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

Cox AJ, Ng MC, Xu J, Langefeld CD, Koch KL, Dawson PA, Carr JJ, Freedman BI, Hsu FC, Bowden DW
Atherosclerosis. 2013 229 (1): 155-60

PMID: 23642732 · PMCID: PMC3691283 · DOI:10.1016/j.atherosclerosis.2013.04.008

OBJECTIVE - A 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.

METHODS - This 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.

RESULTS - A 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.

CONCLUSION - These 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.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

MeSH Terms (17)

Aged Bilirubin Cardiovascular Diseases Diabetes Complications Diabetes Mellitus, Type 2 European Continental Ancestry Group Female Genetic Variation Genome-Wide Association Study Glucuronosyltransferase Humans Male Middle Aged Multigene Family Polymorphism, Single Nucleotide Risk Factors Vascular Calcification

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