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Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women

Research investigators from Massachusetts General Hospital have found that women with premature menopause often exhibit certain blood cell changes that elevate their risk of developing coronary artery disease. 

Results of the study, which included whole-genome sequencing of nearly 20k women in the US and UK, details the mechanism behind premature menopause and its link to increased risk of cardiovascular disease while also uncovering a potential biomarker for identifying women at greater risk.

Investigators made an efffort to determine whether clonal hematopoiesis of indeterminate potential (CHIP), was associated with premature menopause. With this in mind,the research team sought to assess this association using blood sample data from the UK Biobank and the Women’s Health Initiative.

From the UK Biobank and Women’s Health Initiative, investigators identified cohorts of 11,495 postmenopausal women 40-70 years of age and 8111 postmenopausal women 50-79 years of age, respectively, for inclusion in their analysis. Of note, patients from the UK Biobank had a median follow-up of 10.0 years and those from the Women’s Health Initiative had a median follow-up of 13.1 years. For the purpose of analysis, investigators defined premature menopause as natural or surgical menopause occurring before 40 years of age.

The primary outcomes of the analysis were the presence of any CHIP and CHIP with variant allele frequency greater than 0.1. Investigators used logistic regression to test the association of premature menopause with CHIP and adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Investigators pointed secondary analysis assessed natural versus surgical premature menopause and gene-specific CHIP subtypes and multivariable-adjusted Cox models were used to test associations between CHIP and incident coronary artery disease.

Abstract

Background:

Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown.

Methods:

We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women's Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD).

Results:

The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005).

Conclusions:

Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.

Reference

Michael C. Honigberg et al, Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women, Circulation (2020). DOI: 10.1161/CIRCULATIONAHA.120.051775

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