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

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 to 70 years with whole exome sequences and from the Women's Health Initiative (n=8111) aged 50 to 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 any CHIP and CHIP with variant allele frequency >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, and hormone therapy use. Secondary analyses considered natural versus surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease.

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 versus without a history of premature menopause was 8.8% versus 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: odds ratio, 1.36 [95% 1.10-1.68]; P=0.004; CHIP with variant allele frequency >0.1: odds ratio, 1.40 [95% CI, 1.10-1.79]; P=0.007). Associations were larger for natural premature menopause (all CHIP: odds ratio, 1.73 [95% CI, 1.23-2.44]; P=0.001; CHIP with variant allele frequency >0.1: odds ratio, 1.91 [95% CI, 1.30-2.80]; P<0.001) but smaller and nonsignificant 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 (hazard ratio associated with all CHIP: 1.36 [95% CI, 1.07-1.73]; P=0.012; hazard ratio associated with CHIP with variant allele frequency >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.

Keywords: clonal hematopoiesis; coronary artery disease; hematology; inflammation; menopause, premature; women.

Figure 1.. Creation of the study cohort.

The study cohort included postmenopausal women from the UK Biobank with whole exome sequencing (WES) and from the Women’s Health Initiative (WHI) with whole genome sequencing (WGS).

Figure 2.. Prevalence of (A) any CHIP and (B) CHIP with variant allele frequency >0.1 by age and premature menopause status in the UK Biobank and Women’s Health Initiative.

As expected, CHIP prevalence increased with age. Prevalence of CHIP was higher in women with a history of premature menopause than in women without a history of premature menopause irrespective of age at blood draw. Error bars represent ±1 standard error of the sample proportion. WHI = Women’s Health Initiative; CHIP = clonal hematopoiesis of indeterminate potential; VAF = variant allele frequency.

Figure 3.. Meta-analysis of associations between premature menopause and CHIP in the UK Biobank and Women’s Health Initiative.

Premature menopause was independently associated with CHIP. Associations were larger for natural premature menopause but smaller and non-significant for surgical premature menopause. Models for both cohorts are adjusted for age, the first 10 principal components of ancestry, ever-smoking, diabetes mellitus, and use of hormone therapy. WHI models are further adjusted for race/ethnicity, enrollment in the WHI observational study vs. clinical trial, and whether women were randomized to hormone therapy vs. placebo. WHI = Women’s Health Initiative; CHIP = clonal hematopoiesis of indeterminate potential; VAF = variant allele frequency.

Figure 4.. Incidence of coronary artery disease in women with and without CHIP in the UK Biobank and Women’s Health Initiative.

CHIP was independently associated with incident coronary artery disease in meta-analyzed results from postmenopausal women in the UK Biobank (age 40–70 years at blood draw) and postmenopausal women <70 years old at blood draw in the Women’s Health Initiative (WHI). Cox proportional hazard models are adjusted for age, the first 10 principal components of ancestry, current or former tobacco use, prevalent diabetes mellitus, systolic blood pressure, antihypertensive medication use, cholesterol-lowering medication use, body-mass index, prior hysterectomy, and a history of prior hormone therapy use; WHI models are further adjusted for race/ethnicity, enrollment in the WHI observational study vs. clinical trial, whether women were randomized to hormone therapy vs. placebo, and a WHI inverse probability weight. CHIP = clonal hematopoiesis of indeterminate potential; VAF = variant allele frequency; HR = hazard ratio.