Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study
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- N. Maneka G. De Silva
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K.
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- Maria Carolina Borges
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K.
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- Aroon D. Hingorani
- UCL Institute of Cardiovascular Science, Research Department of Population Science and Experimental Medicine, Centre for Translational Genomics, University College London, London, U.K.
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- Jorgen Engmann
- UCL Institute of Cardiovascular Science, Research Department of Population Science and Experimental Medicine, Centre for Translational Genomics, University College London, London, U.K.
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- Tina Shah
- UCL Institute of Cardiovascular Science, Research Department of Population Science and Experimental Medicine, Centre for Translational Genomics, University College London, London, U.K.
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- Xiaoshuai Zhang
- MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
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- Jian'an Luan
- MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
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- Claudia Langenberg
- MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.
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- Andrew Wong
- MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, U.K.
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- Diana Kuh
- MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, U.K.
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- John C. Chambers
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, U.K.
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- Weihua Zhang
- Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
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- Marjo-Ritta Jarvelin
- Department of Epidemiology and Biostatistics, Imperial College London, London, U.K.
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- Sylvain Sebert
- Center for Life Course Health Research, University of Oulu, Oulu, Finland
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- Juha Auvinen
- Center for Life Course Health Research, University of Oulu, Oulu, Finland
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- Tom R. Gaunt
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K.
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- Deborah A. Lawlor
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K.
説明
<jats:p>Liver dysfunction and type 2 diabetes (T2D) are consistently associated. However, it is currently unknown whether liver dysfunction contributes to, results from, or is merely correlated with T2D due to confounding. We used Mendelian randomization to investigate the presence and direction of any causal relation between liver function and T2D risk including up to 64,094 T2D case and 607,012 control subjects. Several biomarkers were used as proxies of liver function (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and γ-glutamyl transferase [GGT]). Genetic variants strongly associated with each liver function marker were used to investigate the effect of liver function on T2D risk. In addition, genetic variants strongly associated with T2D risk and with fasting insulin were used to investigate the effect of predisposition to T2D and insulin resistance, respectively, on liver function. Genetically predicted higher circulating ALT and AST were related to increased risk of T2D. There was a modest negative association of genetically predicted ALP with T2D risk and no evidence of association between GGT and T2D risk. Genetic predisposition to higher fasting insulin, but not to T2D, was related to increased circulating ALT. Since circulating ALT and AST are markers of nonalcoholic fatty liver disease (NAFLD), these findings provide some support for insulin resistance resulting in NAFLD, which in turn increases T2D risk.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 68 (8), 1681-1691, 2019-05-14
American Diabetes Association