P-275: Singular and epistatic effects of three candidate genes on carotid and femoral intima-media thickness in a Caucasian population

Abstract

We recently found that the prevalence of hypertension was significantly higher among subjects carrying both the α-adducin Trp allele (ADD/Trp) and the aldosterone-synthase T allele (AS/T). Carriers of the D allele of the angiotensin-converting enzyme gene (ACE/D) have higher ACE activity, which may promote generation of angiotensin II, a vascular growth factor. We therefore investigated whether intima-media thickening, a precursor of atherosclerosis, is related to these genetic polymorphisms. We used a wall-tracking ultrasound system to measure carotid and femoral intima-media thickness (IMT) in 380 subjects enrolled in a population study. They were genotyped for the presence of the ADD/Trp, AS/T and ACE/D alleles. The statistical analysis allowed for confounders and epistatic interactions among genes. The sample included 188 men (49.5%). Mean age was 39.8 years (range 12-76). IMT of the carotid and femoral arteries averaged 575 μm and 719 μm, respectively. The IMT of the femoral artery – but not carotid artery – increased with the number of ACE/D alleles, whereas none of the other single-gene associations with either artery reached statistical significance. The effect of ACE genotype on femoral IMT was confined to carriers of the ADD/Trp allele and the AS/T allele. Expressed as a percentage of the population mean, the mean differences between II and DD homozygotes averaged 12.5% (95% Cl 5.3–19.8%) in all subjects, 21.4% (8.5–34.3%) in carriers of the ADD/Trp allele, 15.4% (4.4–26.4%) in carriers of the AS/T allele, and 25.7% (18.5–32.9%) if the ADD/Trp and AS/T alleles were both present. In conclusion, complex epistatic interactions between the ACE, ADD and AS genes contribute to the IMT of large muscular arteries. If confirmed, these findings may have important clinical implications for the assessment of cardiovascular risk and the treatment of hypertension.

Intima-media thickness, Angiotensin-converting enzyme, α-Adducin