Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study

- UGT1A gene cluster associated with total bilirubin concentrations in the DHS.
- Bilirubin-associated SNPs were not associated vascular calcified plaque.
- Bilirubin-associated SNPs were also associated with risk for all-cause mortality.

ObjectiveA negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality.MethodsThis investigation included 1220 self-described European American (EA) individuals from the DHS, a family-based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome-wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality.ResultsA genome-wide association study detected 18 SNPs within the UGT1A gene family associated with TBili at p < 5 × 10−8. The top hit was rs887829 (p = 8.67 × 10−20). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p = 0.05-0.88). There was, however, evidence of association with all-cause mortality (p = 0.0004-0.06), the top hit being rs2741034.ConclusionThese findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required.