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

Abstract

Estrogen has multiple effects on lipid and lipoprotein metabolism. We investigated the association between the four common single nucleotide polymorphisms in the estrogen receptor 1 (ESR1) gene locus, -1989T>G, +261G>C, IVS1-397T>C and IVS1-351A>G, and lipid and lipoprotein levels in southern Brazilians. The sample consisted in 150 men and 187 premenopausal women. The women were considered premenopausal if they had regular menstrual bleeding within the previous 3 months and were 18-50 years of age. Exclusion criteria were pregnancy, secondary hyperlipidemia due to renal, hepatic or thyroid disease, and diabetes. Smoking status was self-reported; subjects were classified as never smoked and current smokers. DNA was amplified by PCR and was subsequently digested with the appropriate restriction enzymes. Statistical analysis was carried out for men and women separately. In the study population, major allele frequencies were -1989*T (0.83), +261*G (0.96), IVS1-397 *T (0.58), and IVS1-351*A (0.65). Multiple linear regression analyses indicated that an interaction between +261G>C polymorphism and smoking was a significant factor affecting high-density lipoprotein cholesterol (HDL-C) levels (P = 0.028) in women. Nonsmoking women with genotype G/C of +261G>C polymorphism had mean HDL-C levels higher than those with G/ G genotype (1.40 ± 0.33 vs 1.22 ± 0.26 mmol/L; P = 0.033). No significant associations with lipid and lipoprotein levels in women and men were detected for other polymorphisms. In conclusion, the +261G>C polymorphism might influence lipoprotein and lipid levels in premenopausal women, but these effects seem to be modulated by smoking, whereas in men ESR1 polymorphisms were not associated with high lipoprotein levels.

The ABCA1 Gene R230C Variant Is Associated with Decreased Risk of Premature Coronary Artery Disease: The Genetics of Atherosclerotic Disease (GEA) Study

“…The BMI-R230C interactions observed only in pre-menopausal women suggest that these effects may be estrogen-related. Several lines of evidence are consistent with this finding: ABCA1 -diet interactions affecting HDL-C levels have been reported in pre-menopausal women [17], improved lipid profiles have been observed in response to estrogen [42]–[43], and estrogen increased ABCA1 expression in different tissues in both mice and humans [44]–[46]. The increased risk of these metabolic parameters in pre-menopausal women is again in discrepancy with their risk of CAD, and whether this has to do with other systemic effects of estrogen, and/or with pleiotropic effects of the R230C variant in platelets, endothelium, inflammatory or other cell types remains to be elucidated.…”

Lack of Association of Estrogen Receptor Alpha Gene Polymorphisms with Cardiorespiratory and Metabolic Variables in Young Women

“…Some studies have evaluated the impact of ESR1 polymorphisms (rs2234693 and rs9340799) on basal serum lipids in patients with coronary artery disease (CAD) [2,21,23], including healthy females at peak reproductive age [24,25], postmenopausal females [20,26] and premenopausal female smokers [27]. In Iranian population with symptoms related to CAD subgroups of patients stratified by gender, Boroumand et al [2] observed no effects of ESR1 c.454-39T > C and c.454-351A > G variants on serum lipids and lipoprotein(a) levels.…”

Carbohydrate Intake Modulates the Effect of the ABCA1 -R230C Variant on HDL Cholesterol Concentrations in Premenopausal Women

“…In contrast, the R230C variant and carbohydrate intake showed an independent, nonadditive effect in men. Although the cause of sex-related differences is not fully understood, estrogen is known to have an effect in premenopausal women by increasing HDL-C concentrations (37,38). Moreover, there is evidence that estrogen increases ABCA1 expression in different tissues (39,40) and estrogen therapy increases ABCA1 expression in leukocytes and improves lipid profile in menopausal women (41), suggesting that the sexspecific interaction here could be mediated by the effect of estrogen on ABCA1 expression.…”