title: Association of SNPs in the UGT1A gene cluster with total bilirubin and mortality in the Diabetes Heart Study.
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.
  
  
  CONCLUSIONS
  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.
authors: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors: Amanda J
authors: AJ
authors: Cox
authors: Maggie C-Y
authors: MC
authors: Ng
authors: Jianzhao
authors: J
authors: Xu
authors: Carl D
authors: CD
authors: Langefeld
authors: Kenneth L
authors: KL
authors: Koch
authors: Paul A
authors: PA
authors: Dawson
authors: J Jeffrey
authors: JJ
authors: Carr
authors: Barry I
authors: BI
authors: Freedman
authors: Fang-Chi
authors: FC
authors: Hsu
authors: Donald W
authors: DW
authors: Bowden
mesh_terms: D000368:Aged; D001663:Bilirubin / Q000097:blood*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D048909:Diabetes Complications / Q000235:genetics / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000401:mortality; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D061205:Vascular Calcification / Q000235:genetics / Q000401:mortality; D044465:White People / Q000235:genetics / Q000706:statistics & numerical data; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme
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