Low-renin hypertension: familial and genetic associations

Abstract

Low-renin hypertension, representing roughly one quarter of all essential hypertension, is widely recognized by distinct physiologic features, including salt-sensitivity and a favorable natural history. We have reported the familial concordance for renin status, defining low-renin vigorously by plasma renin activity <0.69 ngAngI/L/sec, drawn with subjects upright after seven days on a 10 mmol sodium diet. There were twice as many low-renin sibships as expected, in sharp contrast to the normal-renin state, where the observed and expected were similar (p=0.01). To pursue the implication that genetic determinants play a large role in low-renin status, we performed association studies on 8 polymorphisms in 5 candidate genes: aldosterone synthase promoter region CYP11B2 C-344T; angiotensinogen (AGT) M235T, AGT A-20C, AGT A-6G; the angiotensin II AT1 Receptor AT1R A1166C and T573C; angiotensin-converting enzyme insertion/deletion ACE I/D; and alpha adducin G460T. Four genes belong to the renin-angiotensin system, and adducin codes for a gene whose product has been associated with renin status. Significant association was found between low-renin status and the alpha Gly460Trp polymorphism. Genotype frequencies in the hypertensive population were consistent with Hardy-Weinberg equilibrium. Genotype frequencies revealed 23% 460GG and 17% of the GT heterozygotes to be low-renin hypertensives, contrasted with 67% of the 460TT homozygotes (p=0.004). Genotype frequencies within low-renin were 39 for GG, 13 for GT, and 6 for TT; for normal renin the corresponding frequencies were 133, 62 and 3. The association was significant with whites alone; p = 0.01. The alpha-adducin G460W association was highly significant among females (p=0.003) but not among men (p=0.8). Of all the other genotypes, a trend toward significant association was seen among men only for the aldosterone synthase gene CYPC344T (p=0.08). On exploring the interaction between the two suspect genes, we observed a significant association among males (p=0.03) but not among females (p=0.2). Of 58 low-renin hypertensives genotyped at both the adducin 460 and CYP 344, 10% are homozygous at adducin 460; taking into account the heterozygotes for adducin, those who are also homozygous for the CYP344T represent an additional 30% of low-renin males. Familial determinants, probably genetic, contribute to the low-renin hypertension state.