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Bui TH, Kaga H, Kakehi S, Someya Y, Tabata H, Yoshizawa Y, Naito H, Tajima T, Ito N, Kadowaki S, Nishida Y, Kawamori R, Watada H, Tamura Y. Factors Associated With Type 2 Diabetes in Older Japanese With Similar Genetic Risk Scores: The Bunkyo Health Study. J Endocr Soc 2025; 9:bvaf019. [PMID: 39902403 PMCID: PMC11788508 DOI: 10.1210/jendso/bvaf019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Indexed: 02/05/2025] Open
Abstract
Context Genome-wide association studies have identified numerous single-nucleotide variations (SNVs, formerly single-nucleotide polymorphisms) linked to type 2 diabetes (T2D), thus improving the accuracy of genetic risk scores (GRS) in predicting T2D. Objective This study aimed to investigate the association between the novel GRS and the prevalence of T2D and clarify the characteristics that differentiate individuals with and without T2D with similar genetic risk. Methods This cross-sectional study analyzed 1610 Japanese individuals aged 65 to 84 years. GRS were calculated using 110 SNVs associated with T2D in Japanese, and GRS classified individuals as having low, average, or high risk for T2D. The characteristics of participants with or without diabetes were compared by sex at each risk level. Results The prevalences of T2D were 7.8%, 14.7%, and 16.7% at low-, average-, and high-risk levels, respectively. The odds ratios at the high- and average-risk levels were significantly higher than those at the low-risk level, even after adjusting for confounding factors. The diabetes group had a higher visceral fat area (VFA) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) value, but a lower insulinogenic index, than the nondiabetes group across all risk levels. In the nondiabetes group, the II decreased significantly as GRS increased, but the HOMA-IR and Matsuda index values showed no association. In men with diabetes, VFA tended to decrease with higher GRS. Conclusion A higher GRS was significantly associated with increased T2D prevalence in older Japanese individuals. Our data demonstrated that the contribution of VFA to the development of diabetes varies with genetic risk.
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Affiliation(s)
- Thu Hien Bui
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Saori Kakehi
- Sports Medicine and Sportology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Yuki Someya
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Hiroki Tabata
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Juntendo Advanced Research Institute for Health Science, Tokyo 113-8421, Japan
| | - Yasuyo Yoshizawa
- Juntendo Advanced Research Institute for Health Science, Tokyo 113-8421, Japan
- Faculty of International Liberal Arts, Juntendo University, Tokyo 113-8421, Japan
| | - Hitoshi Naito
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Tsubasa Tajima
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Naoaki Ito
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Yuya Nishida
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Ryuzo Kawamori
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sports Medicine and Sportology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sports Medicine and Sportology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sports Medicine and Sportology, Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Sportology Center, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan
- Juntendo Advanced Research Institute for Health Science, Tokyo 113-8421, Japan
- Faculty of International Liberal Arts, Juntendo University, Tokyo 113-8421, Japan
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Jia W, Chan JC, Wong TY, Fisher EB. Diabetes in China: epidemiology, pathophysiology and multi-omics. Nat Metab 2025; 7:16-34. [PMID: 39809974 DOI: 10.1038/s42255-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.
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Affiliation(s)
- Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute for Proactive Healthcare, Shanghai Jiao Tong University, Shanghai, China.
| | - Juliana Cn Chan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences and Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Tien Y Wong
- Tsinghua Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Singapore National Eye Center, SingHealth, Singapore, Singapore
| | - Edwin B Fisher
- Peers for Progress, Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Nagarajah S, Alkandari A, Marques-Vidal P. Genetic risk scores: are they important for diabetes management? results from multiple cross-sectional studies. Diabetol Metab Syndr 2023; 15:227. [PMID: 37950303 PMCID: PMC10636836 DOI: 10.1186/s13098-023-01204-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Several genetic risk scores (GRS) for type 2 diabetes (T2DM) have been published, but not replicated. We aimed to 1) replicate previous findings on the association between GRS on prevalence of T2DM and 2) assess the association between GRS and T2DM management in a sample of community-dwelling people from Switzerland. METHODS Four waves from a prospective study conducted in Lausanne. Seven GRS related to T2DM were selected, and compared between participants with and without T2DM, and between controlled and uncontrolled participants treated for T2DM. RESULTS Data from 5426, 4017, 2873 and 2170 participants from the baseline, first, second and third follow-ups, respectively, was used. In all study periods, participants with T2DM scored higher than participants without T2DM in six out of seven GRS. Data from 367, 437, 285 and 207 participants with T2DM was used. In all study periods, approximately half of participants treated for T2DM did not achieve adequate fasting blood glucose or HbA1c levels, and no difference between controlled and uncontrolled participants was found for all seven GRS. Power analyses showed that most GRS needed a sample size above 1000 to consider the difference between controlled and uncontrolled participants as statistically significant at p = 0.05. CONCLUSION In this study, we confirmed the association between most published GRS and diabetes. Conversely, no consistent association between GRS and diabetes control was found. Use of GRS to manage patients with T2DM in clinical practice is not justified.
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Affiliation(s)
- Sureka Nagarajah
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Office BH10-642, 46 Rue du Bugnon, 1011, Lausanne, Switzerland
| | | | - Pedro Marques-Vidal
- Department of Medicine, Internal Medicine, Lausanne University Hospital and University of Lausanne, Office BH10-642, 46 Rue du Bugnon, 1011, Lausanne, Switzerland.
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Yu L, Liu W, Zhou M, Yang S, Tan Q, Fan L, Wang B, Chen W. Long-term effect of styrene and ethylbenzene exposure on fasting plasma glucose: A gene-environment interaction study. JOURNAL OF HAZARDOUS MATERIALS 2023; 452:131346. [PMID: 37030230 DOI: 10.1016/j.jhazmat.2023.131346] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/16/2023] [Accepted: 04/01/2023] [Indexed: 05/03/2023]
Abstract
Styrene and ethylbenzene (S/EB) are hazardous pollutants that have attracted worldwide concern. In this prospective cohort study, S/EB exposure biomarker (the sum of mandelic acid and phenylglyoxylic acid [MA+PGA]) and fasting plasma glucose (FPG) were repeatedly measured three times. The polygenic risk score (PRS) based on 137 single nucleotide polymorphisms for type 2 diabetes mellitus (T2DM) was calculated to evaluate cumulative genetic effect. In repeated-measures cross-sectional analyses, MA+PGA (β [95% confidence interval]: 0.106 [0.022, 0.189]) and PRS (0.111 [0.047, 0.176]) were significantly related to FPG. For long-term effect assessment, participants with sustained high MA+PGA or with high PRS had 0.021 (95% CI: -0.398, 0.441) or 0.465 (0.064, 0.866) mmol/L increase in FPG, respectively, over 3 years follow-up, and had 0.256 (0.017, 0.494) or 0.265 (0.004, 0.527) mmol/L increase in FPG, respectively, over 6 years follow-up. We further detected a significant interaction effect between MA+PGA and PRS on FPG change, compared with participants with sustained low MA+PGA and low PRS, those with sustained high MA+PGA and high PRS had 0.778 (0.319, 1.258) mmol/L increase in FPG (P for interaction=0.028) over 6 years follow-up. Our study provides the first evidence that long-term exposure to S/EB potentially increases FPG, which might be aggravated by genetic susceptibility.
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Affiliation(s)
- Linling Yu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Wei Liu
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Min Zhou
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shijie Yang
- Hubei Provincial Center for Disease Control and Prevention, Wuhan, China
| | - Qiyou Tan
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Lieyang Fan
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Bin Wang
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
| | - Weihong Chen
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
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Tan Q, Yang S, Wang B, Wang M, Yu L, Liang R, Liu W, Song J, Guo Y, Zhou M, Chen W. Gene-environment interaction in long-term effects of polychlorinated biphenyls exposure on glucose homeostasis and type 2 diabetes: The modifying effects of genetic risk and lifestyle. JOURNAL OF HAZARDOUS MATERIALS 2023; 457:131757. [PMID: 37276697 DOI: 10.1016/j.jhazmat.2023.131757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/26/2023] [Accepted: 05/30/2023] [Indexed: 06/07/2023]
Abstract
The longitudinal relationships of polychlorinated biphenyls (PCBs) exposure with glucose homeostasis and type 2 diabetes (T2D) risk among Chinese population have not been assessed, and interactions of PCB exposure with genetic susceptibility and lifestyle are unclear. In this prospective cohort study, fasting plasma glucose (FPG) and insulin (FPI) and seven serum indicator-PCBs were measured for each participant. We constructed polygenic risk score (PRS) of T2D and healthy lifestyle score. Each 1-unit increment of ln-transformed PCB-118 was related with a 0.141 mmol/L, 11.410 pmol/L, 0.661, and 74.5% increase in FPG, FPI, homeostasis model assessment of insulin resistance, and incident T2D risk over 6 years, respectively. Each 1-unit increment in T2D-PRS was related with a 0.169 mmol/L elevation of FPG and 65.5% elevation of incident T2D risk during 6 years. Compared with participants who had low T2D-PRS and low PCB-118, participants with high T2D-PRS and high PCB-118 showed a significant increase in FPG (0.162 mmol/L; P for interaction <0.001) and incident T2D risk [hazard ratio (HR)= 2.222]. Participants with low PCB-118, low PRS, and healthy lifestyle had the lowest incident T2D risk (HR=0.232). Our findings highlighted the significance of reducing PCB exposure and improvement in lifestyle for T2D prevention and management, especially for individuals with higher genetic risk of T2D.
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Affiliation(s)
- Qiyou Tan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Shijie Yang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, Hubei, China
| | - Bin Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Mengyi Wang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Linling Yu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ruyi Liang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Wei Liu
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jiahao Song
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Yanjun Guo
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Min Zhou
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Insulin resistance in children. Curr Opin Pediatr 2022; 34:400-406. [PMID: 35796641 DOI: 10.1097/mop.0000000000001151] [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] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Insulin resistance (IR) is a clinical condition due to the decline in the efficiency of insulin promoting glucose uptake and utilization. The aim of this review is to provide an overview of the current knowledge on IR in children, focusing on its physiopathology, the most appropriate methods of measurement of IR, the assessment of risk factors, the effects of IR in children, and finally giving indications on screening and treatment. RECENT FINDINGS IR has evolved more and more to be a global public health problem associated with several chronic metabolic diseases. SUMMARY Detecting a correct measurement method and specific risk predictors, in order to reduce the incidence of IR, represents a challenging goal.
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Fry JL, Munson BD, Thompson KL, Fry CS, Paddon-Jones D, Arentson-Lantz EJ. The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults. Sci Rep 2022; 12:6897. [PMID: 35477971 PMCID: PMC9046412 DOI: 10.1038/s41598-022-10683-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 04/11/2022] [Indexed: 12/19/2022] Open
Abstract
Inpatient populations are at increased risk of hyperglycemia due to factors such as medications, physical inactivity and underlying illness, which increases morbidity and mortality. Unfortunately, clinicians have limited tools available to prospectively identify those at greatest risk. We evaluated the ability of 10 common genetic variants associated with development of type 2 diabetes to predict impaired glucose metabolism. Our research model was a simulated inpatient hospital stay (7 day bed rest protocol, standardized diet, and physical inactivity) in a cohort of healthy older adults (n = 31, 65 ± 8 years) with baseline fasting blood glucose < 100 mg/dL. Participants completed a standard 75 g oral glucose tolerance test (OGTT) at baseline and post-bed rest. Bed rest increased 2-h OGTT blood glucose and insulin independent of genetic variant. In multiple regression modeling, the transcription factor 7-like 2 (TCF7L2) rs7903146 T allele predicted increases in 2-h OGTT blood glucose (p = 0.039). We showed that the TCF7L2 rs7903146 T allele confers risk for loss of glucose tolerance in nondiabetic older adults following 7 days of bed rest.
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Affiliation(s)
- Jean L Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA.
| | - Brooke D Munson
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA
| | - Katherine L Thompson
- Dr. Bing Zhang Department of Statistics, University of Kentucky, Lexington, KY, 40536-0082, USA
| | - Christopher S Fry
- Department of Athletic Training and Clinical Nutrition, University of Kentucky, Lexington, KY, 40536-0200, USA
| | - Douglas Paddon-Jones
- Department of Nutrition & Metabolism, Center for Rehabilitation, Physical Activity and Nutrition, University of Texas Medical Branch, Galveston, TX, 77555-1028, USA
| | - Emily J Arentson-Lantz
- Department of Nutrition & Metabolism, Center for Rehabilitation, Physical Activity and Nutrition, University of Texas Medical Branch, Galveston, TX, 77555-1028, USA
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Balkhiyarova Z, Luciano R, Kaakinen M, Ulrich A, Shmeliov A, Bianchi M, Chioma L, Dallapiccola B, Prokopenko I, Manco M. Relationship between glucose homeostasis and obesity in early life-a study of Italian children and adolescents. Hum Mol Genet 2022; 31:816-826. [PMID: 34590674 PMCID: PMC8895752 DOI: 10.1093/hmg/ddab287] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 01/09/2023] Open
Abstract
Epidemic obesity is the most important risk factor for prediabetes and type 2 diabetes (T2D) in youth as it is in adults. Obesity shares pathophysiological mechanisms with T2D and is likely to share part of the genetic background. We aimed to test if weighted genetic risk scores (GRSs) for T2D, fasting glucose (FG) and fasting insulin (FI) predict glycaemic traits and if there is a causal relationship between obesity and impaired glucose metabolism in children and adolescents. Genotyping of 42 SNPs established by genome-wide association studies for T2D, FG and FI was performed in 1660 Italian youths aged between 2 and 19 years. We defined GRS for T2D, FG and FI and tested their effects on glycaemic traits, including FG, FI, indices of insulin resistance/beta cell function and body mass index (BMI). We evaluated causal relationships between obesity and FG/FI using one-sample Mendelian randomization analyses in both directions. GRS-FG was associated with FG (beta = 0.075 mmol/l, SE = 0.011, P = 1.58 × 10-11) and beta cell function (beta = -0.041, SE = 0.0090 P = 5.13 × 10-6). GRS-T2D also demonstrated an association with beta cell function (beta = -0.020, SE = 0.021 P = 0.030). We detected a causal effect of increased BMI on levels of FI in Italian youths (beta = 0.31 ln (pmol/l), 95%CI [0.078, 0.54], P = 0.0085), while there was no effect of FG/FI levels on BMI. Our results demonstrate that the glycaemic and T2D risk genetic variants contribute to higher FG and FI levels and decreased beta cell function in children and adolescents. The causal effects of adiposity on increased insulin resistance are detectable from childhood age.
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Affiliation(s)
- Zhanna Balkhiyarova
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre Russian Academy of Sciences, Ufa 450008, Russian Federation
- Department of Endocrinology, Bashkir State Medical University, Ufa 450054, Russian Federation
| | - Rosa Luciano
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
- Department of Laboratory Medicine, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | - Marika Kaakinen
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
| | - Anna Ulrich
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London SW7 2AZ, UK
| | - Aleksey Shmeliov
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
| | - Marzia Bianchi
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
| | - Laura Chioma
- Unit of Endocrinology, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
| | - Bruno Dallapiccola
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome 00146, Italy
| | - Inga Prokopenko
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre Russian Academy of Sciences, Ufa 450008, Russian Federation
- UMR 8199—EGID, Institut Pasteur de Lille, CNRS, University of Lille, Lille 59000, France
| | - Melania Manco
- Research Area for Multifactorial Disease, Bambino Gesù Children’s Hospital, IRCCS, Rome 00146, Italy
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Xu J, Jin L, Chen J, Zhang R, Zhang H, Li Y, Peng D, Gu Y, Wheeler MB, Hu C. Common variants in genes involved in islet amyloid polypeptide (IAPP) processing and the degradation pathway are associated with T2DM risk: A Chinese population study. Diabetes Res Clin Pract 2022; 185:109235. [PMID: 35131375 DOI: 10.1016/j.diabres.2022.109235] [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: 03/26/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 11/28/2022]
Abstract
AIM To explore the genetic effects of SLC30A8, IAPP, PCSK1, PCSK2, CPE, PAM and IDE, key genes involved in IAPP processing and degradation pathway on T2DM risk and metabolic traits in Chinese population. METHODS Common variants were genotyped in 10936 Chinese subjects by Asian Screening Array and Multi-Ethnic Global Array. Associations of SNPs with occurrences of T2DM and related traits were evaluated through logistic and multiple linear regression. Genetic risk score (GRS) model was constructed based on 6 T2DM-variants, and its relationship with T2DM and related traits was assessed. RESULTS SLC30A8-rs13266634, PCSK1-rs155980, PCSK2-rs6136035, CPE-rs532192464, PAM-rs7716941, and IDE-rs117929184 were the top SNPs significantly associated with T2DM after adjusting for age, sex, and BMI, associated with blood glucose level, insulin secretion, and insulin sensitivity (all FDR p < 0.05). GRS calculated based on the above SNPs was remarkably correlated with T2DM, blood glucose, and insulin secretion. Furthermore, there was a significant interaction between SLC30A8 and IAPP in patients with T2DM (P = 0.0083). CONCLUSION Our study showed that common variants in genes involved in IAPP processing and the degradation pathway were associated with T2DM in Chinese population. Subjects with high GRS exhibited poorer glucose metabolism and insulin secretion.
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Affiliation(s)
- Jie Xu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Department of Physiology, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S4L5, Canada
| | - Li Jin
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Jie Chen
- Department of Clinical Laboratory, Shanghai Xuhui Central Hospital, Shanghai 200020, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Hong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yangyang Li
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Danfeng Peng
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China
| | - Yunjuan Gu
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu 226001, China.
| | - Michael B Wheeler
- Department of Physiology, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S4L5, Canada.
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China.
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10
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Rattanatham R, Settasatian N, Komanasin N, Kukongviriyapan U, Sawanyawisuth K, Intharaphet P, Senthong V, Settasatian C. Association of Combined TCF7L2 and KCNQ1 Gene Polymorphisms with Diabetic Micro- and Macrovascular Complications in Type 2 Diabetes Mellitus. Diabetes Metab J 2021; 45:578-593. [PMID: 33752320 PMCID: PMC8369220 DOI: 10.4093/dmj.2020.0101] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 09/27/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Vascular complications are the major morbid consequences of type 2 diabetes mellitus (T2DM). The transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and inwardly-rectifying potassium channel, subfamily J, member 11 gene (KCNJ11) are common T2DM susceptibility genes in various populations. However, the associations between polymorphisms in these genes and diabetic complications are controversial. This study aimed to investigate the effects of combined gene-polymorphisms within TCF7L2, KCNQ1, and KCNJ11 on vascular complications in Thai subjects with T2DM. METHODS We conducted a case-control study comprising 960 T2DM patients and 740 non-diabetes controls. Single nucleotide polymorphisms in TCF7L2, KCNQ1, and KCNJ11 were genotyped and evaluated for their association with diabetic vascular complications. RESULTS The gene variants TCF7L2 rs290487-T, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-C were associated with increased risk of T2DM. TCF7L2 rs7903146-C, TCF7L2 rs290487-C, KCNQ1 rs2237892-T, and KCNQ1 rs2237897-T revealed an association with hypertension. The specific combination of risk-alleles that have effects on T2DM and hypertension, TCF7L2 rs7903146-C, KCNQ1 rs2237892-C, and KCNQ1 rs2237897-T, as genetic risk score (GRS), pronounced significant association with coronary artery disease (CAD), cumulative nephropathy and CAD, and cumulative microvascular and macrovascular complications (respective odds ratios [ORs] with 95% confidence interval [95% CI], comparing between GRS 2-3 and GRS 5-6, were 7.31 [2.03 to 26.35], 3.92 [1.75 to 8.76], and 2.33 [1.13 to 4.79]). CONCLUSION This study demonstrated, for the first time, the effect conferred by specific combined genetic variants in TCF7L2 and KCNQ1 on diabetic vascular complications, predominantly with nephropathy and CAD. Such a specific pattern of gene variant combination may implicate in the progression of T2DM and life-threatening vascular complications.
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Affiliation(s)
- Rujikorn Rattanatham
- Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand
| | - Nongnuch Settasatian
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- School of Medical Technology, Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, Thailand
| | - Nantarat Komanasin
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- School of Medical Technology, Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, Thailand
| | - Upa Kukongviriyapan
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | | | - Phongsak Intharaphet
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- Queen Sirikit Heart Center of the Northeast, Khon Kaen University, Khon Kaen, Thailand
| | - Vichai Senthong
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Queen Sirikit Heart Center of the Northeast, Khon Kaen University, Khon Kaen, Thailand
| | - Chatri Settasatian
- Cardiovascular Research Group, Khon Kaen University, Khon Kaen, Thailand
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Corresponding author: Chatri Settasatian https://orcid.org/0000-0002-2555-8700 Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mittraphap Rd, Muang Khon Kaen District, Khon Kaen 40002, Thailand E-mail:
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11
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Miranda-Lora AL, Vilchis-Gil J, Juárez-Comboni DB, Cruz M, Klünder-Klünder M. A Genetic Risk Score Improves the Prediction of Type 2 Diabetes Mellitus in Mexican Youths but Has Lower Predictive Utility Compared With Non-Genetic Factors. Front Endocrinol (Lausanne) 2021; 12:647864. [PMID: 33776940 PMCID: PMC7994893 DOI: 10.3389/fendo.2021.647864] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 02/18/2021] [Indexed: 01/07/2023] Open
Abstract
Background Type 2 diabetes (T2D) is a multifactorial disease caused by a complex interplay between environmental risk factors and genetic predisposition. To date, a total of 10 single nucleotide polymorphism (SNPs) have been associated with pediatric-onset T2D in Mexicans, with a small individual effect size. A genetic risk score (GRS) that combines these SNPs could serve as a predictor of the risk for pediatric-onset T2D. Objective To assess the clinical utility of a GRS that combines 10 SNPs to improve risk prediction of pediatric-onset T2D in Mexicans. Methods This case-control study included 97 individuals with pediatric-onset T2D and 84 controls below 18 years old without T2D. Information regarding family history of T2D, demographics, perinatal risk factors, anthropometric measurements, biochemical variables, lifestyle, and fitness scores were then obtained. Moreover, 10 single nucleotide polymorphisms (SNPs) previously associated with pediatric-onset T2D in Mexicans were genotyped. The GRS was calculated by summing the 10 risk alleles. Pediatric-onset T2D risk variance was assessed using multivariable logistic regression models and the area under the receiver operating characteristic curve (AUC). Results The body mass index Z-score (Z-BMI) [odds ratio (OR) = 1.7; p = 0.009] and maternal history of T2D (OR = 7.1; p < 0.001) were found to be independently associated with pediatric-onset T2D. No association with other clinical risk factors was observed. The GRS also showed a significant association with pediatric-onset T2D (OR = 1.3 per risk allele; p = 0.006). The GRS, clinical risk factors, and GRS plus clinical risk factors had an AUC of 0.66 (95% CI 0.56-0.75), 0.72 (95% CI 0.62-0.81), and 0.78 (95% CI 0.70-0.87), respectively (p < 0.01). Conclusion The GRS based on 10 SNPs was associated with pediatric-onset T2D in Mexicans and improved its prediction with modest significance. However, clinical factors, such the Z-BMI and family history of T2D, continue to have the highest predictive utility in this population.
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Affiliation(s)
- América Liliana Miranda-Lora
- Epidemiological Research Unit in Endocrinology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | - Jenny Vilchis-Gil
- Epidemiological Research Unit in Endocrinology and Nutrition, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | | | - Miguel Cruz
- Medical Research Unit in Biochemistry, Hospital de Especialidades Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Miguel Klünder-Klünder
- Research Subdirectorate, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
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12
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Abstract
Background The prevalence and incidence of type 2 diabetes (T2D), representing >90% of all cases of diabetes, are increasing rapidly worldwide. Identification of individuals at high risk of developing diabetes is of great importance as early interventions might delay or even prevent full-blown disease. T2D is a complex disease caused by multiple genetic loci in interplay with lifestyle and environmental factors. Recently over 400 distinct association signals were published; these explain 18% of the risk of T2D. Scope of review In this review there is a major focus on risk factors and genetic and non-genetic biomarkers for the risk of T2D identified especially in large prospective population-based studies, and studies testing causality of the biomarkers for T2D in Mendelian randomization studies. Another focus is on understanding genome-phenome interplay in the classification of individuals with T2D into subgroups. Major conclusions Several recent large population-based studies and their meta-analyses have identified multiple potential genetic and non-genetic biomarkers for the risk of T2D. Combination of genetic variants and physiologically characterized pathways improves the classification of individuals with T2D into subgroups, and is also paving the way to a precision medicine approach, in T2D.
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Affiliation(s)
- Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210, Kuopio, Finland.
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13
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Viinikainen J, Bryson A, Böckerman P, Elovainio M, Hutri-Kähönen N, Juonala M, Lehtimäki T, Pahkala K, Rovio S, Pulkki-Råback L, Raitakari O, Pehkonen J. Do childhood infections affect labour market outcomes in adulthood and, if so, how? ECONOMICS AND HUMAN BIOLOGY 2020; 37:100857. [PMID: 32078928 DOI: 10.1016/j.ehb.2020.100857] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 06/10/2023]
Abstract
A burgeoning body of literature suggests that poor childhood health leads to adverse health outcomes, lower educational attainment and weaker labour market outcomes in adulthood. We focus on an important but under-researched topic, which is the role played by infection-related hospitalization (IRH) in childhood and its links to labour market outcomes later in life. The participants aged 24-30 years in 2001 N = 1706 were drawn from the Young Finns Study, which includes comprehensive registry data on IRHs in childhood at ages 0-18 years. These data are linked to longitudinal registry information on labour market outcomes (2001-2012) and parental background (1980). The estimations were performed using ordinary least squares (OLS). The results showed that having an additional IRH is associated with lower log earnings (b = -0.110, 95 % confidence interval (CI): -0.193; -0.026), fewer years of being employed (b = -0.018, 95 % CI: -0.031; -0.005), a higher probability of receiving any social income transfers (b = 0.012, 95 % CI: -0.002; 0.026) and larger social income transfers, conditional on receiving any (b = 0.085, 95 % CI: 0.025; 0.145). IRHs are negatively linked to human capital accumulation, which explains a considerable part of the observed associations between IRHs and labour market outcomes. We did not find support for the hypothesis that adult health mediates the link.
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Affiliation(s)
- Jutta Viinikainen
- Jyväskylä University School of Business and Economics, P.O.Box 35, FI-40014, Jyväskylä, Finland.
| | - Alex Bryson
- University College London, NIESR, London, United Kingdom and IZA, Bonn, Germany.
| | - Petri Böckerman
- Jyväskylä University School of Business and Economics, University of Jyväskylä, Jyväskylä, Finland; Labour Institute for Economic Research, Helsinki, Finland and IZA, Bonn, Germany.
| | - Marko Elovainio
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland and National Institute for Health and Welfare, Helsinki, Finland.
| | - Nina Hutri-Kähönen
- Department of Paediatrics, Tampere University Hospital, Tampere, Finland and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland, Division of Medicine, Turku University Hospital, Turku, Finland, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center, Tampere University, Tampere, Finland.
| | - Katja Pahkala
- Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, Sports & Exercise Medicine Unit, Department of Physical Activity and Health, Paavo Nurmi Centre, Turku, Finland.
| | - Suvi Rovio
- Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
| | - Laura Pulkki-Råback
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki,Finland.
| | - Olli Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
| | - Jaakko Pehkonen
- Jyväskylä University School of Business and Economics, University of Jyväskylä, Jyväskylä, Finland.
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14
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Kong X, Xing X, Zhang X, Hong J, Yang W. Early-onset type 2 diabetes is associated with genetic variants of β-cell function in the Chinese Han population. Diabetes Metab Res Rev 2020; 36:e3214. [PMID: 31465628 DOI: 10.1002/dmrr.3214] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/24/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023]
Abstract
AIMS To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations. MATERIALS AND METHODS For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted β-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to β-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively. RESULTS From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10-7 ; 6.07 × 10-8 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10-2 , 1.78 × 10-2 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: β (SE) = -0.0033(0.0016), P = 3.74 × 10-2 ; wB-GRS: -0.0076(0.0028), 7.45 × 10-3 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10-5 ; wB-GRS: -0.0722(0.0176), 4.21 × 10-5 ]. CONCLUSION Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to β-cell function, suggesting the β-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.
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Affiliation(s)
- Xiaomu Kong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoyan Xing
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Xuelian Zhang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Jing Hong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
| | - Wenying Yang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China
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15
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Eriksen R, Gibson R, Aresu M, Heard A, Chan Q, Evangelou E, Gao H, Elliott P, Frost G. Gene-diet quality interactions on haemoglobin A1c and type 2 diabetes risk: The Airwave Health Monitoring Study. Endocrinol Diabetes Metab 2019; 2:e00074. [PMID: 31592155 PMCID: PMC6775444 DOI: 10.1002/edm2.74] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 04/28/2019] [Accepted: 05/04/2019] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Type 2 diabetes (T2D) is multifactorial involving lifestyle, environmental and genetic risk factors. This study aims to investigate the impact of genetic interactions with alcohol and diet quality on glycated haemoglobin A1c (HbA1c) independent of obesity, in a British population. METHODS Cross-sectional study of 14 089 white British participants from Airwave Health Monitoring Study and a subsample of 3733 participants with dietary data. A T2D genetic risk score (GRS) was constructed, and its interactions with diet on HbA1c were assessed. RESULTS GRS was associated with a higher HbA1c% (β = 0.03, P < 0.0001) and a higher risk of prediabetes (OR = 1.09, P < 0.0001) and T2D (OR = 1.14, P = 0.006). The genetic effect on HbA1c% was significantly higher in obese participants (β = 1.88, P interaction = 0.03). A high intake of wholegrain attenuated the effect on HbA1c% in high-risk individuals P interaction = 0.04. CONCLUSION The genetic effect on HbA1c was almost doubled in obese individuals, compared with those with a healthy weight, and independent of weight, there was a modest offset on HbA1c in high-genetic-risk individuals consuming a diet high in wholegrain. This supports the importance of a healthy diet high in wholegrains and along with maintaining a healthy weight in controlling HbA1c among high-genetic-risk groups.
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Affiliation(s)
- Rebeca Eriksen
- Nutrition and Dietetic Research Group, Faculty of MedicineImperial CollegeLondonUK
| | - Rachel Gibson
- Nutrition and Dietetic Research Group, Faculty of MedicineImperial CollegeLondonUK
- Department of Nutritional Sciences, School of Life Course SciencesKing's College LondonLondonUK
| | - Maria Aresu
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - Andy Heard
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - Queenie Chan
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - Evangelos Evangelou
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - He Gao
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - Paul Elliott
- Department of Epidemiology and Biostatistics, MRC‐PHE Centre for Environment and Health, School of Public HealthImperial CollegeLondonUK
| | - Gary Frost
- Nutrition and Dietetic Research Group, Faculty of MedicineImperial CollegeLondonUK
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Krause C, Sievert H, Geißler C, Grohs M, El Gammal AT, Wolter S, Ohlei O, Kilpert F, Krämer UM, Kasten M, Klein C, Brabant GE, Mann O, Lehnert H, Kirchner H. Critical evaluation of the DNA-methylation markers ABCG1 and SREBF1 for Type 2 diabetes stratification. Epigenomics 2019; 11:885-897. [PMID: 31169416 DOI: 10.2217/epi-2018-0159] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Validation of epigenome-wide association studies is sparse. Therefore, we evaluated the methylation markers cg06500161 (ABCG1) and cg11024682 (SREBF1) as classifiers for diabetes stratification. Patients & methods: DNA methylation was measured in blood (n = 167), liver (n = 99) and visceral adipose tissue (n = 99) of nondiabetic or Type 2 diabetic subjects by bisulfite pyrosequencing. Results: DNA methylation at cg11024682 in blood and liver correlated with BMI. Methylation at cg06500161 was influenced by the adjacent SNP rs9982016. Insulin-resistant and sensitive subjects could be stratified by DNA methylation status in blood or visceral adipose tissue. Conclusion: DNA methylation at both loci in blood presents a promising approach for risk group stratification and could be valuable for personalized Type 2 diabetes risk prediction in the future.
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Affiliation(s)
- Christin Krause
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany
| | - Helen Sievert
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany
| | - Cathleen Geißler
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany
| | - Martina Grohs
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany
| | - Alexander T El Gammal
- Department of General, Visceral & Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Wolter
- Department of General, Visceral & Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Olena Ohlei
- Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Integrative & Experimental Genomics, University of Lübeck, Lübeck, Germany
| | - Fabian Kilpert
- Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Integrative & Experimental Genomics, University of Lübeck, Lübeck, Germany
| | - Ulrike M Krämer
- Department of Neurology, University of Lübeck, Lübeck, Germany.,Institute of Psychology II, University of Lübeck, Lübeck, Germany
| | - Meike Kasten
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.,Department of Psychiatry & Psychotherapy, University of Lübeck, Lübeck, Germany
| | - Christine Klein
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Georg E Brabant
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany
| | - Oliver Mann
- Department of General, Visceral & Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hendrik Lehnert
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Henriette Kirchner
- Medical Department I, Division Epigenetics & Metabolism, University of Lübeck, Lübeck, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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17
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Pogoriler J, O'Neill AF, Voss SD, Shamberger RC, Perez-Atayde AR. Hepatocellular Carcinoma in Fanconi-Bickel Syndrome. Pediatr Dev Pathol 2018; 21:84-90. [PMID: 28382841 DOI: 10.1177/1093526617693540] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Fanconi-Bickel syndrome is a rare autosomal recessive disorder due to mutations in the facilitative glucose transporter 2 ( GLUT2 or SLC2A2) gene resulting in excessive glycogen storage predominantly in the liver and kidney. Previous case reports of this condition have described liver biopsies with glycogen storage and variable steatosis and/or fibrosis. Unlike in other types of glycogen storage disease, hepatocellular adenomas and carcinomas have not been described to date in this syndrome. A 6-year-old boy with consanguineous parents had short stature, poorly controlled rickets, hepatosplenomegaly, and renal tubular dysfunction clinically consistent with Fanconi-Bickel Syndrome. Sequencing of the SLC2A2 gene showed a homozygous variant of unknown significance [c.474A > C (p.Arg158Ser)] causing a missense mutation in an evolutionarily conserved residue. An incidental single hepatic lesion was discovered on imaging, and subsequent resection showed a 2.6 cm well-differentiated hepatocellular carcinoma with moderate atypia, diffuse immunoreactivity for glypican-3, and nuclear b-catenin, and with focal complete loss of the reticulin framework. The non-neoplastic liver showed marked glycogen accumulation with mild periportal fibrosis, rare bridging fibrosis, and no regenerative or adenomatous nodules. By electron microscopy, tumor cells had pleomorphic nuclei, prominent nucleoli, and scant cytoplasm with numerous mitochondria. Well-developed canaliculi were occasionally seen. The non-neoplastic liver showed glycogenosis with abundant cytoplasmic free (non-membrane bound) glycogen. Hepatocellular carcinoma should be considered as a possible complication of Fanconi-Bickel syndrome. This well differentiated carcinoma did not appear to be associated with hepatic adenomatosis as has been described in some hepatocellular carcinomas associated with other hepatic glycogen storage disorders. The nuclear beta-catenin immunoreactivity indicates a role for the Wnt signaling pathway in the pathogenesis of this tumor.
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Affiliation(s)
- Jennifer Pogoriler
- 1 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Allison F O'Neill
- 2 Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Stephan D Voss
- 3 Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert C Shamberger
- 4 Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Antonio R Perez-Atayde
- 1 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Hu C, Jia W. Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication. Diabetes 2018; 67:3-11. [PMID: 29263166 DOI: 10.2337/dbi17-0013] [Citation(s) in RCA: 254] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/03/2017] [Indexed: 12/15/2022]
Abstract
The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10-20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. Furthermore, individualized antidiabetes treatment should be a top priority to prevent complications and mortality. In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.
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Affiliation(s)
- Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, People's Republic of China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
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Mediterranean Diet Adherence and Genetic Background Roles within a Web-Based Nutritional Intervention: The Food4Me Study. Nutrients 2017; 9:nu9101107. [PMID: 29019927 PMCID: PMC5691723 DOI: 10.3390/nu9101107] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 10/04/2017] [Accepted: 10/09/2017] [Indexed: 01/02/2023] Open
Abstract
Mediterranean Diet (MedDiet) adherence has been proven to produce numerous health benefits. In addition, nutrigenetic studies have explained some individual variations in the response to specific dietary patterns. The present research aimed to explore associations and potential interactions between MedDiet adherence and genetic background throughout the Food4Me web-based nutritional intervention. Dietary, anthropometrical and biochemical data from volunteers of the Food4Me study were collected at baseline and after 6 months. Several genetic variants related to metabolic risk features were also analysed. A Genetic Risk Score (GRS) was derived from risk alleles and a Mediterranean Diet Score (MDS), based on validated food intake data, was estimated. At baseline, there were no interactions between GRS and MDS categories for metabolic traits. Linear mixed model repeated measures analyses showed a significantly greater decrease in total cholesterol in participants with a low GRS after a 6-month period, compared to those with a high GRS. Meanwhile, a high baseline MDS was associated with greater decreases in Body Mass Index (BMI), waist circumference and glucose. There also was a significant interaction between GRS and the MedDiet after the follow-up period. Among subjects with a high GRS, those with a high MDS evidenced a highly significant reduction in total carotenoids, while among those with a low GRS, there was no difference associated with MDS levels. These results suggest that a higher MedDiet adherence induces beneficial effects on metabolic outcomes, which can be affected by the genetic background in some specific markers.
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Stančáková A, Kuulasmaa T, Kuusisto J, Mohlke KL, Collins FS, Boehnke M, Laakso M. Genetic risk scores in the prediction of plasma glucose, impaired insulin secretion, insulin resistance and incident type 2 diabetes in the METSIM study. Diabetologia 2017; 60:1722-1730. [PMID: 28573393 DOI: 10.1007/s00125-017-4313-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/28/2017] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS Many SNPs have been associated with glycaemic traits and type 2 diabetes, but their joint effects on glycaemic traits and the underlying mechanisms leading to hyperglycaemia over time are largely unknown. We aimed to investigate the association of six genetic risk scores (GRSs) with changes in plasma glucose, insulin sensitivity, insulin secretion and incident type 2 diabetes in the prospective METabolic Syndrome In Men (METSIM) study. METHODS We generated weighted GRSs for fasting plasma glucose ([FPG] GRSFPG, 35 SNPs), 2 h plasma glucose ([2hPG] GRS2hPG, 9 SNPs), insulin secretion (GRSIS, 17 SNPs), insulin resistance (GRSIR, 9 SNPs) and BMI (GRSBMI, 95 SNPs) and a non-weighted GRS for type 2 diabetes (GRST2D, 76 SNPs) in up to 8749 non-diabetic Finnish men. Linear regression was used to test associations of the GRSs with changes in glycaemic traits over time. RESULTS GRST2D, GRSFPG and GRSIS were associated with an increase in FPG, GRST2D with an increase in glucose AUC and a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG during the follow-up (p < 0.0017 for all models). GRST2D, GRSFPG and GRSIS were associated with incident type 2 diabetes (p < 0.008 for all models). GRSBMI and GRSIR were not significantly associated with any changes in glycaemic traits. CONCLUSIONS/INTERPRETATION In the METSIM follow-up study, GRST2D, GRSFPG and GRSIS were associated with the worsening of FPG and an increase in incident type 2 diabetes. GRST2D was additionally associated with a decrease in insulin secretion, and GRS2hPG with an increase in 2hPG.
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Affiliation(s)
- Alena Stančáková
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 B, 70210, Kuopio, Finland
| | - Teemu Kuulasmaa
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 B, 70210, Kuopio, Finland
| | - Johanna Kuusisto
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 B, 70210, Kuopio, Finland
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Karen L Mohlke
- Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
| | - Francis S Collins
- National Human Genome Research Institute, National Institutes for Health (NIH), Bethesda, MD, USA
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Yliopistonranta 1 B, 70210, Kuopio, Finland.
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
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21
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Shen JZ, Ge WH, Fang Y, Liu H. A novel polymorphism in protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is associated with type 2 diabetes in the Han Chinese population. J Diabetes 2017; 9:606-612. [PMID: 27427333 DOI: 10.1111/1753-0407.12449] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/24/2016] [Accepted: 07/12/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND It has been proposed that the energy-sensing enzyme AMP-activated protein kinase (AMPK) is a key agent in the pathophysiology of type 2 diabetes mellitus (T2DM). The gene encoding protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is located at one of the Asian T2DM loci (1p32). Therefore, the aim of the present study was to test for the association of common variants in PRKAA2 with T2DM in the Han Chinese population. METHODS We genotyped 221 T2DM patients and 111 controls to assess possible associations of two tagging single nucleotide polymorphisms (tSNPs) in the PRKAA2 gene with T2DM. RESULTS The clinical characteristics of T2DM cases compared with controls differed significantly. No significant association was observed with the rs2143754 polymorphism whereas the rs2746342 polymorphism exhibited a highly significant association with T2DM. Fasting plasma glucose (FPG) of subjects carrying the G/G genotype of the rs2746342 polymorphism was higher than that of subjects carrying the T allele (P = 0.0049). These associations were magnified in the presence of the G/G genotype of the rs2143754 polymorphism. CONCLUSIONS The rs2746342 polymorphism is significantly associated with susceptibility to T2DM and seems to interact with the rs2143754 polymorphism in the modulation of FPG in the Han Chinese population.
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Affiliation(s)
- Ji-Zhong Shen
- Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Wei-Hong Ge
- Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Yun Fang
- Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Hang Liu
- Department of Pharmacy, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
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Jørgensen ME, Borch-Johnsen K. Is diabetes preventable in the general population? Prev Med 2017; 96:156-157. [PMID: 28237368 DOI: 10.1016/j.ypmed.2016.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 10/26/2016] [Indexed: 11/28/2022]
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23
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Lau CJ, Pisinger C, Husemoen LLN, Jacobsen RK, Linneberg A, Jørgensen T, Glümer C. Reply to "Is diabetes preventable in the general population?". Prev Med 2017; 96:158-159. [PMID: 28043829 DOI: 10.1016/j.ypmed.2016.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 12/09/2016] [Accepted: 12/13/2016] [Indexed: 10/20/2022]
Affiliation(s)
- Cathrine J Lau
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark.
| | - Charlotta Pisinger
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lise Lotte N Husemoen
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark
| | - Rikke Kart Jacobsen
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark
| | - Allan Linneberg
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Experimental Research, Rigshospitalet, 2600 Glostrup, Denmark
| | - Torben Jørgensen
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Faculty of Medicine, Aalborg University, 9229 Aalborg East, Denmark
| | - Charlotte Glümer
- Research Centre for Prevention and Health, Centre for Health, The Capital Region of Denmark Rigshospitalet - Glostrup, 2600 Glostrup, Denmark; Faculty of Medicine, Aalborg University, 9229 Aalborg East, Denmark
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Lau CJ, Pisinger C, Husemoen LLN, Jacobsen RK, Linneberg A, Jørgensen T, Glümer C. Effect of general health screening and lifestyle counselling on incidence of diabetes in general population: Inter99 randomised trial. Prev Med 2016; 91:172-179. [PMID: 27514243 DOI: 10.1016/j.ypmed.2016.08.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 07/05/2016] [Accepted: 08/07/2016] [Indexed: 01/19/2023]
Abstract
UNLABELLED We aimed to examine the effect of a large population-based multifactorial screening and lifestyle intervention programme on 10-year incidence of diabetes. In a randomised trial of the general Danish population initiated in 1999-2001 59,616 men and women aged 30-60years were assigned to a five year screening and lifestyle counselling programme (n=11,629) or control group (n=47,987) and followed for ten years in nationwide registers. Intention to treat was applied and risk of diabetes was modeled by Cox regression and expressed as hazard ratios (HRs). We found that 1692 individuals had diabetes at baseline. Among 57,924 individuals without diabetes at baseline, 1267 emigrated, 2593 died and 3369 (Intervention group=684, Control group=2685) developed diabetes. We saw no significant difference in diabetes incidence between the groups after 10-year follow-up (Grey's test: p=0.22). In the first year of follow-up, incidence of diabetes was significantly higher in the intervention group than the control group (HR=1.68, 95%CI 1.29 to 2.29). We observed no difference in incidence of diabetes between the groups in the follow-up intervals from 1 to 6years or after 6-10years (HR=0.94, 0.83 to 1.06; HR=1.03, 0.91 to 1.17). Inviting the general population to participate in a repeated screening and lifestyle counselling programme over five years did not result in lower incidence of diabetes after 10years of follow-up. As expected, significantly more individuals were diagnosed with diabetes in the intervention group during the first year, but this was not followed by a decrease in the following years. TRIALS REGISTRATION Clinical trials NCT00289237.
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Affiliation(s)
- Cathrine J Lau
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark.
| | - Charlotta Pisinger
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Lise Lotte N Husemoen
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark
| | - Rikke Kart Jacobsen
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark
| | - Allan Linneberg
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark
| | - Torben Jørgensen
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Faculty of Medicine, Aalborg University, 9229 Aalborg East, Denmark
| | - Charlotte Glümer
- Research Centre for Prevention and Health, Capital Region of Denmark, 2600 Glostrup, Denmark; Faculty of Medicine, Aalborg University, 9229 Aalborg East, Denmark
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Eze IC, Imboden M, Kumar A, von Eckardstein A, Stolz D, Gerbase MW, Künzli N, Pons M, Kronenberg F, Schindler C, Probst-Hensch N. Air pollution and diabetes association: Modification by type 2 diabetes genetic risk score. ENVIRONMENT INTERNATIONAL 2016; 94:263-271. [PMID: 27281273 DOI: 10.1016/j.envint.2016.04.032] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Revised: 04/11/2016] [Accepted: 04/22/2016] [Indexed: 05/26/2023]
Abstract
Exposure to ambient air pollution (AP) exposure has been linked to type 2 diabetes (T2D) risk. Evidence on the impact of T2D genetic variants on AP susceptibility is lacking. Compared to single variants, joint genetic variants contribute substantially to disease risk. We investigated the modification of AP and diabetes association by a genetic risk score (GRS) covering 63 T2D genes in 1524 first follow-up participants of the Swiss cohort study on air pollution and lung and heart diseases in adults. Genome-wide data and covariates were available from a nested asthma case-control study design. AP was estimated as 10-year mean residential particulate matter <10μm (PM10). We computed count-GRS and weighted-GRS, and applied PM10 interaction terms in mixed logistic regressions, on odds of diabetes. Analyses were stratified by pathways of diabetes pathology and by asthma status. Diabetes prevalence was 4.6% and mean exposure to PM10 was 22μg/m(3). Odds of diabetes increased by 8% (95% confidence interval: 2, 14%) per T2D risk allele and by 35% (-8, 97%) per 10μg/m(3) exposure to PM10. We observed a positive interaction between PM10 and count-GRS on diabetes [ORinteraction=1.10 (1.01, 1.20)], associations being strongest among participants at the highest quartile of count-GRS [OR: 1.97 (1.00, 3.87)]. Stronger interactions were observed with variants of the GRS involved in insulin resistance [(ORinteraction=1.22 (1.00, 1.50)] than with variants related to beta-cell function. Interactions with count-GRS were stronger among asthma cases. We observed similar results with weighted-GRS. Five single variants near GRB14, UBE2E2, PTPRD, VPS26A and KCNQ1 showed nominally significant interactions with PM10 (P<0.05). Our results suggest that genetic risk for T2D may modify susceptibility to air pollution through alterations in insulin sensitivity. These results need confirmation in diabetes cohort consortia.
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Affiliation(s)
- Ikenna C Eze
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland
| | - Medea Imboden
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland
| | - Ashish Kumar
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland; Karolinska Institutet, Stockholm, Sweden
| | | | - Daiana Stolz
- Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland
| | | | - Nino Künzli
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland
| | - Marco Pons
- Department of Internal Medicine, Regional Hospital of Lugano, Lugano, Switzerland
| | - Florian Kronenberg
- Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Schindler
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland
| | - Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
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Pitkänen N, Juonala M, Rönnemaa T, Sabin MA, Hutri-Kähönen N, Kähönen M, Lehtimäki T, Viikari JSA, Raitakari OT. Role of Conventional Childhood Risk Factors Versus Genetic Risk in the Development of Type 2 Diabetes and Impaired Fasting Glucose in Adulthood: The Cardiovascular Risk in Young Finns Study. Diabetes Care 2016; 39:1393-9. [PMID: 27298332 DOI: 10.2337/dc16-0167] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 05/06/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We examined whether the addition of novel genetic risk variant data to conventional childhood risk factors improves risk assessment of impaired fasting glucose (IFG) and type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS An association of a weighted genetic risk score (wGRS) based on 73 risk variants with IFG and type 2 diabetes was analyzed in 2,298 participants of the Cardiovascular Risk in Young Finns Study who were followed for 24-31 years from childhood to adulthood. In addition, the value of the wGRS in pediatric prediction of type 2 diabetes was examined. RESULTS Of the 2,298 participants, 484 (21.8%) and 79 (3.4%) had IFG or type 2 diabetes in adulthood, respectively. Adjusting for age, sex, baseline BMI, parental diabetes, mother's BMI, fasting insulin concentration, systolic blood pressure, and smoking status, wGRS was associated with an increased risk of IFG (odds ratio 1.64 [95% CI 1.33-2.01] per unit increase in the wGRS) and type 2 diabetes (2.22 [1.43-3.44]). Incorporating wGRS into pediatric risk models improved model discrimination and reclassification properties. Area under the receiver operating curve improved for IFG (from 0.678 to 0.691, P = 0.015), combined IFG and type 2 diabetes outcome (from 0.678 to 0.692, P = 0.007), and type 2 diabetes (from 0.728 to 0.749, P = 0.158). The net reclassification improvement and integrated discrimination improvement were significant for all outcomes. CONCLUSIONS A multifactorial approach combining genetic and clinical risk factors may be useful in identifying children at high risk for adult IFG and type 2 diabetes.
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Affiliation(s)
- Niina Pitkänen
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
| | - Markus Juonala
- Division of Medicine, Turku University Hospital, Turku, Finland Department of Medicine, University of Turku, Turku, Finland
| | - Tapani Rönnemaa
- Division of Medicine, Turku University Hospital, Turku, Finland Department of Medicine, University of Turku, Turku, Finland
| | - Matthew A Sabin
- Murdoch Childrens Research Institute, Royal Children's Hospital, Australia, and Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Nina Hutri-Kähönen
- Department of Pediatrics, University of Tampere, and Tampere University Hospital, Tampere, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, University of Tampere, and Tampere University Hospital, Tampere, Finland
| | - Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland
| | - Jorma S A Viikari
- Division of Medicine, Turku University Hospital, Turku, Finland Department of Medicine, University of Turku, Turku, Finland
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
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Bats: Body mass index, forearm mass index, blood glucose levels and SLC2A2 genes for diabetes. Sci Rep 2016; 6:29960. [PMID: 27439361 PMCID: PMC4954980 DOI: 10.1038/srep29960] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 06/28/2016] [Indexed: 11/13/2022] Open
Abstract
Bats have an unusually large volume of endocrine tissue, with a large population of beta cells, and an elevated sensitivity to glucose and insulin. This makes them excellent animal models for studying diabetes mellitus. We evaluated bats as models for diabetes in terms of lifestyle and genetic factors. For lifestyle factors, we generated data sets of 149 body mass index (BMI) and 860 forearm mass index (FMI) measurements for different species of bats. Both showed negative inter-species correlations with blood glucose levels in sixteen bats examined. The negative inter-species correlations may reflect adaptation of a small insectivorous ancestor to a larger frugivore. We identified an 11 bp deletion in the proximal promoter of SLC2A2 that we predicted would disrupt binding sites for the transcription repressor ZNF354C. In frugivorous bats this could explain the relatively high expression of this gene, resulting in a better capacity to absorb glucose and decrease blood glucose levels.
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Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients: Increased Genetic Load of Islet-Expressed and Cytokine-Regulated Candidate Genes Predicts Poorer Glycemic Control. J Diabetes Res 2016; 2016:9570424. [PMID: 26904692 PMCID: PMC4745814 DOI: 10.1155/2016/9570424] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 11/04/2015] [Indexed: 01/12/2023] Open
Abstract
Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease progression. Two-thirds of 46 GWAS candidate genes examined were expressed in human islets, and 11 of these significantly changed expression levels following exposure to proinflammatory cytokines (IL-1β + IFNγ + TNFα) for 48 h. Using the GWAS single nucleotide polymorphisms (SNPs) from each locus, we constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several of the 11 candidate genes have overlapping biological functions and interact in a common network. Our results may help predict disease progression in newly diagnosed children with T1D which can be exploited for optimizing treatment.
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Walker CG, Solis-Trapala I, Holzapfel C, Ambrosini GL, Fuller NR, Loos RJF, Hauner H, Caterson ID, Jebb SA. Modelling the Interplay between Lifestyle Factors and Genetic Predisposition on Markers of Type 2 Diabetes Mellitus Risk. PLoS One 2015; 10:e0131681. [PMID: 26154605 PMCID: PMC4496090 DOI: 10.1371/journal.pone.0131681] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 06/04/2015] [Indexed: 01/21/2023] Open
Abstract
The risk of developing type 2 diabetes mellitus (T2DM) is determined by a complex interplay involving lifestyle factors and genetic predisposition. Despite this, many studies do not consider the relative contributions of this complex array of factors to identify relationships which are important in progression or prevention of complex diseases. We aimed to describe the integrated effect of a number of lifestyle changes (weight, diet and physical activity) in the context of genetic susceptibility, on changes in glycaemic traits in overweight or obese participants following 12-months of a weight management programme. A sample of 353 participants from a behavioural weight management intervention were included in this study. A graphical Markov model was used to describe the impact of the intervention, by dividing the effects into various pathways comprising changes in proportion of dietary saturated fat, physical activity and weight loss, and a genetic predisposition score (T2DM-GPS), on changes in insulin sensitivity (HOMA-IR), insulin secretion (HOMA-B) and short and long term glycaemia (glucose and HbA1c). We demonstrated the use of graphical Markov modelling to identify the importance and interrelationships of a number of possible variables changed as a result of a lifestyle intervention, whilst considering fixed factors such as genetic predisposition, on changes in traits. Paths which led to weight loss and change in dietary saturated fat were important factors in the change of all glycaemic traits, whereas the T2DM-GPS only made a significant direct contribution to changes in HOMA-IR and plasma glucose after considering the effects of lifestyle factors. This analysis shows that modifiable factors relating to body weight, diet, and physical activity are more likely to impact on glycaemic traits than genetic predisposition during a behavioural intervention.
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Affiliation(s)
- Celia G. Walker
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom
| | - Ivonne Solis-Trapala
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom
| | - Christina Holzapfel
- Else Kroener-Fresenius-Center for Nutritional Medicine, Faculty of Medicine, Technische Universität München, Munich, Germany
| | - Gina L. Ambrosini
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom
| | - Nicholas R. Fuller
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, NSW, Australia
| | - Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, The Genetics of Obesity and Related Metabolic Traits Programme, The Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Hans Hauner
- Else Kroener-Fresenius-Center for Nutritional Medicine, Faculty of Medicine, Technische Universität München, Munich, Germany
| | - Ian D. Caterson
- Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, Sydney, NSW, Australia
| | - Susan A. Jebb
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge, United Kingdom
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Saisho Y. β-cell dysfunction: Its critical role in prevention and management of type 2 diabetes. World J Diabetes 2015; 6:109-124. [PMID: 25685282 PMCID: PMC4317303 DOI: 10.4239/wjd.v6.i1.109] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 08/17/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Although, in contrast to type 1 diabetes, insulin resistance is assumed to be a major pathophysiological feature of T2DM, T2DM never develops unless β-cells fail to compensate insulin resistance. Recent studies have revealed that a deficit of β-cell functional mass is an essential component of the pathophysiology of T2DM, implying that β-cell deficit is a common feature of both type 1 and type 2 diabetes. β-cell dysfunction is present at the diagnosis of T2DM and progressively worsens with disease duration. β-cell dysfunction is associated with worsening of glycemic control and treatment failure; thus, it is important to preserve or recover β-cell functional mass in the management of T2DM. Since β-cell regenerative capacity appears somewhat limited in humans, reducing β-cell workload appears to be the most effective way to preserve β-cell functional mass to date, underpinning the importance of lifestyle modification and weight loss for the treatment and prevention of T2DM. This review summarizes the current knowledge on β-cell functional mass in T2DM and discusses the treatment strategy for T2DM.
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Proitsi P, Lupton MK, Velayudhan L, Hunter G, Newhouse S, Lin K, Fogh I, Tsolaki M, Daniilidou M, Pritchard M, Craig D, Todd S, Johnston JA, McGuinness B, Kloszewska I, Soininen H, Mecocci P, Vellas B, Passmore PA, Sims R, Williams J, Brayne C, Stewart R, Sham P, Lovestone S, Powell JF. Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease. Neurobiol Aging 2014; 35:2883.e3-2883.e10. [PMID: 25150574 DOI: 10.1016/j.neurobiolaging.2014.07.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 07/20/2014] [Indexed: 11/26/2022]
Abstract
Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
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Affiliation(s)
- Petroula Proitsi
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
| | - Michelle K Lupton
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Latha Velayudhan
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Gillian Hunter
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK
| | - Stephen Newhouse
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Kuang Lin
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Isabella Fogh
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Magda Tsolaki
- Memory and Dementia Centre, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Makrina Daniilidou
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Megan Pritchard
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - David Craig
- Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Stephen Todd
- Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Janet A Johnston
- Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Bernadette McGuinness
- Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Iwona Kloszewska
- Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Hilkka Soininen
- Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland
| | - Patrizia Mecocci
- Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy
| | - Bruno Vellas
- Department of Internal and Geriatrics Medicine, INSERM U 1027, Gerontopole, Hôpitaux de Toulouse, Toulouse, France
| | - Peter A Passmore
- Ageing group, Centre for Public Health, School of Medicine and Dentistry, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Rebecca Sims
- MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Julie Williams
- MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
| | - Carol Brayne
- Department of Public Health and Primary Care, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK
| | - Robert Stewart
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
| | - Pak Sham
- Department of Psychiatry, State Key Laboratory of Brain and Cognitive Sciences, and Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong
| | - Simon Lovestone
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK; Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK
| | - John F Powell
- King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK
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32
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Zhang C, Hu FB, Olsen SF, Vaag A, Gore-Langton R, Chavarro JE, Bao W, Yeung E, Bowers K, Grunnet LG, Sherman S, Kiely M, Strøm M, Hansen S, Liu A, Mills J, Fan R. Rationale, design, and method of the Diabetes & Women's Health study--a study of long-term health implications of glucose intolerance in pregnancy and their determinants. Acta Obstet Gynecol Scand 2014; 93:1123-30. [PMID: 24828694 PMCID: PMC4205761 DOI: 10.1111/aogs.12425] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 05/07/2014] [Indexed: 01/11/2023]
Abstract
Women who develop gestational diabetes mellitus or impaired glucose tolerance during pregnancy are at substantially increased risk for type 2 diabetes and comorbidities after pregnancy. Little is known about the role of genetic factors and their interactions with environmental factors in determining the transition from gestational diabetes mellitus to overt type 2 diabetes mellitus. These critical data gaps served as the impetus for this Diabetes & Women's Health study with the overall goal of investigating genetic factors and their interactions with risk factors amenable to clinical or public health interventions in relation to the transition of gestational diabetes mellitus to type 2 diabetes mellitus. To achieve the goal efficiently, we are applying a hybrid design enrolling and collecting data longitudinally from approximately 4000 women with a medical history of gestational diabetes mellitus in two existing prospective cohorts, the Nurses' Health Study II and the Danish National Birth Cohort. Women who had a medical history of gestational diabetes mellitus in one or more of their pregnancies are eligible for the present study. After enrollment, we follow study participants for an additional 2 years to collect updated information on major clinical and environmental factors that may predict type 2 diabetes mellitus risk as well as with biospecimens to measure genetic and biochemical markers implicated in glucose metabolism. Newly collected data will be appended to the relevant existing data for the creation of a new database inclusive of genetic, epigenetic and environmental data. Findings from the study are critical for the development of targeted and more effective strategies to prevent type 2 diabetes mellitus and its complications in this high-risk population.
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Affiliation(s)
- Cuilin Zhang
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - Frank B. Hu
- Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Maryland, USA
| | - Sjurdur F. Olsen
- Center for Fetal Programming, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Allan Vaag
- Department of Endocrinology, Rigshospitalet University Hospital, Copenhagen, Denmark
| | | | - Jorge E. Chavarro
- Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Maryland, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Maryland, USA
| | - Wei Bao
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - Edwina Yeung
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - Katherine Bowers
- Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Louise G. Grunnet
- Department of Endocrinology, Rigshospitalet University Hospital, Copenhagen, Denmark
| | | | - Michele Kiely
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - Marin Strøm
- Center for Fetal Programming, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Susanne Hansen
- Center for Fetal Programming, Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark
| | - Aiyi Liu
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - James Mills
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
| | - Ruzong Fan
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
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Rozman J, Klingenspor M, Hrabě de Angelis M. A review of standardized metabolic phenotyping of animal models. Mamm Genome 2014; 25:497-507. [DOI: 10.1007/s00335-014-9532-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 06/03/2014] [Indexed: 12/17/2022]
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Hornbak M, Allin KH, Jensen ML, Lau CJ, Witte D, Jørgensen ME, Sandbæk A, Lauritzen T, Andersson Å, Pedersen O, Hansen T. A combined analysis of 48 type 2 diabetes genetic risk variants shows no discriminative value to predict time to first prescription of a glucose lowering drug in Danish patients with screen detected type 2 diabetes. PLoS One 2014; 9:e104837. [PMID: 25157406 PMCID: PMC4144838 DOI: 10.1371/journal.pone.0104837] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 07/03/2014] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE To investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes. METHODS We studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001-2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug. RESULTS The GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09-1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93-0.99]), increased BMI (1.05 [1.01-1.09]), increased HbA1c (1.50 [1.36-.66]), increased TG (1.24 [1.11-1.39]) and reduced fasting serum HDL (0.37 [0.17-0.80]) at baseline. Similar results were obtained for the conventional treatment group. CONCLUSION Higher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression.
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Affiliation(s)
- Malene Hornbak
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- * E-mail:
| | - Kristine Højgaard Allin
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Majken Linnemann Jensen
- Steno Diabetes Center A/S, Gentofte, Denmark
- Section for Social and Clinical Pharmacy, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cathrine Juel Lau
- Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup Hospital, Glostrup, Denmark
| | - Daniel Witte
- Public Research Centre for Health, Centre for Health Studies, Strassen, Luxembourg
| | | | - Annelli Sandbæk
- Department of Public Health, Section of General Practice Medicine, Aarhus University, Aarhus, Denmark
| | - Torsten Lauritzen
- Department of Public Health, Section of General Practice Medicine, Aarhus University, Aarhus, Denmark
| | - Åsa Andersson
- School of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Biomedical Science, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Section of Molecular Diabetes & Metabolism, Institute of Clinical Research & Institute of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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35
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Vaxillaire M, Yengo L, Lobbens S, Rocheleau G, Eury E, Lantieri O, Marre M, Balkau B, Bonnefond A, Froguel P. Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study. Diabetologia 2014; 57:1601-10. [PMID: 24893864 DOI: 10.1007/s00125-014-3277-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 05/02/2014] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. METHODS Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. RESULTS The two most inclusive GRS were significantly associated with increased FPG (β = 0.0011 mmol/l per year per risk allele, p GRS-1 = 8.2 × 10(-5) and p GRS-2 = 6.0 × 10(-6)), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p = 4.3 × 10(-9) and HR GRS-2 1.04, p = 1.0 × 10(-16)), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p = 1.9 × 10(-14) for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p = 7.8 × 10(-25), for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p = 6.6 × 10(-7); NRI GRS-2 17.6%, p = 4.2 × 10(-7); NRI GRS-3 13.1%, p = 1.7 × 10(-4)). CONCLUSIONS/INTERPRETATION Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.
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Basile KJ, Johnson ME, Xia Q, Grant SFA. Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies. Int J Endocrinol 2014; 2014:769671. [PMID: 24719615 PMCID: PMC3955626 DOI: 10.1155/2014/769671] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/17/2014] [Accepted: 01/20/2014] [Indexed: 12/13/2022] Open
Abstract
Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.
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Affiliation(s)
- Kevin J. Basile
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Matthew E. Johnson
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Qianghua Xia
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Struan F. A. Grant
- Division of Human Genetics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- Center for Applied Genomics, The Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 1216F Children's Hospital of Philadelphia Research Institute, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA
- *Struan F. A. Grant:
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