Abstract 1437: Polymorphisms in the Estrogen Receptor Genes and Endothelium-Dependent Vasodilation in Elderly
Background: Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and 2 (ESR2) genes have been associated with blood pressure, subclinical and overt cardiovascular disease, but their relation to endothelium-dependent vasodilation is unknown.
Methods: We evaluated 959 70-year-old participants of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, using invasive forearm technique with intra-brachial infusion of acetylcholine (EDV; reflecting vasodilation in resistance arteries), and brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting vasodilation in conduit arteries). We analyzed 25 common SNPs in the ESR1 gene and 5 in the ESR2 gene by minisequencing, and related them to EDV and FMD using multivariable linear regression, adjusting for sex, systolic blood pressure, diastolic blood pressure, pulse rate, anti-hypertensive treatment, total cholesterol, high-density cholesterol, lipid-lowering medication, fasting glucose, anti-diabetic medication, body mass index, current smoking, and prior diagnosis of cardiovascular disease. Haplotypes were estimated using the PHASE software.
Results: We observed an association between rs1709183 in the ESR1 gene and EDV (nominal P=0.0012), with a lower EDV in carriers of the minor allele (C). This association remained significant after adjustment for multiple testing (empirical P=0.031, obtained using bootstrap re-sampling). Two ESR1 haplotypes in the block containing rs1709183 were associated with EDV (individual haplotype P=0.0015 and P=0.025); the directions of effect were consistent with the individual SNP analyses. There were no associations between SNPs in the ESR2 gene and EDV with a nominal P=0.01. FMD was not associated with either ESR1 or ESR2.
Conclusions: In our community-based study of elderly, a polymorphism in the ESR1 gene was associated with endothelium-dependent vasodilation in resistance arteries, but not in conduit arteries. Our findings should stimulate to replication and further exploration in other settings.