Heme Oxygenase-1 Gene Promoter Polymorphism With Hypertension And Coronary Heart Disease

Background:Heme oxygenase(HO)is a cytoprotective enzyme that degrades heme (a potent oxidant)to generate equimolar quantities of bilirubin(an antioxidant derived from biliverdin),carbon monoxide(a vasodilatory gas that has anti-inflammatory properties)and iron.The length of a polymorphic(GT)n dinucleotid repeats sequence in the HO-1 gene promoter influences the transcriptional activity,with the short allele associated with higher gene expression.This article evaluated whether an association existed between this polymorphism and essential hypertension(EH)or coronary heart disease(CHD).Recently,there is increasing evidence suggesting that inflammation and oxidative stress are involved in the development of hypertension,so we speculate that the serum concentrations of tumor necrosis factor-alpha(TNF-α),one proinflammatory cytokine,interleukin-10(IL-10), the anti-inflammatory cytokine and bilirubin may be different between EH group and control group,we also examined the correlation between the concentrations and genotypes.Methods:This research involved 102 hypertensives,100 subjects with CHD and 134 healthy people.All of them were unrelated Chinese Hart origin.In order to embody the hereditary nature of hypertension,all the hypertension patients had a positive parental history of hypertension(hypertension in both patents,in mother alone or in father alone).All subjects had no history of diabetes mellitus,kidney failure,liver disease.Moreover,in order to find the relationship between one disease with the genetic polymorphisms,hypertension group should excluded CHD and CHD group should excluded hypertension.Genomic DNA was extracted from whole peripheral blood leukocytes,the HO-1 gene was amplified by polymerase chain reaction(PCR)and the(GT)n repeat length polymorphism was assessed by polyacrylamide gel electrophoresis(PAGE).According to the manufacturer's instructions,the serum concentrations of TNF-αand IL-10 were measured with a commercially available radioimmunity kit and enzyme-linked immunosorbent assay (ELISA)kit,separately.Full Automatic Biochemical Analysor was used to test the concentration of serum total bilirubin.Result:1.We divided the alleles according to (GT)n repeats:class S less repeats(≤25),M(26～31)and class L more repeats(≥32), leading to SS,SM,SL,ML,MM and LL genotypes.The HO-1 genotypes were classified into two groups:groupⅠwere genotypes without class L allele(SS,SM,MM),and groupⅡwere those with class L allele(SL,ML,LL).2.The long allele with≥32(GT)n repeats(L allele)was found more frequently in hypertension group compared to healthy control population(26.5%vs14.6%,P=0.005),but the allele frequency distributions were not different between the control group and CHD group. 3.The bilirubin concentration was higher in hypertension group than the control group(12.53±4.41vs 11.46±3.30,P=0.033),but the difference between CHD group and the control group was not so obviously(12.09±4.30 vs 11.46±3.30,P=0.210).4. According the control group,both the TNF-αand IL-10 levels were higher in the hypertension group(2.22±0.57vs 1.97±0.47,P=0.035;40.87±5.35vs38.17±4.46, P=0.016,separately).5.Carriers of L allele had lower serum total bilirubin levels compared to carriers of S,M alleles in hypertensive patients(11.62±3.48 vs 13.49±5.06,P=0.032),but this difference was not found in the control group and CHD group;the concentrations of TNF-αand IL-10 had no significant differences between genotypes.Conclusion:1.The long allele of GT repeats in HO-1 gene promoter may be associated with the development of hypertension,but not with coronary heart disease. 2.There is relationship between hypertension and inflammatory cytokines,which suggests inflammation might act as a pathogenetic factor in hypertension.3. Hypertensives had higher bilirubin level,this may be one of the protect mechanism of ourselves but also may promote the development of hypertension.4.The length polymorphism of HO-linfluences serum total bilirubin levels,which may be the reason for its susceptible to hypertension.