Epistatic interactions between ACE, ADD, and AS genes significantly influenced hypertension incidence, with ACE/DD homozygotes showing a 252% higher incidence among those with ADD/Trp and AS/CC genotypes (P=0.001).
Cohort (n=1,461)
Do epistatic interactions between the ACE, ADD, and AS genes influence the prevalence and incidence of hypertension in a Caucasian population?
Epistatic interactions between the ACE, ADD, and AS genes significantly contribute to the risk of developing hypertension in Caucasian populations.
Relative Risk: 1.29
p-value: p=0.05
BACKGROUND: The genes encoding angiotensin converting enzyme (ACE, I/D), alpha-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, -344C/T) share the potential of influencing blood pressure (BP) via sodium homeostasis. However, most studies in humans focused on single-gene effects and disregarded epistasis, the suppression or potentiation of a gene by other non-allelic genes. METHODS: We studied the singular and combined effects of the aforementioned candidate genes: (1) in relation to BP, plasma renin activity (PRA) and urinary aldosterone in 1461 subjects randomly selected from a Caucasian population; and (2) in relation to the incidence of hypertension in a subgroup of 678 initially normotensive subjects followed up for 9.1 years (median). RESULTS: In cross-sectional analyses, AS/CC homozygosity was associated with slightly lower systolic BP (-1.32 mmHg; P = 0.08). AS/TT homozygotes showed both lower PRA and higher urinary aldosterone excretion (P < or = 0.05). In multiple-gene analyses, compared with the whole study population, ADD/Trp subjects had a higher relative risk of hypertension in the presence of the AS/T allele (1.29; P = 0.05), whereas in combination with AS/CC homozygosity ADD/Trp subjects had the smallest relative risk (0.48; P = 0.003). Hypertension developed in 229 subjects (36.6 cases per 1000 person-years). ACE/DD homozygosity, in comparison with the other ACE genotypes, was associated with increases in the incidence of hypertension, which amounted to 31% (P = 0.005) in single-gene analyses, to 59% (P = 0.004) in carriers of the ADD/Trp allele and to 122% (P = 0.0007) in AS/CC subjects. Among subjects who had both the ADD/Trp allele and the AS/CC genotype, ACE/DD homozygotes manifested a 252% (P = 0.001) higher incidence of hypertension. CONCLUSIONS: Epistatic interactions between the ACE, ADD and AS genes contribute to the prevalence and incidence of hypertension in Caucasians. The clinical relevance of the risk-conferring haplotypes identified in our prospective study was underscored by their positive predictive values, which under the assumption of a 20% life-time risk of hypertension, ranged from 29.8-40.1%.
Staessen et al. (2001) conducted a cohort in Hypertension (n=1,461). ACE, ADD, and AS gene polymorphisms vs. Other genotypes was evaluated on Incidence of hypertension (RR 1.29, p=0.05). Epistatic interactions between ACE, ADD, and AS genes significantly influenced hypertension incidence, with ACE/DD homozygotes showing a 252% higher incidence among those with ADD/Trp and AS/CC genotypes (P=0.001).