Thread by @mchonig

For those interested in some science after much excitement 🇺🇸🇺🇸🇺🇸 this past week, thrilled to share our latest in @CircAHA (simultaneous pub w/ #AHA20)

Why do women with premature menopause have ⬆️ risk of CVD?

ahajournals.org/doi/abs/10.116…

👇 (thread)

We previously described diverse accelerated cardiovascular aging in women with premature menopause (jamanetwork.com/journals/jama/…), a “risk-enhancing factor” for ASCVD

Mechanisms underlying these associations remain unclear 🤔

In genome-wide association studies of age at natural menopause (nature.com/articles/ng.34…), ~2/3 of identified genetic loci map to DNA damage repair enzymes

➡️ implies women with natural premature menopause may be genetically predisposed to accumulate DNA mutations 🧬🧬

Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of hematologic stem cells w/ mutations in leukemia-associated genes (but no detectable cancer)

CHIP is common (~10% age >70 y), independently associates w/ accelerated ASCVD in humans, causes ASCVD in 🐭

We tested

1) whether premature menopause (<40 y) associated w/ CHIP in postmenopausal women in the @uk_biobank + Women’s Health Initiative with next-generation 🧬 sequencing

2) whether CHIP is an independent risk factor for CAD in postmenopausal women

Among 19,606 postmenopausal women across the 2 cohorts, crude prevalence of CHIP was 60% ⬆️ in 👭 w/ history of premature menopause

Premature menopause, esp natural premature menopause, independently associated w/ ⬆️ odds of CHIP

No signif association seen w/ surgical menopause

➡️ implies postmenopausal ⬇️ in estrogen alone did not explain relationship

(No association w/ age of menarche or parity)

There was no confounding by use of hormone therapy (HT)

In addition, premature menopause (esp natural premature menopause) was associated w/ mosaic chromosomal alterations

➡️ implies natural premature menopause may signal global genomic 🧬 instability not limited to CHIP

CHIP was associated with incident CAD events (and also w/ all-cause mortality) in postmenopausal middle-aged women independent of conventional ♥️ risk factors

To summarize:

1) H/o premature menopause, esp natural premature menopause, independently associated w/ ⬆️ odds of CHIP, a recently recognized CVD risk factor

2) CHIP associated w/ incident CAD in postmenopausal middle-aged 👭 independent of conventional ASCVD ♥️ risk factors

Implications:

1) Natural premature menopause = risk signal for latent 🧬 predilection for CHIP + CHIP-associated CVD

2) 👭 w/ premature menopause may be well suited to CHIP screening/surveillance + precision approaches to ⬇️ CHIP-associated CVD (e.g., IL-1B/IL-6 inhibition)

This was a highly collaborative effort

Huge thanks to @pnatarajanmd @AlexBickMDPhD @zekavatm @jpirruccello @abhinrl @l_farland (and many others, incl Tet Nakao, JoAnn Manson, Peter Libby, Alex Reiner, Ben Ebert) + @MGHHeartHealth @broadinstitute

ahajournals.org/doi/abs/10.116…