DNMT3A clonal hematopoiesis is associated with cardiovascular disease in women

Abstract Background Clonal hematopoiesis (CH) is an independent risk factor for cardiovascular disease (CVD). Recent studies employing targeted next generation sequencing (NGS) have highlighted the contribution of smaller clones with 2% variant allele frequency (VAF) to CVD, particularly for DNMT3A and TET2 CH, the two most frequently occurring CH mutations. DNMT3A CH has a higher frequency in women than men. However, whether sex affects the association between CH and CVD is unknown. Methods We included 5,527 participants of the Lifelines (LL) cohort, a prospective population-based cohort from the North of the Netherlands, who had previously undergone targeted NGS for the identification of CH. Our studied cohort is enriched for giant cell arthritis and blood count abnormalities. We investigated the sex-specific associations between CH and prior myocardial infarction (MI) or coronary artery calcium (CAC). In addition, we investigated the association of sex or prior MI with clonal expansion. Results We identified 2,111 participants carrying 3,110 somatic mutations in 26 genes. DNMT3A was the most commonly mutated gene and occurred more frequently in women compared to men (OR 1.28; P = 5.0x10-4). Women with DNMT3A CH had a higher odds of prior MI (OR 1.77; P = 2.1x10-2), while men did not (OR 0.98; P = 8.8x10-1; Pinteraction = 4.4x10-2). Female sex or prior MI did not associate with gain or loss of CH clones, or clonal expansion. DNMT3A clone size positively associated with age- and sex-adjusted CAC percentile scores in women (B 28.97; P = 9.7x10-3), but not in men (B 2.34; P = 8.2x10-1; Pinteraction = 8.9x10-2). Women with a higher-than-average DNMT3A clonal expansion had higher CAC percentile scores compared to women with lower-than-average clonal expansion, independent of initial DNMT3A clone size (B 18.46; P = 8.1x10-3). Conclusions Our results indicate that DNMT3A CH is associated with previous MI and higher atherosclerotic burden only in women. This highlights the need to better understand the sex-specific risks that CH may confer on CVD.