Polymorphisms Of Renin-Angiotensin System Gene And Essential Hypertension

Hypertension is a leading cause of human cardiovascular morbidity and mortality. The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and influence the cardiovascular remodeling. As candidate genes for essential hypertension, the genes encoding the components of renin-angiotensin system, including angiotensinogen (AGT) and angiotensin-converting enzyme (ACE), have been studied for their polymorphisms and association with the disease. Also genetic-association study has been widely used to search for new genes of such a complex disease as hypertension. Present studies examined the DNA polymorphisms in the AGT and ACE genes in a large group of well charactized Chinese EH patients in Henan province of central China. By using PCR-RFLP and maximum likelihood estimation (MLE), the pattern of intragenic linkage disequilibrium and the haplotype structure were estimated and the possible association between the polymorphisms of AGT, ACE genesand essential hypertension.PART 1: Polymorphisms of angiotensinogen (AGT) gene and hypertension1. 7 polymorphic sites (SNPs), namely A-217G, G-152A, A-20C, A-6G, C+31T, C3889T and C4072T of the genes were analyzed which created H1-H7 7 haplotypes. The most common three haplotypes were H1(-217: A, -152: G, -20: A, -6: A, +31: C, 3889: C; 4072: C), H2(-217: A, -152: G, -20: A, -6: G, +31: T, 3889: C; 4072: T) and H3(-217: G, -152: G, -20: A, -6: A, +31: C, 3889: C; 4072: C)。2. Among the individual SNP pairs examined, G-152 and C3889T, G-152A and A-217G did not exhibit significantly lingkage disequilibrium. But strong linkage disequilibrium was observed between all other loci. The A-6G, C67T and M235T are nearly completely disequilibrium. 3. All single polymorphism sites analyzed were associated with hypertension. But we described the frequency of haplotype H7 (-217: G, -152: G, -20: A, -6: G, +31: T, 3889: C; 4072: T) was significantly higher in controls than patients (P=0.010). PART2. Polymorphisms of angiotensin-converting enzyme (ACE) gene and the enzyme activity, as well as blood pressureA-5499C, T-3892C, A-240T, T1237C, G2215A, I/D of Alu fragment in intron 16, G2350A, 4656(CT)3/2 were investigated in1. case-control samples with measurement of ACE in serum activity in 204 individuals in present samples.2. 9 common haplotypes from 8 sites of the ACE gene were observed. The three most frequent haplotypes are A(A-T-A-T-G-I-A-3), B(C-C-T-C-A-D-G-2) and C(A-T-A-C-A-D-G-2). All the loci constituting the haplotype A were individually associated with low-ACE activity.3. All the 8 polymorphism pairs exhibited significantly lingkage disequilibrium. 4. Except for A-240T, no other single-locus was associated with high pressure, however we found that the haplotype B has a trend to increasing the risk of high pressure. CONCLUSIONIn present study, 7-9 major haplotype constructed by 7 and 8 polymorphism loci account for mostly of the variation in ACE and AGT genes. The haplotype H7 of AGT gene might represent a genetic susceptibility factor for EH and haplotype B of ACE may increase the risk of EH. Also our data support the presence of a gene-dose effect for some haplotypes but not for the single polymorphism sites.