. The role of long non-coding RNAs and circular RNAs in cervical cancer: modulating miRNA function. Front Cell Dev Biol 2024; 12:1308730. [PMID: 38434620 PMCID: PMC10906305 DOI: 10.3389/fcell.2024.1308730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/24/2024] [Indexed: 03/05/2024] Open
Abstract
Cervical cancer (CC) is a primary global health concern, ranking as the fourth leading cause of cancer-related death in women. Despite advancements in prognosis, long-term outcomes remained poor. Beyond HPV, cofactors like dietary deficiencies, immunosuppression, hormonal contraceptives, co-infections, and genetic variations are involved in CC progression. The pathogenesis of various diseases, including cancer, has brought to light the critical regulatory roles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). The aberrant expression of these miRNAs, lncRNAs, and circRNAs plays a pivotal role in the initiation and progression of CC. This review provides a comprehensive summary of the recent literature regarding the involvement of lncRNAs and circRNAs in modulating miRNA functions in cervical neoplasia and metastasis. Studies have shown that lncRNAs and circRNAs hold great potential as therapeutic agents and innovative biomarkers in CC. However, more clinical research is needed to advance our understanding of the therapeutic benefits of circRNAs and lncRNAs in CC.
Collapse
Affiliation(s)
- Sama Heidari-Ezzati
- School of Nursing and Midwifery, Bonab University of Medical Sciences, Bonab, Iran
| | - Parisa Moeinian
- Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahar Ahmadian-Nejad
- School of Nursing and Midwifery, Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | | | - Sheida Abbasi
- Department of obstetrics and gynecology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahlagha Zahedi
- Department of Pathology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Alireza Shadab
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
- Iran University of Medical Sciences, Deputy of Health, Tehran, Iran
| | - Nayereh Sajedi
- Department of Anatomy, Faculty of Medicine, Qom Medical Sciences, Islamic Azad University, Qom, Iran
| |
Collapse
|
|
7
|
Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: The growing challenge. Hepatology 2023; 77:323-338. [PMID: 35478412 PMCID: PMC9970023 DOI: 10.1002/hep.32542] [Citation(s) in RCA: 117] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide. With the obesity pandemic, NAFLD-related HCC is contributing to the burden of disease exponentially. Genetic predisposition and clinical risk factors for NAFLD-related HCC have been identified. Cirrhosis is a well-known and major risk factor for NAFLD-related HCC. However, the occurrence of NAFLD-related HCC in patients without cirrhosis is increasingly recognized and poses a significant challenge regarding cancer surveillance. It is of paramount importance to develop optimal risk stratification scores and models to identify subsets of the population at high risk so they can be enrolled in surveillance programs. In this review, we will discuss the risks and prediction models for NAFLD-related HCC.
Collapse
Affiliation(s)
- Pir Ahmad Shah
- Department of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Rashmee Patil
- South Texas Research Institute, Edinburg, Texas, USA
| | | |
Collapse
|
|
8
|
Qiao M, Yang JH, Zhu Y, Hu JP. Association of sorting and assembly machinery component 50 homolog gene polymorphisms with nonalcoholic fatty liver disease susceptibility. Medicine (Baltimore) 2022; 101:e29958. [PMID: 35866791 PMCID: PMC9302252 DOI: 10.1097/md.0000000000029958] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Sorting and assembly machinery component 50 homolog (SAMM50) gene single-nucleotide polymorphisms (SNPs) have been connected with the susceptibility of nonalcoholic fatty liver disease (NAFLD), but with inconsistent results across the current evidence. The present work was schemed to explore the association between SAMM50 gene SNPs and NAFLD vulnerability via meta-analysis. METHODS PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang were retrieved for eligible literature previous to June 10, 2021. The odds ratios (ORs) of the dichotomic variables and the standardized mean difference of quantitative variables with corresponding 95% confidence intervals (95% CIs) were computed to evaluate the strength of the associations. The quality of included studies was assessed using Newcastle-Ottawa Scale (NOS). RESULTS In total, 8 case-control studies encompassing 6297 NAFLD patients and 7306 disease-free controls in this meta-analysis. Ultimately, this analysis included 8, 6, and 5 studies for rs2143571, rs3761472, and rs738491 polymorphisms respectively. The pooled data revealed that the 3 polymorphisms had conspicuous associations with NAFLD susceptibility: rs2143571, A vs. G, OR=1.51, 95% CI, 1.37-1.66, P < .01; rs3761472, A vs. G, OR=1.50, 95% CI, 1.35-1.67, P < .01; rs738491, A vs. G, OR=1.51, 95% CI, 1.40-1.63, P < .01. CONCLUSION This meta-analysis suggests that rs2143571, rs3761472, and rs738491 polymorphisms of the SAMM50 gene are appreciably associated with augmented risk of NAFLD vulnerability. It will provide the latest evidence to support the susceptibility of SAMM50 gene polymorphisms and NAFLD, and provide strategies for the prevention and treatment of NAFLD.
Collapse
Affiliation(s)
- Ming Qiao
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jian-hua Yang
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yi Zhu
- Department of Pharmacy, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Jun-ping Hu
- College of Pharmacy, Xinjiang Medical University, Urumqi, China
- * Correspondence: Jun-ping Hu, College of Pharmacy, Xinjiang Medical University, 137 Liyushan Avenue, Xinshi District, Urumqi, Xinjiang 830017, China (e-mail: )
| |
Collapse
|
|
9
|
Update on Non-Alcoholic Fatty Liver Disease-Associated Single Nucleotide Polymorphisms and Their Involvement in Liver Steatosis, Inflammation, and Fibrosis: A Narrative Review. IRANIAN BIOMEDICAL JOURNAL 2022; 26:252-68. [PMID: 36000237 PMCID: PMC9432469 DOI: 10.52547/ibj.3647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Genetic factors are involved in the development, progression, and severity of NAFLD. Polymorphisms in genes regulating liver functions may increase liver susceptibility to NAFLD. Therefore, we conducted this literature study to present recent findings on NAFLD-associated polymorphisms from published articles in PubMed from 2016 to 2021. From 69 selected research articles, 20 genes and 34 SNPs were reported to be associated with NAFLD. These mutated genes affect NAFLD by promoting liver steatosis (PNPLA3, MBOAT7, TM2SF6, PTPRD, FNDC5, IL-1B, PPARGC1A, UCP2, TCF7L2, SAMM50, IL-6, AGTR1, and NNMT), inflammation (PNPLA3, TNF-α, AGTR1, IL-17A, IL-1B, PTPRD, and GATAD2A), and fibrosis (IL-1B, PNPLA3, MBOAT7, TCF7L2, GATAD2A, IL-6, NNMT, UCP, AGTR1, and TM2SF6). The identification of these genetic factors helps to better understand the pathogenesis pathways of NAFLD
Collapse
|
|
10
|
Association between rs738408, rs738409 and rs139051polymorphisms in PNPLA3 gene and non-alcoholic fatty liver disease. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2021.101472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
11
|
Shaheen M, Pan D, Schrode KM, Kermah D, Puri V, Zarrinpar A, Elisha D, Najjar SM, Friedman TC. Reassessment of the Hispanic Disparity: Hepatic Steatosis Is More Prevalent in Mexican Americans Than Other Hispanics. Hepatol Commun 2021; 5:2068-2079. [PMID: 34558824 PMCID: PMC8631095 DOI: 10.1002/hep4.1775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/06/2021] [Accepted: 06/13/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic steatosis (HS) is a growing problem in adults worldwide, with racial/ethnic disparity in the prevalence of the disease. The purpose of this study was to characterize the racial/ethnic prevalence of the stages (normal/mild [S0/S1], moderate [S2], and severe [S3]) of HS in Mexican Americans and other Hispanics compared to other racial/ethnic groups. We analyzed data for 5,492 individuals 12 years and older from the newly released National Health and Nutrition Examination Survey 2017-2018, which is a representative sample of the US adult population. HS was diagnosed by FibroScan using controlled attenuation parameter values: S0, <238; S1, 238-259; S2, 260-290; S3, >290. We analyzed the data using the bivariate chi-squared test and multinomial regression. The prevalence of HS overall was 46.9% (S2,16.6%; S3, 30.3%). The prevalence of S3 was highest among Mexican Americans (42.8%), lowest among Blacks (21.6%), 27.6% in other Hispanics, and 30.6% in Whites (P < 0.05). Mexican Americans were about 2 times more likely than Whites to have S2 and S3, while other Hispanics showed no difference from Whites. In an adjusted model, the common risk factors of S2 and S3 were male sex, older ages, high waist-to-hip ratio, body mass index ≥25, and high triglycerides (P < 0.05). Other risk factors for S3 were hemoglobin A1c ≥5.7 and highly sensitive C-reactive protein ≥10 mg/dL (P < 0.05). Conclusion: Our study challenges the paradigm that HS is higher in Hispanics overall; rather, our data show that HS is higher in Mexican Americans and not non-Mexican American Hispanics.
Collapse
Affiliation(s)
| | - Deyu Pan
- Charles R. Drew UniversityLos AngelesCAUSA
| | | | | | - Vishwajeet Puri
- Heritage College of Osteopathic MedicineOhio UniversityAthensOHUSA
| | - Ali Zarrinpar
- University of Florida College of MedicineGainesvilleFLUSA
| | | | - Sonia M. Najjar
- Heritage College of Osteopathic MedicineOhio UniversityAthensOHUSA
| | | |
Collapse
|
|
12
|
Parameswaran M, Hasan HA, Sadeque J, Jhaveri S, Avanthika C, Arisoyin AE, Dhanani MB, Rath SM. Factors That Predict the Progression of Non-alcoholic Fatty Liver Disease (NAFLD). Cureus 2021; 13:e20776. [PMID: 35111461 PMCID: PMC8794413 DOI: 10.7759/cureus.20776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) refers to a spectrum of diseases involving the deposition of fat in the hepatocytes of people with little to no alcohol consumption. NAFLD is associated with hypertension, diabetes, obesity, etc. As their prevalence increases, the propensity and severity of NAFLD might increase. As per the recently developed multi-hit hypothesis, factors like oxidative stress, genetic predisposition, lipotoxicity, and insulin resistance have been found to play a key role in the development of NAFLD and its associated complications. This article focuses on NAFLD, its pathophysiology, risk factors, and the various genetic and epigenetic factors involved in its development along with possible treatment modalities. We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: “NAFLD,” “NASH,” “Fibrosis,” and “Insulin Resistance.” We explored the literature on NAFLD for its epidemiology, pathophysiology, the role of various genes, and how they influence the disease and associated complications about the disease and its hepatic and extrahepatic complications. With its rapidly increasing prevalence rates across the world and serious complications like NASH and hepatocellular carcinoma, NAFLD is becoming a major public health issue and more research is needed to formulate better screening tools and treatment protocols.
Collapse
Affiliation(s)
| | | | - Jafor Sadeque
- Internal Medicine, Al Mostaqbal Hospital, Jeddah, SAU
| | - Sharan Jhaveri
- Internal Medicine, Smt. Nathiba Hargovandas Lakhmichand Municipal Medical College, Ahmedabad, IND
| | | | | | - Maulik B Dhanani
- Internal Medicine, Southwestern University School of Medicine, Cebu City, PHL
| | - Swaroopa M Rath
- Medicine, Srirama Chandra Bhanja Medical College and Hospital, Cuttack, IND
| |
Collapse
|
|
13
|
Flores YN, Amoon AT, Su B, Velazquez-Cruz R, Ramírez-Palacios P, Salmerón J, Rivera-Paredez B, Sinsheimer JS, Lusis AJ, Huertas-Vazquez A, Saab S, Glenn BA, May FP, Williams KJ, Bastani R, Bensinger SJ. Serum lipids are associated with nonalcoholic fatty liver disease: a pilot case-control study in Mexico. Lipids Health Dis 2021; 20:136. [PMID: 34629052 PMCID: PMC8504048 DOI: 10.1186/s12944-021-01526-5] [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: 05/14/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and cirrhosis. NAFLD is mediated by changes in lipid metabolism and known risk factors include obesity, metabolic syndrome, and diabetes. The aim of this study was to better understand differences in the lipid composition of individuals with NAFLD compared to controls, by performing direct infusion lipidomics on serum biospecimens from a cohort study of adults in Mexico. Methods A nested case-control study was conducted with a sample of 98 NAFLD cases and 100 healthy controls who are participating in an on-going, longitudinal study in Mexico. NAFLD cases were clinically confirmed using elevated liver enzyme tests and liver ultrasound or liver ultrasound elastography, after excluding alcohol abuse, and 100 controls were identified as having at least two consecutive normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (< 40 U/L) results in a 6-month period, and a normal liver ultrasound elastography result in January 2018. Samples were analyzed on the Sciex Lipidyzer Platform and quantified with normalization to serum volume. As many as 1100 lipid species can be identified using the Lipidyzer targeted multiple-reaction monitoring list. The association between serum lipids and NAFLD was investigated using analysis of covariance, random forest analysis, and by generating receiver operator characteristic (ROC) curves. Results NAFLD cases had differences in total amounts of serum cholesterol esters, lysophosphatidylcholines, sphingomyelins, and triacylglycerols (TAGs), however, other lipid subclasses were similar to controls. Analysis of individual TAG species revealed increased incorporation of saturated fatty acyl tails in serum of NAFLD cases. After adjusting for age, sex, body mass index, and PNPLA3 genotype, a combined panel of ten lipids predicted case or control status better than an area under the ROC curve of 0.83. Conclusions These preliminary results indicate that the serum lipidome differs in patients with NAFLD, compared to healthy controls, and suggest that assessing the desaturation state of TAGs or a specific lipid panel may be useful clinical tools for the diagnosis of NAFLD. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-021-01526-5.
Collapse
Affiliation(s)
- Yvonne N Flores
- Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. .,UCLA Center for Cancer Prevention and Control and UCLA-Kaiser Permanente Center for Health Equity, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. .,Unidad de Investigación Epidemiológica y en Servicios de Salud, Morelos, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, Mexico.
| | - Aryana T Amoon
- UCLA Center for Cancer Prevention and Control and UCLA-Kaiser Permanente Center for Health Equity, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Baolong Su
- UCLA Lipidomics Laboratory, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Rafael Velazquez-Cruz
- Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica (INMEGEN), Ciudad de México, Mexico
| | - Paula Ramírez-Palacios
- Unidad de Investigación Epidemiológica y en Servicios de Salud, Morelos, Instituto Mexicano del Seguro Social, Cuernavaca, Morelos, Mexico
| | - Jorge Salmerón
- Centro de Investigación en Políticas, Población y Salud, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Berenice Rivera-Paredez
- Centro de Investigación en Políticas, Población y Salud, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Janet S Sinsheimer
- UCLA Department of Human Genetics and Computational Medicine, Los Angeles, CA, USA.,Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA
| | - Aldons J Lusis
- UCLA Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA.,UCLA Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Adriana Huertas-Vazquez
- UCLA Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Sammy Saab
- UCLA Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA, USA.,Pfleger Liver Institute, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Beth A Glenn
- Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Center for Cancer Prevention and Control and UCLA-Kaiser Permanente Center for Health Equity, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Folasade P May
- Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Center for Cancer Prevention and Control and UCLA-Kaiser Permanente Center for Health Equity, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.,UCLA Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA, USA.,Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Kevin J Williams
- UCLA Lipidomics Laboratory, David Geffen School of Medicine, Los Angeles, CA, USA.,UCLA Department of Biological Chemistry, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Roshan Bastani
- Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Center for Cancer Prevention and Control and UCLA-Kaiser Permanente Center for Health Equity, Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Steven J Bensinger
- UCLA Lipidomics Laboratory, David Geffen School of Medicine, Los Angeles, CA, USA.,UCLA Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
| |
Collapse
|
|
14
|
Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
Collapse
Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| |
Collapse
|
|
15
|
Zhu Y, Zhang S, Yang C, Xue W, Zhang J, Li J, Zhao J, Xu J, Huang W. [Quantitative analysis of differential proteins in liver tissues of patients with non-alcoholic steatohepatitis using iTRAQ technology]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2021; 41:1381-1387. [PMID: 34658353 DOI: 10.12122/j.issn.1673-4254.2021.09.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To screen differentially expressed proteins (DSPs) in the liver tissues of patients with nonalcoholic steatohepatitis (NASH) using proteomic technologies to identify potential therapeutic targets of NASH. METHODS Liver tissue specimens were obtained from 3 patients with pathologically confirmed NASH and 3 normal control subjects. The total proteins were extracted from the specimens, and iTRAQ reagent was used to label the peptides for liquid chromatography tandem mass spectrometry (LC-MS/MS) detection. The DSPs were identified by comparing the data against UniProt protein database using Mascot2.3.02 software and were annotated and enriched using GO database; KEGG database was used for enrichment of the pathways involving these proteins. Real-time fluorescent quantitative PCR (qPCR) was performed to detect the mRNA expressions of the significant DSPs in NASH. RESULTS By the criteria that a DSP has >1.2 or < 0.8 fold difference between NASH group and the control group and with P < 0.05 as the threshold, a total of 648 significant DSPs in NASH were identified, including 246 up-regulated and 402 down-regulated proteins. GO functional enrichment analysis showed that the DSPs were involved mainly in small molecule metabolism, organic acid metabolism, oxygen acid metabolism and other biological processes, and were enriched in KEGG pathways including the metabolic pathways, complement coagulation cascades, and ribosomes. Among the 25 DEPs with a fold difference >2.0 or < 0.5 (P < 0.05), 6 proteins showed consistent results between qPCR verification and proteomic analysis, including 5 down-regulated proteins: Jumonji protein (JARID2), Lebasillinlike protein (LCA5L), synaptophysin 1 (SYN1) and collagen α-1 (XIII) chain (COL13A1), FYVE, RhoGEF and PH domain protein 5 (FGD5), and 1 upregulated protein glutathione S-transferase Mu 4 (GSTM4). CONCLUSION We identified 648 DEPs inthe liver tissue of patients NASH using iTRAQ technology and bioinformatics methods, and among them JARID2, SYN1, COL13A1, FGD5, and GSTM4 may serve as the key target proteins of NASH.
Collapse
Affiliation(s)
- Y Zhu
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - S Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - C Yang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - W Xue
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Li
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Zhao
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - J Xu
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - W Huang
- Department of Infectious Diseases, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| |
Collapse
|
|
16
|
Li Z, Shen W, Wu G, Qin C, Zhang Y, Wang Y, Song G, Xiao C, Zhang X, Deng G, Wang R, Wang X. The role of SAMM50 in non-alcoholic fatty liver disease: from genetics to mechanisms. FEBS Open Bio 2021; 11:1893-1906. [PMID: 33728819 PMCID: PMC8255833 DOI: 10.1002/2211-5463.13146] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 02/02/2021] [Accepted: 02/09/2021] [Indexed: 12/17/2022] Open
Abstract
Non‐alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. SAMM50 encodes Sam50, a mitochondrial outer membrane protein involved in the removal of reactive oxygen species, mitochondrial morphology and regulation of mitophagy. Certain single nucleotide polymorphisms of SAMM50 have been reported to be correlated with NAFLD. However, the contribution of SAMM50 polymorphisms to the occurrence and severity of fatty liver in the Chinese Han cohort has rarely been reported. Here, we investigated the association between SAMM50 polymorphisms (rs738491 and rs2073082) and NAFLD in a Chinese Han cohort, as well as the mechanistic basis of this association. Clinical information and blood samples were collected from 380 NAFLD cases and 380 normal subjects for the detection of genotypes and biochemical parameters. Carriers of the rs738491 T allele or rs2073082 G allele of SAMM50 exhibit increased susceptibility to NAFLD [odds ratio (OR) = 1.39; 95% confidence interval (CI) = 1.14–1.71, P = 0.001; OR = 1.31; 95% CI = 1.05–1.62, P = 0.016, respectively] and are correlated with elevated serum triglyceride, alanine aminotransferase and aspartate aminotransferase levels. The presence of the T allele (TT + CT) of rs738491 (P < 0.01) or G allele (AG + GG) of rs2073082 (P = 0.03) is correlated with the severity of fatty liver in the NAFLD cohort. In vitro studies indicated that SAMM50 gene polymorphisms decrease its expression and SAMM50 deficiency results in increased lipid accumulation as a result of a decrease in fatty acid oxidation. Overexpression of SAMM50 enhances fatty acid oxidation and mitigates intracellular lipid accumulation. Our results confirm the association between the SAMM50 rs738491 and rs2073082 polymorphisms and the risk of fatty liver in a Chinese cohort. The underlying mechanism may be related to decreased fatty acid oxidation caused by SAMM50 deficiency.
Collapse
Affiliation(s)
- Zuyin Li
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Weixing Shen
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Gang Wu
- Department of General Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Henan, China
| | - Changjiang Qin
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, China
| | - Yijie Zhang
- Department of Medical Oncology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Yupeng Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Guohe Song
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Chao Xiao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xin Zhang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Guilong Deng
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Ruitao Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Xiaoliang Wang
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| |
Collapse
|
|
17
|
Ricciardello A, Tomaiuolo P, Persico AM. Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes. Am J Med Genet A 2021; 185:2211-2233. [PMID: 33949759 PMCID: PMC8251815 DOI: 10.1002/ajmg.a.62222] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 03/28/2021] [Accepted: 04/04/2021] [Indexed: 12/19/2022]
Abstract
Phelan‐McDermid syndrome (PMS, OMIM #606232), also known as chromosome 22q13 deletion syndrome, is a rare genetic disorder characterized by intellectual disability, hypotonia, delayed or absent speech, motor impairment, autism spectrum disorder, behavioral anomalies, and minor aspecific dysmorphic features. Haploinsufficiency of SHANK3, due to intragenic deletions or point mutations, is sufficient to cause many neurobehavioral features of PMS. However, several additional genes located within larger 22q13 deletions can contribute to the great interindividual variability observed in the PMS phenotype. This review summarizes the phenotypic contributions predicted for 213 genes distributed along the largest 22q13.2‐q13.33 terminal deletion detected in our sample of 63 PMS patients by array‐CGH analysis, spanning 9.08 Mb. Genes have been grouped into four categories: (1) genes causing human diseases with an autosomal dominant mechanism, or (2) with an autosomal recessive mechanism; (3) morphogenetically relevant genes, either involved in human diseases with additive co‐dominant, polygenic, and/or multifactorial mechanisms, or implicated in animal models but not yet documented in human pathology; (4) protein coding genes either functionally nonrelevant, with unknown function, or pathogenic through mechanisms other than haploinsufficiency; piRNAs, noncoding RNAs, miRNAs, novel transcripts and pseudogenes. Our aim is to understand genotype–phenotype correlations in PMS patients and to provide clinicians with a conceptual framework to promote evidence‐based genetic work‐ups, clinical assessments, and therapeutic interventions.
Collapse
Affiliation(s)
- Arianna Ricciardello
- Interdepartmental Program "Autism 0-90", "Gaetano Martino" University Hospital, University of Messina, Messina, Italy
| | - Pasquale Tomaiuolo
- Interdepartmental Program "Autism 0-90", "Gaetano Martino" University Hospital, University of Messina, Messina, Italy
| | - Antonio M Persico
- Interdepartmental Program "Autism 0-90", "Gaetano Martino" University Hospital, University of Messina, Messina, Italy
| |
Collapse
|
|
18
|
Wong WK, Chan WK. Nonalcoholic Fatty Liver Disease: A Global Perspective. Clin Ther 2021; 43:473-499. [PMID: 33526312 DOI: 10.1016/j.clinthera.2021.01.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 12/14/2022]
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing over the years and is now as high in Asia as in the Western world, so much so that it should no longer be considered a Western disease. In fact, China is expected to have the largest increase in the number of NAFLD cases in the coming years. The increase in prevalence of NAFLD in Asia lags behind that of the Western world; thus, there will be a lag in more severe liver disease in Asia despite a similar prevalence of the disease. NAFLD is more prevalent among patients with diabetes mellitus, which is also an important risk factor for more severe liver disease. Patients with diabetes mellitus thus represent an important target for screening for NAFLD and more severe liver disease. Although the PNPLA3 gene polymorphism is the most studied in NAFLD, it is increasingly clear that the cumulative effect of multiple genes likely predisposes to NAFLD and more severe liver disease in the different ethnic groups, and polygenic risk scores are emerging. Lean NAFLD has been largely reported in Asia but is increasingly recognized worldwide. Multiple risk factors have been identified for the disease that manifests in metabolically unhealthy normal weight individuals; however, it responds to lifestyle intervention, similar to the disease in obese individuals. Lastly, the newer term "metabolic dysfunction-associated fatty liver disease" provides a more accurate reflection of the disease, giving more focus to clinicians and researchers in tackling this increasingly common and challenging disease.
Collapse
Affiliation(s)
- Wei-Kei Wong
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
| |
Collapse
|
|
19
|
Samji NS, Snell PD, Singal AK, Satapathy SK. Racial Disparities in Diagnosis and Prognosis of Nonalcoholic Fatty Liver Disease. Clin Liver Dis (Hoboken) 2020; 16:66-72. [PMID: 32922753 PMCID: PMC7474141 DOI: 10.1002/cld.948] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 01/29/2020] [Accepted: 02/11/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Naga Swetha Samji
- Department of Internal MedicineTennova Cleveland HospitalClevelandTN
| | - Peter D. Snell
- Department of Internal MedicineUniversity of Tennessee Health Science CenterMemphisTN
| | - Ashwani K. Singal
- Department of Internal MedicineUniversity of South Dakota Sanford School of Medicine and Avera Transplant InstituteSioux FallsSD
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver DiseasesNorthwell HealthManhassetNY
| |
Collapse
|
|
20
|
Gender-specific differences in clinical and metabolic variables associated with NAFLD in a Mexican pediatric population. Ann Hepatol 2020; 18:693-700. [PMID: 31151875 DOI: 10.1016/j.aohep.2019.04.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 04/05/2019] [Accepted: 02/08/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in children and it is more prevalent in Hispanic males. The gender differences can be explained by body fat distribution, lifestyle, or sex hormone metabolism. We evaluated anthropometric and metabolic differences by gender in children with and without NAFLD. METHODS We included 194 participants (eutrophic, overweight, and individuals with obesity). The presence of NAFLD was determined using ultrasonography, and we evaluated the association between this disease with metabolic and anthropometric variables by gender. RESULTS The mean age was 10.64±2.54 years. The frequency of NAFLD in boys was 24.51% and in girls was 11.96% (OR=2.39; 95%CI=1.10-5.19; p=0.025). For girls, NAFLD was significantly associated with triglycerides (p=0.012), homeostatic model assessment of insulin resistance (HOMA-IR) (p=0.048), and the visceral adiposity index (VAI) (p=0.024). The variables related to NAFLD in a gender-specific manner were body mass index (BMI) (p=0.001), waist circumference (WC) (p<0.001), HDL cholesterol (p=0.021), alanine aminotransferase (ALT) (p<0.001), and aspartate aminotransferase (AST) (p=0.002). CONCLUSIONS In our study NAFLD is more frequent in boys, only ALT, and no other clinical or metabolic variables, were associated with NAFLD in these patients. HOMA-IR, VAI, triglyceride levels, and ALT were associated with NAFLD only in girls. The ALT cut-off points for the development of NAFLD in our study were 28.5U/L in females and 27.5U/L in males. Our findings showed that NAFLD should be intentionally screened in patients with obesity, particularly in boys.
Collapse
|
|
21
|
Validation of PNPLA3 polymorphisms as risk factor for NAFLD and liver fibrosis in an admixed population. Ann Hepatol 2020; 18:466-471. [PMID: 31054980 DOI: 10.1016/j.aohep.2018.10.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 09/12/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND AIM Studies have shown that two polymorphisms were associated with steatosis and progression of non-alcoholic fatty liver disease (NAFLD) in different populations: the Patatin-like Phospholipase Domain Containing 3 (PNPLA3) and Transmembrane 6 Superfamily Member 2 (TM6SF2). However, the frequency and significance of these polymorphisms in an admixed population, i.e., Brazilian, is unknown. Therefore, we aimed to evaluate them in healthy subjects in comparison to patients with NAFLD. MATERIAL AND METHODS This was a multicenter cross-sectional study in 248 patients with biopsy-proven NAFLD and in 134 healthy controls from two tertiary centers in Brazil. PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) polymorphisms were evaluated. RESULTS In controls, the frequencies of PNPLA3 CC and CG+GG were 49.25% and 50.74%, respectively; in NAFLD patients, this was 31.05% and 68.88% (p=0.0044, 95% CI 1.037-2.977). PNPLA3 GG subjects had an increased risk (3.29-fold) of having NAFLD when compared to CC subjects (p=0.0044, 95% CI 1.504-7.225). In patients with nonalcoholic steatohepatitis (NASH), PNPLA3 GG compared to CC was associated with higher AST levels [38.4±25.3 versus 36.7±40.1IU/L, p=0.0395)] and with the presence of liver fibrosis (≥F2 fibrosis, p=0.0272). TM6SF2 polymorphisms were not in Hardy-Weinberg equilibrium in our NAFLD group precluding further analysis. CONCLUSION We demonstrated for the first time that PNPLA3 CG+GG increase the risk of NAFLD among Brazilian subjects. Moreover, PNPLA3 GG was associated with liver enzyme elevation and fibrosis in NASH patients.
Collapse
|
|
22
|
Young KA, Palmer ND, Fingerlin TE, Langefeld CD, Norris JM, Wang N, Xiang AH, Guo X, Williams AH, Chen YDI, Taylor KD, Rotter JI, Raffel LJ, Goodarzi MO, Watanabe RM, Wagenknecht LE. Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium. Obesity (Silver Spring) 2019; 27:1331-1337. [PMID: 31219225 PMCID: PMC6656610 DOI: 10.1002/oby.22527] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 04/18/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry. METHODS Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis. RESULTS In the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. CONCLUSIONS PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
Collapse
Affiliation(s)
- Kendra A Young
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Nicholette D Palmer
- Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Tasha E Fingerlin
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
| | - Carl D Langefeld
- Department of Biostatistical Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Nan Wang
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Anny H Xiang
- Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, California, USA
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Adrienne H Williams
- Department of Biostatistical Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Yii-Der I Chen
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Leslie J Raffel
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Mark O Goodarzi
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Richard M Watanabe
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Lynne E Wagenknecht
- Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| |
Collapse
|
|
23
|
Namjou B, Lingren T, Huang Y, Parameswaran S, Cobb BL, Stanaway IB, Connolly JJ, Mentch FD, Benoit B, Niu X, Wei WQ, Carroll RJ, Pacheco JA, Harley ITW, Divanovic S, Carrell DS, Larson EB, Carey DJ, Verma S, Ritchie MD, Gharavi AG, Murphy S, Williams MS, Crosslin DR, Jarvik GP, Kullo IJ, Hakonarson H, Li R, Xanthakos SA, Harley JB. GWAS and enrichment analyses of non-alcoholic fatty liver disease identify new trait-associated genes and pathways across eMERGE Network. BMC Med 2019; 17:135. [PMID: 31311600 PMCID: PMC6636057 DOI: 10.1186/s12916-019-1364-z] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 06/11/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver illness with a genetically heterogeneous background that can be accompanied by considerable morbidity and attendant health care costs. The pathogenesis and progression of NAFLD is complex with many unanswered questions. We conducted genome-wide association studies (GWASs) using both adult and pediatric participants from the Electronic Medical Records and Genomics (eMERGE) Network to identify novel genetic contributors to this condition. METHODS First, a natural language processing (NLP) algorithm was developed, tested, and deployed at each site to identify 1106 NAFLD cases and 8571 controls and histological data from liver tissue in 235 available participants. These include 1242 pediatric participants (396 cases, 846 controls). The algorithm included billing codes, text queries, laboratory values, and medication records. Next, GWASs were performed on NAFLD cases and controls and case-only analyses using histologic scores and liver function tests adjusting for age, sex, site, ancestry, PC, and body mass index (BMI). RESULTS Consistent with previous results, a robust association was detected for the PNPLA3 gene cluster in participants with European ancestry. At the PNPLA3-SAMM50 region, three SNPs, rs738409, rs738408, and rs3747207, showed strongest association (best SNP rs738409 p = 1.70 × 10- 20). This effect was consistent in both pediatric (p = 9.92 × 10- 6) and adult (p = 9.73 × 10- 15) cohorts. Additionally, this variant was also associated with disease severity and NAFLD Activity Score (NAS) (p = 3.94 × 10- 8, beta = 0.85). PheWAS analysis link this locus to a spectrum of liver diseases beyond NAFLD with a novel negative correlation with gout (p = 1.09 × 10- 4). We also identified novel loci for NAFLD disease severity, including one novel locus for NAS score near IL17RA (rs5748926, p = 3.80 × 10- 8), and another near ZFP90-CDH1 for fibrosis (rs698718, p = 2.74 × 10- 11). Post-GWAS and gene-based analyses identified more than 300 genes that were used for functional and pathway enrichment analyses. CONCLUSIONS In summary, this study demonstrates clear confirmation of a previously described NAFLD risk locus and several novel associations. Further collaborative studies including an ethnically diverse population with well-characterized liver histologic features of NAFLD are needed to further validate the novel findings.
Collapse
Affiliation(s)
- Bahram Namjou
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.
- College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
| | - Todd Lingren
- College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Yongbo Huang
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
| | - Sreeja Parameswaran
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
| | - Beth L Cobb
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
| | - Ian B Stanaway
- Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, USA
| | - John J Connolly
- Center for Applied Genomics, Children's Hospital of Philadelphia, Bethesda, MD, USA
| | - Frank D Mentch
- Center for Applied Genomics, Children's Hospital of Philadelphia, Bethesda, MD, USA
| | - Barbara Benoit
- Research IS and Computing, Partners HealthCare, Harvard University, Somerville, MA, USA
| | - Xinnan Niu
- Departments of Biomedical Informatics and Medicine, Vanderbilt University, Nashville, TN, USA
| | - Wei-Qi Wei
- Departments of Biomedical Informatics and Medicine, Vanderbilt University, Nashville, TN, USA
| | - Robert J Carroll
- Departments of Biomedical Informatics and Medicine, Vanderbilt University, Nashville, TN, USA
| | - Jennifer A Pacheco
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Isaac T W Harley
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Senad Divanovic
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David S Carrell
- Kaiser Permanente Washington Health Research Institute (Formerly Group Health Cooperative-Seattle), Kaiser Permanente, Seattle, WA, USA
| | - Eric B Larson
- Kaiser Permanente Washington Health Research Institute (Formerly Group Health Cooperative-Seattle), Kaiser Permanente, Seattle, WA, USA
| | - David J Carey
- Department of Molecular and Functional Genomics, Geisinger, Danville, PA, USA
| | - Shefali Verma
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Marylyn D Ritchie
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Ali G Gharavi
- Department of Medicine, Columbia University, New York City, NY, USA
| | - Shawn Murphy
- Research Information Science and Computing, Partners HealthCare, Boston, MA, USA
| | - Marc S Williams
- Genomic Medicine Institute (M.S.W.), Geisinger, Danville, PA, USA
| | - David R Crosslin
- Department of Biomedical Informatics Medical Education, School of Medicine, University of Washington, Seattle, WA, USA
| | - Gail P Jarvik
- Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA, USA
| | - Iftikhar J Kullo
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Bethesda, MD, USA
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Rongling Li
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH, USA
| | - John B Harley
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA
- College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA
- U.S. Department of Veterans Affairs Medical Center, Cincinnati, OH, USA
| |
Collapse
|
|
24
|
Zhang X, Jiang H, Shen J, Zhang Y, Gu Y, Xiao J, Lian Y. Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 171:347-351. [PMID: 30616151 DOI: 10.1016/j.ecoenv.2018.12.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/06/2018] [Accepted: 12/18/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Current researches show that N,N-dimethylformamide (DMF) exposure is associated with liver injury, but it is debatable whether PNPLA3, GCKR, COL13A1 and TM6SF2 gene polymorphisms are associated with liver injury. Our objective was to examine the relationship among DMF exposure, PNPLA3 rs738409, GCKR rs780094, COL13A1 rs1227756, TM6SF2 rs58542926 and liver injury. METHODS The cohort consisted of 461 workers exposed above the DMF threshold limit value (TLV) and 211 exposed below the DMF TLV in China, who were followed for 5 years. The relationship between the measured dose of DMF and the relative risk (RR) of liver injury was also investigated by Poisson analysis. Logistic regression models were used to examine the association between measured dose of DMF, gene locus, and RR for liver injury. All workers had a annual physical examinations were conducted at certified physical examination centers in Taicang CDC, including liver serum transaminase assessment and abdominal ultrasound. Genomic DNA was extracted from peripheral blood leukocytes using a genomic DNA extraction kit. RESULTS The incidence of liver injury in the above DMF TLV group was significantly higher than in the below DMF TLV group. GCKR rs780094 was associated with liver injury. The interaction among the GCKR rs780094, DMF exposure and liver injury showed no significant association. CONCLUSIONS Our data indicated that in DMF exposure, GCKR rs780094 may contribute to the risk of liver injury. Our results suggest that GCKR rs780094 is a useful genetic marker to help identify liver injury.
Collapse
Affiliation(s)
- Xiaoyue Zhang
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Haiyue Jiang
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Jiayang Shen
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Yu Zhang
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Yiyang Gu
- Jiaxing Maternal and Child Health Hospital, Zhejiang, China
| | - Jing Xiao
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China.
| | - Yulong Lian
- Division of Toxicology and Environmental Health, College of Public Health, Nantong University, Nantong, Jiangsu, China.
| |
Collapse
|
|
25
|
Vespasiani-Gentilucci U, Gallo P, Dell’Unto C, Volpentesta M, Antonelli-Incalzi R, Picardi A. Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables. World J Gastroenterol 2018; 24:4835-4845. [PMID: 30487694 PMCID: PMC6250919 DOI: 10.3748/wjg.v24.i43.4835] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 10/22/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma (HCC). Therefore, risk stratification emerges as fundamental in order to optimize human and economic resources, and genetics displays intrinsic characteristics suitable to fulfill this task. According to the available data, heritability estimates for hepatic fat content range from 20% to 70%, and an almost 80% of shared heritability has been found between hepatic fat content and fibrosis. The rs738409 single nucleotide polymorphism (SNP) in patatin-like phospholipase domain-containing protein 3 gene and the rs58542926 SNP in transmembrane 6 superfamily member 2 gene have been robustly associated with NAFLD and with its progression, but promising results have been obtained with many other SNPs. Moreover, there has been proof of the additive role of the different SNPs in determining liver damage, and there have been preliminary experiences in which risk scores created through a few genetic variants, alone or in combination with clinical variables, were associated with a strongly potentiated risk of NAFLD, non-alcoholic steatohepatitis (NASH), NASH fibrosis or NAFLD-HCC. However, to date, clinical translation of genetics in the field of NAFLD has been poor or absent. Fortunately, the research we have done seems to have placed us on the right path: We should rely on longitudinal rather than on cross-sectional studies; we should focus on relevant outcomes rather than on simple liver fat accumulation; and we should put together the genetic and clinical information. The hope is that combined genetic/clinical scores, derived from longitudinal studies and built on a few strong genetic variants and relevant clinical variables, will reach a significant predictive power, such as to have clinical utility for risk stratification at the single patient level and even to esteem the impact of intervention on the risk of disease-related outcomes. Well-structured future studies would demonstrate if this vision can become a reality.
Collapse
Affiliation(s)
| | - Paolo Gallo
- Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
| | - Chiara Dell’Unto
- Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
| | - Mara Volpentesta
- Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
| | - Raffaele Antonelli-Incalzi
- Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
| | - Antonio Picardi
- Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
| |
Collapse
|
|
26
|
Baker PR, Friedman JE. Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease. J Clin Invest 2018; 128:3692-3703. [PMID: 30168806 DOI: 10.1172/jci120846] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic in obese children and adults, and the onset might have fetal origins. A growing body of evidence supports the role of developmental programming, whereby the maternal environment affects fetal and infant development, altering the risk profile for disease later in life. Human and nonhuman primate studies of maternal obesity demonstrate that risk factors for pediatric obesity and NAFLD begin in utero. The pathologic mechanisms for NAFLD are multifactorial but have centered on altered mitochondrial function/dysfunction that might precede insulin resistance. Compared with the adult liver, the fetal liver has fewer mitochondria, low activity of the fatty acid metabolic enzyme carnitine palmitoyl-CoA transferase-1, and little or no gluconeogenesis. Exposure to excess maternal fuels during fetal life uniquely alters hepatic fatty acid oxidation, tricarboxylic acid cycle activity, de novo lipogenesis, and mitochondrial health. These events promote increased oxidative stress and excess triglyceride storage, and, together with altered immune function and epigenetic changes, they prime the fetal liver for NAFLD and might drive the risk for nonalcoholic steatohepatitis in the next generation.
Collapse
Affiliation(s)
- Peter R Baker
- Section of Clinical Genetics and Metabolism, Department of Pediatrics
| | - Jacob E Friedman
- Section of Neonatology, Department of Pediatrics.,Department of Biochemistry and Molecular Genetics, and.,Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| |
Collapse
|