Program Nr: 1735 for the 2006 ASHG Annual Meeting

Angiotensinogen gene polymophism predicts blood pressure response to an angiotensin converting enzyme inhibitors therapy. X. Su1, L. Lee2, X. Li1, J. Lu2, Y. Hu2, S. Zhan2, W. Cao2, ling. Mei1, YM. Tang1, R. Krauss3, J. Rotter1, H. Yang1. 1) Medical Genetics, Cedars-Siniai Medical Center, Los Angeles, CA; 2) Department of Epidemiology, School of Public Health, Peking University Health Science Center, Beijing, China; 3) Children's Hospital Oakland Research Institute, Oakland, CA.
   Bacground-Angiotensinogen(AGT), one of the major structural candidate genes in the Renin-Angiotensin-Aldosterone System pathway, was evaluated for its association with BP response to ACEI therapy in a large sample of Chinese hypertensives by utilizing a haplotype approach in a two-stage design. Methods and Results-1447 hypertensives ascertained from a Chinese community-based screening for hypertension and underwent the benazepril treatment as sole therapy for 3 years were randomly assigned into two groups, an exploratory set(n=733) and a confirmatory set(n=714). Four SNPs, -6 A/G, T207M, M268T and C11537A, were selected based on the TagSNP approach and previous reports. In the exploratory set, all 4 common haplotypes and SNPs were analyzed. Haplotype 2 (H2) carriers had a borderline significant increase in diastolic BP(DBP) reduction than those without H2, p=0.086 after adjusting for baseline BP, gender, age, kidney function and dose of benazepril received. Among the four SNPs, C11537A in the 3 untranslated region(3-UTR)of the AGT gene was significantly associated with DBP response to ACEI therapy(P=0.028). The A allele carrier had a greater DBP reduction than CC homozygotes. Since the H2 is the only common haplotype contained the A allele at C11537A suggests that the observed borderline H2 association is likely driven by A allele in the SNP. In the confirmatory set, we observed a significant association (p=0.018) after adjusting for the same covariates. Electrophoretic mobility shift assay demonstrated that this SNP located on AP4 specific binding site and that the binding affinity was significantly higher with the C than the A allele. Conclusion-We identified that a SNP in 3-UTR of the AGT gene is associated with DBP response to an ACEI therapy and suggest its potential function might be related to its effect on AP4 binding.