Common variants of four bilirubin metabolism genes and their association with serum bilirubin and coronary artery disease in Chinese Han population

Abstract

Studies have revealed an inverse relationship between serum total bilirubin (TBIL) levels and coronary artery disease (CAD). This study investigated the genetic variants of four bilirubin metabolism genes--heme oxygenase-1 (HMOX1), biliverdin reductase A (BLVRA), solute carrier organic anion transporter family member 1B1 (SLCO1B1), and uridine diphosphate glycosyltransferase 1A1 (UGT1A1)--in relation to TBIL levels and CAD. Thirty-five common single nucleotide polymorphisms (SNPs) were genotyped in 2380 unrelated Han participants who underwent angiocardiography at hospitals in Shanghai, China. Only three genetic variants--rs4399719 (UGT1A1 T-2473G), rs887829 (UGT1A1 G-364A), and rs4148323 (UGT1A1 G211A)--were associated with TBIL levels (each P<0.001). Four significant associations with CAD were detected after controlling age and the false discovery rate at 15%: the recessive effect of SNP rs887829 (UGT1A1 G-364A) [age-adjusted odds ratio (OR): 0.24; 95% confidence interval (CI): 0.10-0.60; P=0.0014] and dominant effect of rs4149013 (SLCO1B1 A-12099G) (age-adjusted OR: 0.70; 95% CI: 0.55-0.91; P=0.0069) on male CAD, and the additive effects of rs2877262 (BLVRA G+1238/in6C) (age-adjusted OR: 0.73; 95% CI: 0.59-0.89; P=0.0021) and rs2690381 (BLVRA G+2613/in6A) (age-adjusted OR: 0.70; 95% CI: 0.56-0.86; P=0.0008) on female CAD. SNPs rs2877262 and rs2690381 were both in a linkage disequilibrium block within BLVRA with r greater than 0.750. Correspondingly, this block was identified to be associated with female CAD. Our study provides genetic evidences for the difference in the impact of these four bilirubin metabolism genes on TBIL levels and CAD.