Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization studyAbbasi, A., Deetman, P. E., Corpeleijn, E., Gansevoort, R. T., Gans, R. O. B., Hillege, H. L., van der Harst, P., Stolk, R. P., Navis, G., Alizadeh, B. Z. & Bakker, S. J. L., Apr-2015, In : Diabetes. 64, 4, p. 1459-1469 11 p.
Research output: Contribution to journal › Article › Academic › peer-review
- Reproductive Origins of Adult Health and Disease (ROAHD)
- Lifestyle Medicine (LM)
- Cardiovascular Centre (CVC)
- Groningen Kidney Center (GKC)
- Life Course Epidemiology (LCE)
- Vascular Ageing Programme (VAP)
- Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
- Groningen Institute for Organ Transplantation (GIOT)
- Value, Affordability and Sustainability (VALUE)
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 (aged 28-75 years; women, 52.6%). We used rs6742078 located in UDP-glucuronosyltransferase (UGT1A1) locus as instrumental variable (IV) to study a potential causal effect of serum total bilirubin on T2D risk. A total of 210 (6.2%) participants developed T2D during a median follow-up 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 (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 ORIVestimation 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 chi-square test Pfor difference =0.19). These novel results provide evidence that elevated bilirubin is causally associated with risk of T2D and support its role as a protective determinant.
|Number of pages||11|
|Publication status||Published - Apr-2015|
- MULTIPLE GENETIC-VARIANTS, GENOME-WIDE ASSOCIATION, OXIDATIVE STRESS, SERUM BILIRUBIN, METABOLIC SYNDROME, COMMON VARIANTS, HEART-DISEASE, HYPERBILIRUBINEMIA, MORTALITY, GLUCOSE