Dataset Information

Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.

ABSTRACT: Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to cardiovascular disease, we tested the hypothesis that the polymorphisms were associated with endogenous steroid hormone levels.Multiple regression analysis was used to assess the relation between reported polymorphisms and total serum estradiol, testosterone, and dehydroepiandrosterone sulfate levels in 834 men and 687 women who attended the third and fourth Framingham Heart Study examination cycles.In men, significant associations were detected between CYP19A1 polymorphisms and estradiol and testosterone levels, and the estradiol to testosterone ratio (P ranges 0.0005-0.01). Specifically, carriers of common haplotype rs700518[G]-(TTTA)(n) [L]-rs726547[C] had higher estradiol levels (5% per copy; P = 0.0004), lower testosterone levels (17% per copy; P = 0.036), and a higher estradiol to testosterone ratio (24% per copy; P < 0.0001) compared with the rs700518[A]-(TTTA)(n) [S]-rs726547[C] carriers. In addition, postmenopausal carriers of the ESR2 (CA)(n) long allele and rs1256031 [C] allele had moderately higher estradiol levels (P < or = 0.03). No significant associations with the ESR1 variants were detected.Our findings suggest that variations in CYP19A1 correlate with steroid hormone levels in men. Knowledge that a specific carrier status may predispose to altered steroid hormone levels may lead to targeted intervention strategies to reduce health risks in genetically susceptible individuals.

SUBMITTER: Peter I

PROVIDER: S-EPMC2453049 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.

Peter Inga I Kelley-Hedgepeth Alyson A Fox Caroline S CS Cupples L Adrienne LA Huggins Gordon S GS Housman David E DE Karas Richard H RH Mendelsohn Michael E ME Levy Daniel D Murabito Joanne M JM

The Journal of clinical endocrinology and metabolism 20080429 7

<h4>Background</h4>Younger age at the onset of menopause and lower circulating levels of estrogen are risk factors for cardiovascular disease. Several studies have detected associations between variations in genes encoding estrogen receptors alpha (ESR1) and beta (ESR2), and enzyme aromatase (CYP19A1), which regulates the estrogen to testosterone ratio, and cardiovascular phenotypes in the Framingham Heart Study. To explore potential mechanisms by which these gene variants may contribute to card ...[more]

PMID: 18445666

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Project description:Background and Purpose- Although exogenous hormone therapy (HT) use has been associated with increased risk of ischemic stroke in postmenopausal women, it remains unknown whether sex hormone levels contribute to ischemic stroke risk. We aimed to estimate associations between plasma sex hormone levels and ischemic stroke risk, by HT status, in a nested case-control study of postmenopausal women from the NHS (Nurses' Health Study). Methods- Women with confirmed incident ischemic stroke (n=419) were matched with controls (n=419) by age, HT use, and other factors. Plasma estradiol and testosterone levels were measured using liquid chromatography tandem mass spectrometry; SHBG (sex hormone-binding globulin) was assayed by electrochemiluminescence immunoassay. Associations of total and free estradiol and testosterone, the estradiol/testosterone ratio, and SHBG with ischemic stroke were estimated using conditional logistic regressions stratified by HT status with adjustment for matching and cardiovascular risk factors. Results- Current HT users had different hormone profiles from never/past users. No clear linear trends were observed between estradiol (total or free) levels or the estradiol/testosterone ratio and ischemic stroke risk among either current users (Ptrend>0.1) or never/past users (Ptrend>0.6). For both current and never/past users, the associations between some of the sex hormones and ischemic stroke differed by body mass index categories (Pinteraction≤0.04). For women with a body mass index <25 kg/m2, a higher estradiol/testosterone ratio was associated with significantly elevated ischemic stroke risk among current users (Ptrend=0.01), and higher levels of total and free estradiol were significantly associated with higher ischemic stroke risk among never/past users (Ptrend≤0.04). Testosterone and SHBG were not associated with ischemic stroke in either current or never/past users. Conclusions- Our findings do not support a role of sex hormone levels in mediating ischemic stroke risk among postmenopausal women. Replications in additional larger studies are required.

Project description:The literature on hormone changes in pregnancy has focused largely on cortisol, and changes in sample average concentrations. Within-person changes and variability in hormone concentrations are less commonly reported, particularly for sex hormones, and especially measured in hair. Using a prospective sample of pregnant women and a non-pregnant comparison group, we examined changes in five steroid hormones in hair. Non-pregnant women were recruited from the same area with parallel procedures and assessment timeline. Participants include 68 women (34 pregnant, average age = 29.14, and 34 non-pregnant; average age = 27.18) who were predominately non-Hispanic White (83%), and above the 2020 poverty line (75%). Pregnant women provided 3cm hair samples and completed questionnaires three times during pregnancy: 1) at 12 weeks, 2) at 26 weeks, and 3) at 38 weeks. Non-pregnant women provided 3cm hair samples and completed questionnaires three times, at baseline, 14 weeks later, and 12 weeks after that to mirror the assessment schedule of the pregnant group. There was clear evidence that progesterone was higher initially and increased dramatically across pregnancy whereas non-pregnant patterns showed no systematic change. There was suggestive evidence that cortisol and estradiol increased over pregnancy and in non-pregnant women similarly across the same time course. There was suggestive evidence that DHEA decreased across pregnancy, particularly early in pregnancy, differently from patterns in non-pregnant women over the same time course. Most importantly, there was substantial variability of hormone concentrations and many different within-person patterns of changes in these hormones over time, with little evidence of systematic change or stability within-individuals. Moving beyond discussing sample averages to including within-person and non-linear changes in studies of hormones-behavior associations during pregnancy is an important future direction for further investigation.

Project description:BackgroundThe causal relationships between testosterone, estradiol, estrogen sulfotransferase, and idiopathic pulmonary fibrosis (IPF) are not well understood. This study employs a bidirectional two-sample Mendelian Randomization (MR) approach to explore these associations.MethodsAll genetic data utilized in our study were obtained from the IEU Open GWAS project. For the MR analysis, we employed the inverse variance weighted (IVW), MR-Egger, and weighted median methods to assess the causal relationships. We also conducted a multivariate MR (MVMR) analysis, with adjustments made for smoking. To ensure the robustness of our findings, sensitivity analyses were conducted using Cochran's Q test, MR-Egger regression, the MR-PRESSO global test, and the leave-one-out method.ResultsGenetically predicted increases in serum testosterone levels by one standard deviation were associated with a 58.7% decrease in the risk of developing IPF (OR = 0.413, PIVW=0.029, 95% CI = 0.187 ∼ 0.912), while an increase in serum estrogen sulfotransferase by one standard deviation was associated with a 32.4% increase in risk (OR = 1.324, PIVW=0.006, 95% CI = 1.083 ∼ 1.618). No causal relationship was found between estradiol (OR = 1.094, PIVW=0.735, 95% CI = 0.650 ∼ 1.841) and the risk of IPF. Reverse MR analysis did not reveal any causal relationship between IPF and testosterone (OR = 1.001, PIVW=0.51, 95% CI = 0.998 ∼ 1.004), estradiol (OR = 1.001, PIVW=0.958, 95% CI = 0.982 ∼ 1.019), or estrogen sulfotransferase (OR = 0.975, PIVW=0.251, 95% CI = 0.933 ∼ 1.018). The MVMR analysis demonstrated that the association between testosterone (OR = 0.442, P = 0.037, 95% CI = 0.205 ∼ 0.953) and estrogen sulfotransferase (OR = 1.314, P = 0.001, 95% CI = 1.118 ∼ 1.545) and the risk of IPF persisted even after adjusting for smoking.ConclusionsIncreased serum levels of testosterone are associated with a reduced risk of IPF, while increased levels of serum estrogen sulfotransferase are associated with an increased risk. No causal relationship was found between estradiol and the development of IPF. No causal relationship was identified between IPF and testosterone, estradiol, or estrogen sulfotransferase.

Dataset Information

Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.

Publications

Variation in estrogen-related genes associated with cardiovascular phenotypes and circulating estradiol, testosterone, and dehydroepiandrosterone sulfate levels.

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