Premature Menopause Linked to Risk of Clonal Hematopoiesis of Indeterminate Potential

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Researchers tried to determine whether natural or surgical premature menopause was associated with an elevated risk of clonal hematopoiesis of indeterminate potential with or without incident CAD events.

Premature menopause, especially natural premature menopause, is independently associated with clonal hematopoiesis of indeterminate potential (CHIP) in postmenopausal women, according to a study published in Circulation.

Researchers sought to determine whether premature menopause, both overall and stratified by natural and surgical premature menopause, was associated with an elevated risk of CHIP, including CHIP with incident coronary artery disease (CAD) events.

The study authors included 11,495 women (aged 40 to 70 years, 100% White) from the UK Biobank and 8,111 women (aged 50 to 79 years, 83% White) from the Women’s Health Initiative (WHI) with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40. Primary outcomes were the presence of any CHIP and CHIP with variant allele frequency (VAF) greater than 0.1, and secondary analyses assessed natural versus surgical premature menopause and gene-specific CHIP subtypes.

Among the overall total of 19,606 women, 418 (2.1%) had natural premature menopause and 887 (4.5%) had surgical premature menopause. At blood draw for whole exome and whole genome sequencing, the mean age was 60.1 years (SD, 5.2) for women in the UK Biobank and 68.3 (SD, 6.6) years for those in the WHI cohort. The prevalence of CHIP among postmenopausal women with a history of premature menopause was 8.8% compared with 5.5% in those without a history of premature menopause (P <.001), across the 2 cohorts. After conducting multivariable adjustment, the investigators found that premature menopause was independently associated with CHIP (all CHIP: odds ratio [OR] 1.36, 95% CI, 1.10-1.68, P =.004; CHIP with VAF >0.1: OR 1.40, 95% CI, 1.10-1.79, P =.007).

The associations were greater for women with natural premature menopause (all CHIP: OR 1.73, 95% CI, 1.23-2.44, P =.001; CHIP with VAF >0.1: OR 1.91, 95% CI, 1.30-2.80, P <.001) but smaller and nonsignificant for women with surgical premature menopause. In addition, CHIP was independently associated with coronary artery disease (hazard ratio [HR] associated with all CHIP: 1.36, 95% CI, 1.07-1.73, P =.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI, 1.13-1.94, P =.005).

“A history of premature menopause, especially natural premature menopause, was independently associated with increased odds of CHIP, a recently recognized risk factor for cardiovascular disease, in 2 large cohorts of postmenopausal women with whole exome or genome sequencing of blood DNA,” stated the researchers. “The risks of developing CHIP and specific CHIP driver mutations appeared to differ in women with natural versus surgical premature menopause, implying that postmenopausal reductions in estrogen and other sex steroid hormones alone may not explain the relationship between menopause and CHIP.”

Among several study limitations, the investigators noted that the UK Biobank cohort included women of European ancestry only, and age at menopause was determined by participant self-report in both cohorts, which may be inaccurate.

“CHIP was associated with incident CAD events in postmenopausal middle-aged women independent of conventional CAD risk factors,” the researchers commented. “Natural premature menopause may represent a risk signal for latent genomic instability and predilection to develop CHIP and CHIP-associated cardiovascular disease.”

Disclosures: Some of the authors reported affiliations with pharmaceutical and medical device companies. Please see the original reference for a full list of disclosures.


Honigberg MC, Zekavat SM, Niroula A, et al. Premature menopause, clonal hematopoiesis, and coronary artery disease in postmenopausal women. Published online November 9, 2020. Circulation. doi: 10.1161/CIRCULATIONAHA.120.051775