Association between arterial stiffness and variations in estrogen-related genes

Increased arterial stiffness and wave reflection have been identified as cardiovascular disease risk factors. In light of significant sex differences and the moderate heritability of vascular function measures, we hypothesized that variation in the genes coding for estrogen receptors alpha (ESR1) and beta (ESR2) and aromatase (CYP19A1) is associated with aortic stiffness and pressure wave reflection as measured by noninvasive arterial tonometry. 1261 unrelated Framingham Offspring Study participants who attended the 7(th) examination cycle (mean age 62±10 years, 52% women) and had arterial tonometry and genotyping data were included in the study. ANCOVA was used to assess the association of polymorphisms with forward wave amplitude, augmented pressure, augmentation index, carotid-femoral pulse wave velocity, and mean arterial pressure with adjustment for potential confounders. In the sex-pooled analysis, those homozygous for the minor allele at any of four ESR1 variants that were in strong linkage disequilibrium ((TA)(n), rs2077647, rs2234693 and rs9340799) had on average 18% higher augmented pressure and 16% greater augmentation index compared to carriers of one or two major alleles (p=0.0002–0.01). A similar magnitude of association was detected in those homozygous for the common allele at two ESR2 SNPs (p=0.007–0.02). Our results are consistent with the hypothesis that variation in ESR1 and ESR2, but not CYP19A1, is associated with increased wave reflection, which may contribute to previously demonstrated associations between these variants and adverse clinical events. Our findings will need to be replicated in additional cohorts.