Crowd Bilirubin Metabolism Related Gene Polymorphism And Serum Total Bilirubin, Hypertension And Coronary Heart Disease Correlation Study

The present study focused on four bilirubin metabolism genes:heme oxygenase-1(HO-1),biliverdin reductase A(BLVRA),solute carrier organic anion transporter family member 1B1(SLCO1B1) and uridine diphosphate glycosyltransferase 1A1(UGT1A1).Several recent studies indicated within normal or a little high range serum total bilirubins are effective antioxidants in human body and inversely associated with coronary heart disease(CHD) and mortality from myocardial infarction.UGT1A1 is a candidate gene of CHD for studies have revealed that UGT1A1 is a major gene associated with serum bilirubin levels.Functional studied have also indicated HO-1, BL VRA and SLCO1B1 may be candidate genes of hypertension and CHD for they may be implicated in blood pressure regulation and the development of CHD in some ways.In this study,we investigated whether polymorphisms in HO-1,BLVRA,SLCO1B1 and UGT1A1 are associated with total serum bilirubin levels and conducted a genetic case-control study to assess whether the polymorphisms are associated with essential hypertension or CHD and the associations are conveyed through their influence on serum bilirubin.The study was performed in two populations.The first populations include the Han, Uyghur and Kazak populations from epidemiological survey on hypertension in villages in Xinjiang,China.The second population consists of the Han participants who underwent angiocardiography from several hospitals in Shanghai,China.Three polymorphisms in HO-1,one in BLVRA,five in SLCO1B1 and two in UGT1A1, mostly at the promoter or coding regions,were estimated in the first populations. UGT1A1 was found to be a major gene with the(TA)n repeat polymorphism and single nucleotide polymorphism(SNP) rs4148323(UGT1A1 Gly71Arg) associated with serum total bilirubin levels in all the three ethnic populations(adjusted P＜0.005).The(GT)n repeat polymorphism in the HO-1 promoter region is also associated with total bilirubin levels in the Uyghur population,not in the Han and Kazak populations.Other SNPs enrolled in our research don't relate to serum bilirubin levels.Statistically significant associations of three polymorphisms and two interactions with essential hypertension were found.The(GT)n repeat in the HO-1 promoter is associated with essential hypertension in the Han population.The minor allele of SNP rs4149014(SLCO1B1 -1175T＞G) is associated with increased risk for essential hypertension in the Uyghur population(adjusted odds ratio[OR],1.87;95%confidence interval[CI],1.35 to 2.58; P=-1.22×10^-4).The minor allele of SNP rs699512(BL VRA Thr3Ala) significantly protects against hypertension in the Kazak population(adjusted OR,0.77;95%CI,0.62 to 0.95; P=0.015).Obviously,these associations aren't conveyed through their effects on serum bilirubin levels.Two interactions,SNP rs4149014(SLCO1B1 -1175T＞G)with SNP rs699512(BL VRA Thr3Ala) in the Kazak population and SNP rs2071749(HO-1 intron₃ G＞A) with SNP rs699512(BLVRA Thr3Ala) in the Uyghur population,are associated with hypertension.Thirty-five common SNPs(4 in HO-1,9 in BLVRA,14 in SLCO1B1 and 8 in UGT1A1) were selected to genotype in the second population.Of them,thirty were tag SNPs from HapMap project.Only three SNPs,rs4148323(UGT1A1 Gly71Arg), rs887829(UGT1A1 -364G＞A) and rs4399719(UGT1A1 -2473T＞G),are related to serum total bilirubin levers.SNP rs887829(UGT1A1 -364G＞A) was also observed to be associated with male CHD:male dividuals with genotype A/A of it had the decreased risk for CHD compared with carriers of the G allele(age-adjusted OR,0.24;95%CI,0.10 to 0.60;P=0.0014).That is to say,the association of SNP rs887829 with male CHD may be conveyed through its effect on serum bilirubin levels.The result of 10,000 permutation in all the SLCO1B1 data showed SLCO1B1 is weakly associated with male CHD (P=0.0438).The haplotype block in BLVRA including SNP rs2690381,rs1181576, rs2877262 and rs7738 is associated with female CHD(age-adjusted P=0.011).Obviously, the associations of SLCO1B1 and BL VRA with CHD aren't conveyed through their effects on serum total bilirubin levels.