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Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women
Daniel Ezzat1, Md Mesbah Uddin2, Liying Xue2
1Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA; Faculty of Medicine, KU Leuven, Leuven, Belgium.
Background:
Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP's relevance to CVD may diminish with advancing age.
Objectives:
This study aimed to test the association of CHIP and its key subtypes with incident CVD in an older population.
Methods:
Participants in the Women's Health Initiative Long Life Study completed study assessments in 2012-2013 and underwent high-coverage sequencing (median depth 4,580×). The co-primary exposures were composite CHIP and TET2 CHIP. DNMT3A, ASXL1, JAK2, and non-DNMT3A CHIP were examined as secondary exposures. The primary outcome was incident coronary heart disease. Secondary outcomes were incident heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, venous thromboembolism, and cardiovascular death. Multivariable-adjusted Cox models tested associations between CHIP and incident CVD.
Results:
Among 6,677 women (median age 80 years; median follow-up 10.1 years), 2,176 (32.6%) had any CHIP. TET2 CHIP was independently associated with incident coronary heart disease (aHR: 1.36 [95% CI: 1.05-1.77]; P = 0.02), whereas composite CHIP was not (aHR: 1.07 [95% CI: 0.89-1.28]; P = 0.49). Secondarily, TET2 CHIP was associated with HFpEF (aHR: 1.40 [95% CI: 1.03-1.90]; P = 0.03), ASXL1 CHIP with HFrEF (aHR: 3.16 [95% CI: 1.53-6.55]; P = 0.002), and JAK2 CHIP with ischemic stroke (aHR: 2.49 [95% CI: 1.17-5.30]; P = 0.02), venous thromboembolism (aHR: 2.71 [95% CI: 1.11-6.65]; P = 0.03), and cardiovascular death (aHR: 2.62 [95% CI: 1.68-4.11]; P < 0.001). No other significant associations were observed for composite or DNMT3A CHIP.
Conclusions:
In an older female cohort, key CHIP subtypes (TET2, ASXL1, and JAK2) were associated with incident CVD, with associations that appeared to differ by CVD outcome. These findings suggest that CHIP remains associated with cardiovascular health into later life. (Women's Health Initiative [WHI]; NCT00000611).
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