Estrogen-metabolizing gene polymorphisms and lipid levels in women with different hormonal status

Abstract

Endogenous and exogenous sex steroid hormones have multiple effects on lipid and lipoprotein metabolism. It is also known that estrogen has antiatherogenic actions, therefore we considered examining whether there was any association between polymorphisms in estrogen-metabolizing genes and lipid levels in women. We investigated the association between variants in genes related to estrogen biosynthesis (CYP19-TTTA n ) and estrogen catabolism (CYP1A1*2A, CYP1A1*2C, CYP1A2-Asn516Asn, CYP3A4*1B, and COMT-Val158Met) with serum lipid levels in a cross-sectional study with 472 Brazilian women of European descent. They were divided into three subgroups according to their hormonal status: premenopausal women (n ¼ 187), postmenopausal women exposed to hormonal replacement therapy (HRT) (n ¼ 118), and postmenopausal women unexposed to HRT (n ¼ 167). The postmenopausal women receiving HRT who were carriers of the CYP3A4*1B variant showed lower low-density lipoprotein cholesterol levels than wild-type homozygotes. Premenopausal women homozygous for the CYP1A1*2C allele had higher high-density lipoprotein cholesterol levels than heterozygotes. While the CYP1A1*2C variant probably has a higher catalytic activity, the functional implications of the CYP3A4 polymorphism are still uncertain. These data are the first attempt to associate estrogen metabolism genes to lipid levels in women.

Genetic polymorphisms of the CYP1A1, GSTM1, and GSTT1 enzymes and their influence on cardiovascular risk and lipid profile in people who live near a natural gas plant

“…In a Mexican study, CYP1A1-m2 allele was significantly associated with high triglycerides (28), and in a Brazilian study in postmenopausal women the same allele was associated with high HDL-cholesterol (29). Unlike these studies, we have found no association between any of the CYP1A1 polymorphisms and lipid parameters and neither has a Japanese study in women with osteopenia or osteoporosis (30).…”

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

“…The same group performed a cross-sectional study investigating possible associations between polymorphisms in genes related to estrogen biosynthesis and estrogen catabolism. In both studies, SNP CYP3A4-V was the only CYP3A4 variant searched for in the upstream region (44). Since these investigations used PCR and restriction mapping analysis as a molecular biology approach, these punctual studies assumed CYP3A4-V to be the only possible variation without a previous SNP screening.…”

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

“…In that work, we also observed a positive correlation of LDL cholesterol change in response to atorvastatin with CYP3A4 and CYP3A5 mRNA levels. Regarding cholesterol-lowering interventions, the effect of the CYP3A4*1B variant was also tested in Brazilian postmenopausal women under HRT, and the authors reported lower LDL cholesterol levels in carriers of the CYP3A4*1B allele [50]. This result suggests that individuals carrying *1B allele could respond more effectively to pharmacological intervention compared to individuals carrying the CYP3A4*1A/1A genotype who may have low response to treatment, and also could present some toxic effects.…”

“…However, some studies investigated the influence of polymorphisms after interventions with tamoxifen, hormone replacement therapy (HRT) and clozapine, an antipsychotic drug (Table 2). Almeida and co-workers [50] reported no association between the variants CYP1A1*2A, CYP1A1*2C and CYP1A2 p.Asn516Asn and the response to HRT monitored by changes in serum lipids. Similarly, a study evaluating the survival in women with breast cancer under tamoxifen treatment also showed no differences according to CYP1A1*2A and CYP1A1*2C genotypes [49].…”