Genotype–phenotype analysis of angiotensinogen polymorphisms and essential hypertension: the importance of haplotypes

Abstract

To better understand the relationship between angiotensinogen (AGT) genetic variation and essential hypertension, AGT genotypes and haplotypes were tested for association with hypertensive endophenotypes and essential hypertension. Two hundred and fifty-six Hypertensive Pathotype (HyperPATH)/Specialized Center of Research (SCOR) cases and 126 controls were genotyped for 24 single-nucleotide polymorphisms (SNPs) in the AGT gene. SNPs and AGT haplotypes were tested for association with plasma AGT, renal plasma flow (RPF), and essential hypertension. New associations between essential hypertension, plasma AGT, and RPF are reported for alleles -1178G, 6066A, 6152A, 6233C, and 12822C. The maximum odds ratio for association of hypertension and AGT genetic variation was 2.3 [95% confidence interval (CI) 1.5-3.8; P < 0.0003] for allele 6233C. Previous associations for -1074T, -532T, -217A, -6A, and 4072C are confirmed (P < 0.05). Sodium depletion enhances associations between AGT SNPs and plasma AGT. Most individually associated SNPs, including -6A and 4072C, are found on a common complete AGT haplotype, H4 (frequency = 0.09). Individuals with haplotype H4 have significantly higher plasma AGT and reduced RPF (P < 0.003 and P < 0.0002, respectively). Other common haplotypes are not associated with increased plasma AGT levels in this data set despite the presence of the -6A and 4072C alleles, suggesting that AGT haplotype H4 is more predictive of elevated plasma AGT than is -6A or 4072C. This study demonstrates the importance of analyzing haplotypes in addition to single genotypes in association studies. By demonstrating the dependence of AGT associations on sodium depletion status, it helps to explain previous conflicting association results.