Abstract
Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies. Observationally, adiposity is associated with poorer liver function. To clarify the etiology, we assessed the association of liver enzymes with adiposity observationally and using two-sample MR for validation. In the “Children of 1997” birth cohort, we used multivariable linear regression to assess the associations of alanine transaminase (ALT) and alkaline phosphatase (ALP) at ~17.5 years with body mass index (BMI) (n = 3,458). Using MR, genetic predictors of ALT, ALP and gamma glutamyltransferase (GGT), were applied to genome-wide association studies of BMI (n = 681,275), waist circumference (WC) (n = 224,459) and waist-hip ratio (WHR) (n = 224,459) to obtain unconfounded estimates. Observationally, ALT was positively associated with BMI (0.10 kg/m2 per IU/L, 95% confidence interval (CI) 0.09 to 0.11). ALP was inversely associated with BMI (−0.018 kg/m2 per IU/L, 95% CI −0.024 to −0.012). Using MR, ALT was inversely associated with BMI (−0.14 standard deviation per 100% change in concentration, 95% CI −0.20 to −0.07), but not WC or WHR. ALP and GGT were unrelated to adiposity. Poorer liver function might not cause adiposity; instead higher ALT might reduce BMI, raising the question as to the role of ALT in body composition.
Highlights
Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies
Mendelian randomization (MR) studies, taking advantage of the random allocation of genetic endowment at conception to obtain un-confounded estimates[3], have clarified the role of liver function in type 2 diabetes mellitus (T2DM). These studies suggest that higher alanine aminotransferase (ALT)[4,5] or aspartate aminotransferase (AST)[5] rather than other measures of liver function, such as glutamyltransferase (GGT)[4,5,6], could play a role in T2DM, one small MR study found no association of alanine transaminase (ALT) with T2DM7
Whether poor hepatocyte function relates to adiposity and contributes to T2DM, and by what mechanism is not entirely clear, within an evolutionary biology framework we have previously suggested a mechanism via sex hormones[4]
Summary
Poorer liver function is positively associated with diabetes in Mendelian randomization (MR) studies. Mendelian randomization (MR) studies, taking advantage of the random allocation of genetic endowment at conception to obtain un-confounded estimates[3], have clarified the role of liver function in T2DM These studies suggest that higher alanine aminotransferase (ALT)[4,5] or aspartate aminotransferase (AST)[5] rather than other measures of liver function, such as glutamyltransferase (GGT)[4,5,6], could play a role in T2DM, one small MR study found no association of ALT with T2DM7. We examined the association of liver function indicated by ALT and alkaline phosphatase (ALP) with adiposity in young people in a setting (Hong Kong) with little clear socio-economic patterning of obesity, so as to reduce confounding by poor health and SEP using Hong Kong’s “Children of 1997” birth cohort[13]. We used an MR study to assess the effects of genetically predicted liver enzymes (ALT, ALP, and GGT)[14] on adiposity indices, i.e., body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR), using the Genetic Investigation of ANthropometric Traits (GIANT) consortium[15,16,17], overall and by sex
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