High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >= 1.4 and P <= 0.015 in tier 1) and identified 75 SNPs that showed similar tendency of association in tier 1 and tier 2 samples (P <= 0.05 for allele frequency and P <= 0.01 for genotype distribution tests). For tier 3 (619 hypertensive and 1406 normotensive subjects), we genotyped the 75 SNPs and found nine SNPs from seven genomic loci to be associated with hypertension (P <= 0.05). In three of these loci, the lowest P-values were observed for rs3755351 (P = 1.7 x 10(-5)) in ADD2, rs3794260 (P = 0.0001) in KIAA0789 and rs1805762 (P = 0.0003) in M6PR when case-control comparison was made in the combined data. An SNP (rs3755351) within ADD2 had the lowest P-value and its experiment-wide significance level is 0.13. Thus, these results have nominated several susceptibility genes for hypertension, and independent replication will clarify their etiological relevance.