Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population.
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
J A
JA
Departement Moleculair en Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Belgium. jan.staessen@med.kuleuven.ac.be
Wang
J G
JG
Brand
E
E
Barlassina
C
C
Birkenhäger
W H
WH
Herrmann
S M
SM
Fagard
R
R
Tizzoni
L
L
Bianchi
G
G
D000328:Adult; D000483:Alleles; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D003430:Cross-Sectional Studies; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000453:epidemiology* / Q000235:genetics*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology; D015995:Prevalence; D044465:White People / Q000235:genetics*; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D019405:Cytochrome P-450 CYP11B2; D007703:Peptidyl-Dipeptidase A; D000099291:Adducins