Author(s): Abbasi A, Deetman PE, Corpeleijn E, Gansevoort RT, Gans RO,
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Abstract Circulating bilirubin, a natural antioxidant, is associated with decreased risk of type 2 diabetes (T2D), but the nature of the relationship remains unknown. We performed Mendelian randomization in a prospective cohort of 3,381 participants free of diabetes at baseline (age 28-75 years; women 52.6\%). We used rs6742078 located in the uridine diphosphate-glucuronosyltransferase locus as an instrumental variable (IV) to study a potential causal effect of serum total bilirubin level on T2D risk. T2D developed in a total of 210 participants (6.2\%) during a median follow-up period of 7.8 years. In adjusted analyses, rs6742078, which explained 19.5\% of bilirubin variation, was strongly associated with total bilirubin (a 0.68-SD increase in bilirubin levels per T allele; P < 1 × 10(-122)) and was also associated with T2D risk (odds ratio [OR] 0.69 [95\% CI 0.54-0.90]; P = 0.006). Per 1-SD increase in log-transformed bilirubin levels, we observed a 25\% (OR 0.75 [95\% CI 0.62-0.92]; P = 0.004) lower risk of T2D. In Mendelian randomization analysis, the causal risk reduction for T2D was estimated to be 42\% (causal OR for IV estimation per 1-SD increase in log-transformed bilirubin 0.58 [95\% CI 0.39-0.84]; P = 0.005), which was comparable to the observational estimate (Durbin-Wu-Hausman χ(2) test, P for difference = 0.19). These novel results provide evidence that an elevated bilirubin level is causally associated with the risk of T2D and support its role as a protective determinant. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
This article was published in Diabetes
and referenced in Biochemistry & Analytical Biochemistry