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

Area of Science:

• Genetics and Genomics
• Cardiovascular Disease Research
• Menopause Studies

Background:

• Premature menopause is an established risk factor for cardiovascular disease (CVD) in women, but the underlying biological mechanisms are not fully understood.
• Clonal Hematopoiesis of Indeterminate Potential (CHIP), characterized by the expansion of hematopoietic cells with mutations, is linked to accelerated atherosclerosis.
• The relationship between premature menopause and the development of CHIP has not been previously investigated.

Purpose of the Study:

• To investigate the association between premature menopause and the prevalence of Clonal Hematopoiesis of Indeterminate Potential (CHIP) in postmenopausal women.
• To determine if CHIP is independently associated with incident coronary artery disease in this population.

Main Methods:

• Analysis of whole exome and whole genome sequences from UK Biobank and Women's Health Initiative cohorts.
• Definition of premature menopause as occurring before age 40 (natural or surgical).
• Logistic regression and multivariable-adjusted Cox models were used to assess associations between premature menopause, CHIP, and incident coronary artery disease, adjusting for relevant covariates.

Main Results:

• Premature menopause was independently associated with a higher prevalence of CHIP (OR 1.36 for all CHIP; OR 1.40 for CHIP with VAF >0.1).
• Natural premature menopause showed a stronger association with CHIP (OR 1.73 for all CHIP; OR 1.91 for CHIP with VAF >0.1) compared to surgical menopause.
• CHIP was independently associated with an increased risk of incident coronary artery disease in postmenopausal women (HR 1.36 for all CHIP; HR 1.48 for CHIP with VAF >0.1).

Conclusions:

• Premature menopause, especially natural onset, is significantly associated with CHIP in postmenopausal women.
• Natural premature menopause may indicate a predisposition to developing CHIP and subsequent CHIP-associated cardiovascular disease.
• These findings suggest CHIP as a potential mediator linking premature menopause to increased cardiovascular risk.