Polymorphisms in the estrogen receptor alpha gene and endothelial function in resistance and conduit arteries in the elderly.
BACKGROUND
Prior evidence suggests an important role for estrogen in the regulation of endothelium-dependent vasodilation, but the mechanisms modulating this are not known. Our aim was to examine the relations of single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) to endothelium-dependent vasodilation.


METHODS
We evaluated 959 70-year-old participants (51% men) 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 genotyped 25 common SNPs in the ESR1 gene, and related them to EDV and FMD using multivariable linear regression, adjusting for sex and other potential confounders, such as major cardiovascular risk factors and medications. 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 individual SNP analyses. FMD was not associated with any of the ESR1 SNPs.


CONCLUSIONS
In our community-based study of elderly, a polymorphism in the estrogen receptor alpha gene was associated with endothelium-dependent vasodilation in resistance, but not conduit arteries. Our findings should stimulate further exploration in other settings.
Department of Public Health and Caring Sciences, Uppsala University, Uppsala Science Park, SE-751 85 Uppsala, Sweden. erik.ingelsson@pubcare.uu.se
Erik
E
Ingelsson
Ann-Christine
AC
Syvänen
Lars
L
Lind
D000109:Acetylcholine / Q000008:administration & dosage; D000368:Aged; D000375:Aging / Q000502:physiology*; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage
D047628:Estrogen Receptor alpha; D014665:Vasodilator Agents; D000109:Acetylcholine