Dataset Information

Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.

ABSTRACT:

Context

Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.

Objective

The objective was to test an interaction between genetic susceptibility and HT on fracture risk.

Design

We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also used the case-only approach to test for a multiplicative interaction.

Setting

Forty US clinical centers.

Participants

A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.

Main outcome measures

Adjudicated fracture incidence.

Results

Both GRSs were associated with fracture risk per 1-unit increment in GRS (hazard ratio, 1.04 [95% confidence interval, 1.02 to 1.06] for Fx-GRS and hazard ratio, 1.03 [95% confidence interval,1.02-1.04] for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a substantial additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS P for RERI = 0.047, BMD-GRS P for RERI = 0.046.

Conclusions

These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5470770 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.

Wang Youjin Y Wactawski-Wende Jean J Sucheston-Campbell Lara E LE Preus Leah L Hovey Kathleen M KM Nie Jing J Jackson Rebecca D RD Handelman Samuel K SK Nassir Rami R Crandall Carolyn J CJ Ochs-Balcom Heather M HM

The Journal of clinical endocrinology and metabolism 20170601 6

<h4>Context</h4>Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.<h4>Objective</h4>The objective was to test an interaction between genetic susceptibility and HT on fracture risk.<h4>Design</h4>We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). ...[more]

PMID: 28324062

Similar Datasets

Project description:ImportanceMenopausal hormone therapy (MHT) is the treatment of choice for symptoms of menopause. However, its adoption is hindered by the risk-benefit trade-off in relation to acute and chronic diseases.ObjectiveTo evaluate trends in and correlates of MHT use among postmenopausal women in the US from 1999 to March 2020.Design, setting, and participantsThis serial cross-sectional analysis of MHT use used data from the nationally representative National Health and Nutrition Examination Survey (NHANES). Participants included noninstitutionalized US postmenopausal women from 10 NHANES study cycles (1999-2000 to 2017-March 2020 [pre-COVID-19 pandemic]). Data were analyzed from December 2023 to April 2024.ExposuresNHANES study cycle.Main outcomes and measuresPrevalence of MHT use was extracted from the prescription medication data collected during NHANES household interviews. MHT formulations were determined by hormone type.ResultsData on 13 048 US postmenopausal women (47.1% ≥65 years old) were analyzed. From 1999 to 2020, the prevalence of MHT use decreased among women of all age groups, from 26.9% (95% CI, 22.6%-31.7%) in 1999 to 4.7% (95% CI, 3.4%-6.5%) in 2020. Until 2002, MHT use was highest among women aged 52 to 65 years, but since 2005, MHT use has been highest among women younger than 52 years. MHT use decreased by 23.5% (95% CI, 11.4%-35.6%), 31.4% (95% CI, 23.4%-39.5%), and 10.6% (95% CI, 6.3%-14.8%) for women younger than 52 years, 52 years to younger than 65 years, and 65 years and older, respectively. Prevalence of MHT use decreased from 13.8% (95% CI, 8.5%-21.7%) to 2.6% (95% CI, 1.5%-4.6%) for Hispanic women, 11.9% (95% CI, 8.5%-16.3%) to 0.5% (95% CI, 0.2%-1.1%) for non-Hispanic Black women, and 31.4% (95% CI, 27.1%-36.1%) to 5.8% (95% CI, 4.1%-8.2%) for non-Hispanic White women. Non-Hispanic White women consistently had the highest prevalence of MHT use. Estrogen-only formulation accounted for more than 50% of the MHT for most study periods. The prevalence of MHT use varied by family income-to-poverty ratio, health insurance coverage in all racial and ethnic groups, weight, and smoking status among non-Hispanic White women, as well as by education attainment among non-Hispanic Black and Hispanic women.Conclusions and relevanceResults of this cross-sectional study show that over the past 2 decades, MHT use declined among US postmenopausal women of all age and racial and ethnic groups. Women of racial and ethnic minority groups had lower prevalence of MHT use compared to non-Hispanic White women.

Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

Project description:ImportanceMenopause is associated with biological aging, and hormone therapy (HT) is associated with health outcomes in postmenopausal women.ObjectiveTo evaluate the association between HT use and discrepancies between chronological and biological age in postmenopausal women as well as the potential modifying role of socioeconomic status (SES).Design, setting, and participantsThis population-based, retrospective cohort study included postmenopausal women registered in the UK Biobank. A baseline survey on HT use and biological aging biomarkers was conducted from March 2006 to October 2010. Data analyses were conducted in December 2023.ExposuresInformation regarding HT use, the age at starting HT, and HT duration was collected via a touchscreen questionnaire. SES was evaluated by education, family income, occupation, and the Townsend Deprivation Index.Main outcomes and measuresBiological aging discrepancy was evaluated using validated phenotypic age, which was calculated using chronological age and 9 biomarkers measured at baseline. All-cause and cause-specific mortality were also assessed.ResultsAmong the 117 763 postmenopausal women (mean [SD] age, 60.2 [5.4] years), 47 461 (40.3%) ever used HT. The mean phenotypic age was 52.1 (7.9) years. Ever use of HT was associated with a smaller biological aging discrepancy than never use of HT (β, -0.17 years; 95% CI, -0.23 to -0.10 years). This smaller aging discrepancy was more evident in those who started HT at age 55 years or older (β, -0.32 years; 95% CI, -0.48 to -0.15 years) and in those who used HT for 4 to 8 years (β, -0.25 years; 95% CI, -0.35 to -0.15 years). The association between HT and a smaller aging discrepancy was more evident in women with low SES, with a significant interaction observed for education (higher education: β, -0.08 years [95% CI, -0.17 to 0.01]; other education: β, -0.23 [95% CI, -0.32 to -0.14] years; P for interaction = .02). Phenotypic aging discrepancy mediated 12.7% (95% CI, 6.3% to 23.9%) of the association between HT and all-cause mortality and cause-specific mortality.Conclusions and relevanceIn this study, postmenopausal women with historical HT use were biologically younger than those not receiving HT, with a more evident association observed in those with low SES. The biological aging discrepancy mediated the association between HT and decreased mortality. Promoting HT in postmenopausal women could be important for healthy aging.

Project description:BackgroundGenome-wide association studies have identified several genomic regions that are associated with stroke risk, but these provide an explanation for only a small fraction of familial stroke aggregation. Genotype by environment interactions may contribute further to such an explanation. The Women's Health Initiative (WHI) clinical trial found increased stroke risk with postmenopausal hormone therapy (HT) and provides an efficient setting for evaluating genotype-HT interaction on stroke risk.MethodsWe examined HT by genotype interactions for 392 SNPs selected from candidate gene studies, and 2,371 SNPs associated with changes in blood protein concentrations after hormone therapy, in analyses that included 2,045 postmenopausal women who developed stroke during WHI clinical trial and observational study follow-up and one-to-one matched controls. A two-stage procedure was implemented where SNPs passing the first stage screening based on marginal association with stroke risk were tested in the second stage for interaction with HT using case-only analysis.ResultsThe two-stage procedure identified two SNPs, rs2154299 and rs12194855, in the coagulation factor XIII subunit A (F13A1) region and two SNPs, rs630431 and rs560892, in the proprotein convertase subtilisin kexin 9 (PCSK9) region, with an estimated false discovery rate <0.05 based on interaction tests. Further analyses showed significant stroke risk interaction between these F13A1 SNPs and estrogen plus progestin (E+P) treatment for ischemic stroke and for ischemic and hemorrhagic stroke combined, and suggested interactions between PCSK9 SNPs with either E+P or estrogen-alone treatment.ConclusionsGenotype by environment interaction information may help to define genomic regions relevant to stroke risk. Two-stage analysis among postmenopausal women generates novel hypotheses concerning the F13A1 and PCSK9 genomic regions and the effects of hormonal exposures on postmenopausal stroke risk for subsequent independent validation.

Dataset Information

Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.

Context

Objective

Design

Setting

Participants

Main outcome measures

Results

Conclusions

Publications

Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets