Association Of Genetic Polymorphisms In Dimethylargine Dimethylaminohydrolase 2 Gene With Essential Hypertension Of Hunan Han Population

Essential hypertension(EH) is a multigenic disease with environmental and genetic factors.The vascular endothelium plays an important role in maintaining the homeostasis of cardiovascular system by secret vasoactive substances such as nitric oxide(NO) and endothelin(ET).It is well known that endothelial dysfunction is the early stage of many cardiovascular diseases including hypertension.NO is synthesized from L-arginine catalyzed by NO synthase(NOS).NO is an important endogenous vasodilator that plays a role in blood pressure regulation.Asymmetric dimethylarginine(ADMA) is an endogenous NOS inhibitor which can competitively inhibit NO production.Majority of ADMA produced in the body is metabolized and inactivated by dimethylarginine dimethylaminohydrolases 1 and 2(DDAH1 and DDAH2).Therefore, interindividual variation in the activity of DDAH enzymes may influence NOS activity and consequently NO level by affecting plasma ADMA level. Thus,DDAH1 and DDAH2 are important candidate genes for EH.Aims:To investigate the association of DDAH2 genetic polymorphisms with EH susceptibility in a Chinese Han population by a case-control study.Methods:By using the public data deposited in the dbSNP database, single nucleotide polymorphisms(SNPs) at DDAH2 locus were recorded. After analysis of linkage disequilibrium(LD) and establishment of haplotypes,haplotype tag SNPs(htSNPs) in Chinese were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the htSNPs.A case-control study consisted of 639 EH patients and 609 normotensive controls of Han nationality recruited from Hunan province was carried out. High-performance liquid chromatography-mass spectrum(HPLC-MS) was employed to determine levels of ADMA in plasma.Unconditional logistic regression was performed to evaluate association of DDAH2 genotypes with EH susceptibility after adjustment for EH risk factor.Results:1) We established and validated PCR-RFLP methods for genotyping of DDAH2 G-1415A and A-1150C polymorphisms.2) No significant difference in either genotype or allele frequencies distribution for DDAH2 G-1415A and A-1150C polymorphisms was observed between overall EH cases and controls.However,when adjusted by EH risk factors and DDAH2 G-1415A genotypes,genotypes of the DDAH2 A-1150C polymorphism associated with increased EH risk(OR=1.203,95% CI:1.005～1.440,p=0.044) in the overall population.3)When stratified by gender,genotypes of the DDAH2 A-1150C polymorphism associated with increased EH risk in males(OR=1.247,95%CI:1.000～1.555,p=0.050) while not in females.4) When stratified by age(age at onset of EH for cases), significantly difference in allele frequency distribution for the DDAH2 A-1150C polymorphism was observed in individuals less than 50 years of old,and the A-1150C genotypes were associated with increased EH risk (OR=1.308,95%CI:1.029～1.662,p=0.028).Neither polymorphism was associated with EH risk in individuals≥50 years of old.5) No difference in haplotype distribution was observed in EH cases and controls.(x~2=6.229, p=0.101) 6) Neither polymorphism was associated with SBP,DBP and plasma levels of ADMA in either cases and controls.Conclusion:DDAH2 A-1150C polymorphism is associated with increased EH risk in Hunan Han nationality.DDAH2 A-1150C genotypes are associated with increased EH risk in males and individuals less than 50 years in this population.