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

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Cox, Amanda J.
C.-Y. Ng, Maggie
Xu, Jianzhao
Langefeld, Carl D.
L. Koch, Kenneth
A. Dawson, Paul
Carr, J. Jeffrey
Freedman, Barry I.
Hsu, Fang-Chi
Bowden, Donald W.
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2013
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Abstract

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.

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Atherosclerosis

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229

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1

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Cardiorespiratory Medicine and Haematology not elsewhere classified

Medical and Health Sciences not elsewhere classified

Cardiorespiratory Medicine and Haematology

Clinical Sciences

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