Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study
Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study
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DOI：
10.2337/db18-1048
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发表时间：
2019-08-01
期刊：
影响因子：
7.7
通讯作者：
Lawlor, Deborah A.
中科院分区：
文献类型：
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作者：
De Silva, N. Maneka G.;Borges, Maria Carolina;Lawlor, Deborah A.
肝功能障碍和2型糖尿病（T2 D）始终相关。然而，由于混杂因素，目前尚不清楚肝功能障碍是否促成、导致或仅与T2 D相关。我们使用孟德尔随机化研究肝功能和T2 D风险之间任何因果关系的存在和方向，包括多达64，094例T2 D病例和607，012例对照受试者。使用几种生物标志物作为肝功能的代表（即，丙氨酸氨基转移酶[ALT]、天冬氨酸氨基转移酶[AST]、碱性磷酸酶[ALP]和γ-谷氨酰转移酶[GGT]）。使用与每种肝功能标志物密切相关的遗传变异来研究肝功能对T2 D风险的影响。此外，与T2 D风险和空腹胰岛素密切相关的遗传变异分别用于研究T2 D易感性和胰岛素抵抗对肝功能的影响。遗传学预测的较高循环ALT和AST与T2 D风险增加相关。遗传预测的ALP与T2 D风险呈中度负相关，没有证据表明GGT与T2 D风险之间存在关联。高空腹胰岛素的遗传易感性与循环ALT升高相关，但与T2 D无关。由于循环中的ALT和AST是非酒精性脂肪肝（NAFLD）的标志物，因此这些发现为导致NAFLD的胰岛素抵抗提供了一些支持，而胰岛素抵抗反过来又增加了T2 D风险。
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 gamma-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.