Reevaluation of the association of seven candidate genes with blood pressure and hypertension: a replication study and meta-analysis with a larger sample size.

To obtain evidence for blood pressure (BP) trait association, we conducted an association study of selected candidate gene variants. In Japan, a total of 19,426 individuals underwent testing for genetic associations with systolic BP (SBP)/diastolic BP (DBP) and 9271 individuals (3460 cases and 5811 controls) underwent testing for genetic associations with dichotomous hypertension. Association with seven notable candidate genes was tested, namely, ACE, ADD1, ADRB2, AGT, CYP11B2, GNB3 and NOS3, followed by a joint meta-analysis involving previously reported multi-study populations, including >20,000 individuals (for SBP/DBP) and >17,000 individuals (for hypertension). BP trait associations at two loci (AGT rs699 and CYP11B2 rs1799998) were consistently replicated in the Japanese association study and joint meta-analysis involving the populations described above. Hypertension association reached genome-wide significance for the two variants, specifically, P=7.3 × 10(-10) for AGT rs699 and P=3.9 × 10(-8) for CYP11B2 rs1799998. In our study panels, the most significant association was found for CYP11B2 rs1799998 with all three BP traits: P=1.5 × 10(-5) for SBP, P=1.8 × 10(-5) for DBP and P=2.3 × 10(-5) for hypertension. A suggestive association with SBP (P=0.042), DBP (P=0.01) and hypertension (P=1.4 × 10(-5)) was also detected for ACE rs4340 (a proxy for ACE D/I polymorphism) in the joint meta-analysis. Our data provide evidence for true BP trait associations with two candidate gene variants. These variants were not identified in the previous genome-wide association studies, presumably because they did not reach a given threshold in the discovery stage. Thus, certain variants in genes with clinical and physiological relevance are likely to account for a portion of BP variance in the general population and are worth following up via a target gene approach.