Estrogen Receptor α Gene Polymorphisms and Risk of Myocardial Infarction

Abstract

ContextThe role of estrogens in ischemic heart disease (IHD) is uncertain. Evidence suggests that genetic variations in the estrogen receptor ␣ (ESR1) gene may influence IHD risk, but the role of common sequence variations in the ESR1 gene is unclear.Objective To determine whether the ESR1 haplotype created by the c.454-397TϾC (PvuII) and c.454-351AϾG (XbaI) polymorphisms is associated with myocardial infarction (MI) and IHD risk. Design, Setting, and ParticipantsIn 2617 men and 3791 postmenopausal women from The Rotterdam Study (enrollment between 1989(enrollment between -1993(enrollment between and follow-up to January 2000, a population-based, prospective cohort study of participants aged 55 years and older, ESR1 c.454-397TϾC and c.454-351AϾG haplotypes were determined. Detailed interviews and physical examinations were performed, blood samples were obtained, and cardiovascular risk factors were assessed.Main Outcome Measure The primary outcome was MI and IHD defined as MIs, revascularization procedures, and IHD mortality.Results Approximately 29% of women and 28.2% of men were homozygous carriers of the ESR1 haplotype 1 (−397 T and −351 A) allele, 49% of women and 50% of men were heterozygous carriers, and 22% of women and 21.4% of men were noncarriers. During a mean follow-up of 7.0 years, 285 participants (115 women; 170 men) had MI, and 440 (168 women; 272 men) had an IHD event, of which 97 were fatal. After adjustment for known cardiovascular risk factors, female heterozygous carriers of haplotype 1 had an increased risk of MI (event rate, 2.8%; relative risk [RR], 2.23; 95% confidence interval [CI], 1.13-4.43) compared with noncarriers (event rate, 1.3%), whereas homozygous carriers had an increased risk (event rate, 3.2%; RR, 2.48; 95% CI, 1.22-5.03). For IHD events, we observed a similar association. In women, the effect of haplotype 1 on fatal IHD was larger than on nonfatal IHD. In men, the ESR1 haplotypes were not associated with an increased risk of MI (event rate, 5.7%; RR, 0.93; 95% CI, 0.59-1.46 for heterozygous carriers; and event rate, 5.1%; RR, 0.82; 95% CI, 0.49-1.38 for homozygous carriers) compared with noncarriers (event rate, 5.8%) and were not associated with an increased risk of IHD. ConclusionsIn this population-based, prospective cohort study, postmenopausal women who carry ESR1 haplotype 1 (c.454-397 T allele and c.454-351 A allele) have an increased risk of MI and IHD, independent of known cardiovascular risk factors. In men, no association was observed.

Estrogen receptor 1 gene polymorphisms in premenopausal women: interaction between genotype and smoking on lipid levels

“…Three large, well-designed and well-implemented studies were published with apparent contradictory results in relation to ESR1 IVS1-397T>C polymorphism and myocardial infarction (9)(10)(11). In relation to ESR1 IVS1-397T>C polymorphism and lipid levels, Demissie et al (12) demonstrated an association between IVS1-397T>C polymorphism T/T genotype and LDL-C particle size reduction in women from the Framingham Heart Study.…”

Estrogen receptor alpha gene polymorphisms are associated with estradiol levels in postmenopausal women

“…Based on previous analyses we chose haplotype 1 as the risk allele (9,11,16,21,22). To account for possible confounding, we adjusted the analysis of sex hormone levels for age, BMI, years since menopause and the direct precursor for each hormone when available.…”

“…Of the polymorphisms identified so far, the PvuII and XbaI SNPs, located in the first intron 397 and 351 bp upstream of exon 2, are the most widely studied. These polymorphisms have previously been associated with disease phenotypes such as osteoporosis (7 -10), cardiovascular disease (11,12) and cancer (13). Recently a potential functional significance of the PvuII polymorphisms was reported (14).…”

Estrogen receptor α gene polymorphisms and anxiety disorder in an elderly population

“…2 All SNPs were genotyped with Taqman Assays-by-Design SNP Genotyping Service and ABI PRISM s 7900HT Sequence Detection System (both: Applied Biosystems). The association of the ERa haplotype with depressive symptoms, and depressive disorders, and anxiety was assessed separately in men and women using logistic regression and testing an allele-dose model.…”

“…2 The translocation leads to an interference in the open reading frame of the Disrupted-in-Schizophrenia-1 (DISC1) gene that could produce a C-terminal truncated DISC1 protein. In a previous study, we conducted a yeast two-hybrid screening in order to identify possible protein interactors involved with cellular signaling of DISC1.…”