Abstract 014: Bilirubin and the Most Highly Associated Variant are Associated with the Risk of Incident Type 2 Diabetes in the Community: A Mendelian Randomization Approach
Background: A higher circulating bilirubin, as an antioxidant, has been shown to be associated with a lower risk of cardiometabolic traits/diseases. We aimed to prospectively investigate the association of serum bilirubin and the most highly associated variant in UGT1A1 locus (rs6742078) with the risk of future diabetes in the community. We performed a mendelian randomisation approach to examine the hypothesis that the association of serum bilirubin with diabetes is causal.
Methods: We performed prospective cohort analysis in 3,381 participants free of diabetes (aged 28-75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, the Netherlands. We genotyped the variant rs6742078 within the gene region encoding hepatic enzyme, UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1). We examined the association of serum bilirubin and the variant rs6742078 with risk of diabetes in multivariable-adjusted logistic regression model for the KORA clinical diabetes score including data on age, sex, BMI, smoking, hypertension, family history of diabetes and glucose. Using rs6742078 allele as an instrument variable in mendelian randomization approach, the expected risk of diabetes per 1-SD increase in log-transformed bilirubin levels was calculated as: exp (ln(OR diabetes-genotupe)/ ß coefficient bilirubin-genotype)).
Results: A total of 210 (6.2%) participants developed diabetes during a median follow-up of 7.8 years. Bilirubin level was strongly associated with rs6742078, -0.68 SD change in log-transformed level with each copy of risk allele (P< 1×10 -122). In multivariable-adjusted model, we observed a 44% (OR=1.44, 95%CI, 1.11-1.86; P=0.006) higher risk of incident diabetes with each copy of risk allele. In multivariable-adjusted model, we observed a 25% (OR=0.75, 95%CI, 0.62-0.92; P=0.004) lower risk of incident diabetes per 1-SD increase in log-transformed bilirubin levels. In mendelian randomization approach, the expected risk of diabetes was 22.2% lower per 1-SD increase of log-transformed bilirubin levels. We observed no associations between confounders and the variant rs6742078.
Conclusions: Both serum bilirubin and the variant rs6742078 in UGT1A1 locus are strongly associated with the risk of developing diabetes. Based on our findings, it seems that bilirubin signalling may have causal role in the development of diabetes. Further studies are warranted to confirm this and translate into practice, such as early screening and prevention.
- © 2013 by American Heart Association, Inc.