title: Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization study.
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.
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, U.K. ali.abbasi@mrc-epid.cam.ac.uk a.abbasi@umcg.nl.
authors.forename: Ali
authors.initials: A
authors.lastname: Abbasi
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Petronella E
authors.initials: PE
authors.lastname: Deetman
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Corpeleijn
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Rijk O B
authors.initials: RO
authors.lastname: Gans
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Stolk
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Behrooz Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.affiliation: Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001663:Bilirubin / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme