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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 ?(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.

SUBMITTER: Abbasi A

PROVIDER: S-EPMC4346199 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization study.

Abbasi Ali A Deetman Petronella E PE Corpeleijn Eva E Gansevoort Ron T RT Gans Rijk O B RO Hillege Hans L HL van der Harst Pim P Stolk Ronald P RP Navis Gerjan G Alizadeh Behrooz Z BZ Bakker Stephan J L SJ

Diabetes 20141103 4

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 ...[more]

PMID: 25368098

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Project description:ObjectiveExtensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM.Design setting and participantsTwo-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes-insomnia, sleep duration, short sleep duration, long sleep duration, and morningness-were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM).Main methodsIndividual Cochran's Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings.ResultsTwo-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09-1.19, p = 1.29E-08) at the Bonferroni-adjusted level of significance (p < 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses.ConclusionFindings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM.

Project description:Background: The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations.Methods and findings: We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study.Conclusions: This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

Dataset Information

Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization study.

Publications

Bilirubin as a potential causal factor in type 2 diabetes risk: a Mendelian randomization study.

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