CV Risk Associated with Premature Menopause: Clonal Hematopoiesis May Contribute
Key findings
- This study tested whether premature menopause is associated with increased risk of clonal hematopoiesis of indeterminate potential (CHIP) among postmenopausal women in the UK Biobank and Women's Health Initiative (WHI)
- Across cohorts, the prevalence of CHIP was 8.8% among women with a history of premature menopause and 5.5% among women without (P<0.001); the prevalence increased with earlier age at menopause
- Premature menopause was independently associated with increased odds of CHIP (OR, 1.36; 95% CI, 1.10–1.68; P=0.004); that was driven by a stronger association between natural premature menopause and CHIP (OR, 1.73; P=0.001)
- Among women in the UK Biobank and WHI <70 years old, CHIP was associated with an increased risk of incident coronary artery disease (HR, 1.36; 95% CI, 1.07–1.73; P=0.01)
- Natural premature menopause seems to signal a predilection to CHIP development and may help indicate good candidates for CHIP screening and pharmaceutical strategies to mitigate CHIP-associated cardiovascular disease
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Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of blood stem cells with somatic mutations in leukemia-associated genes without overt cancer. CHIP is a relatively common age-associated phenomenon, and it has recently been recognized as a risk factor for cardiovascular disease (CVD).
Premature menopause (onset before age 40) has been linked with higher risk of CVD and all-cause mortality, but the mechanisms are unclear. Using next-generation genomic sequencing, Michael C. Honigberg, MD, MPP, cardiologist, and Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center at Massachusetts General Hospital, and colleagues determined that premature menopause was independently associated with increased odds of CHIP.
In turn, CHIP was associated with incident coronary artery disease (CAD) in postmenopausal middle-aged women, independent of conventional risk factors. The team published their findings in Circulation.
Study Cohorts
The study involved two cohorts of postmenopausal women:
- From the UK Biobank: 11,495 women, ages 40–70 at blood draw, with whole-exome sequences; 1.5% had natural premature menopause and 1.8% had surgical premature menopause
- From the Women's Health Initiative (WHI): 8,111 women, ages 50–79 at blood draw, with whole-genome sequences; 3.0% had natural premature menopause and 8.3% had surgical premature menopause
CHIP Prevalence
Across cohorts, the prevalence of CHIP was 8.8% among women with a history of premature menopause and 5.5% among women without (P<0.001). The prevalence increased progressively with earlier age at menopause.
Premature Menopause and CHIP
In multivariable analysis across cohorts, premature menopause was associated with greater odds of CHIP (OR, 1.36; 95% CI, 1.10–1.68; P=0.004). The association was driven by a stronger association between natural premature menopause and CHIP (OR, 1.73; P=0.001); no significant association with surgical premature menopause was observed.
CHIP and Incident CAD
Median follow-up for incident (first-time) myocardial infarction or coronary revascularization was 10 years in the UK Biobank and 13 years in WHI. Among women in the UK Biobank and women <70 in the WHI, CHIP was associated with increased risk of CAD (HR, 1.36; 95% CI, 1.07–1.73; P=0.01).
After adjustment for menopause status (premature or not), the association between CHIP and CAD was unchanged (HR, 1.36; P=0.01).
Across cohorts, the cumulative incidence of CAD was:
- 8.3% in women without premature menopause or CHIP
- 12.5% in women with premature menopause only
- 13.0% in women with CHIP only
- 15.5% in women with premature menopause and CHIP
There was no association between CHIP and CAD among women >70 years old.
What's Ahead
Identification of individuals suitable for CHIP screening will become increasingly important as genomic sequencing continues to become more accessible. Natural premature menopause seems to signal a predilection to CHIP development and may help indicate good candidates for CHIP screening and surveillance.
Moreover, women with a history of premature menopause may be particularly well suited to the emerging precision medicine approaches that mitigate CHIP-associated CVD risk, such as IL-1β/IL-6 inhibition.
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