Clonal hematopoiesis of indeterminate potential do not highly increase the risk of myocardial infarction even when associated with mosaic loss of Y chromosome

While clonal hematopoiesis of indeterminate potential (CHIP) has been initially associated with a 2-fold increased incidence of atherothrombotic events, recent studies showed that in fact, CHIP may be associated with a very modest increase in the risk of Myocardial Infarction (MI). This lower risk than initially suggested could be related to modulation of the pathological effects of CHIP by factors not yet identified. Mosaic loss of Y chromosome (mLOY), a frequent marker of clonal hematopoiesis in men, was recently associated with cardiovascular diseases and as such, represents a candidate modulator of cardiovascular risk associated with CHIP. In this study, we sought to determine the risk associated with each somatic mutation or mLOY and whether mLOY could modulate the cardiovascular risk associated with CHIP. We looked for the presence of CHIP and mLOY using sensitive high-throughput sequencing and digital PCR in 446 subjects enrolled in 2 prospective studies. The 149 patients in the CHAth study had a first myocardial infarction (MI) at inclusion (MI(+) subjects). They were compared with 297 subjects from the 3-city cohort who had no history of a cardiovascular event (CVE) at inclusion (MI(-) subjects). All these subjects underwent fine cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. We searched whether mLOY could modulate the inflammation, atherosclerosis burden and atherothrombotic risk associated with CHIP. CHIP and mLOY were detected with a high prevalence (45.1% and 37.7% respectively), and with a similar frequency between MI(+) and MI(-) subjects. Nearly 40% of CHIP(+) male subjects also carried a mLOY. Separately, neither CHIP nor mLOY increased the plasmatic level of hsCRP, the atherosclerotic burden nor the incidence of MI. mLOY did not increase or decrease the inflammation, atherosclerosis or MI incidence in CHIP(+) male subjects. In MI(-) male subjects, CHIP increased the risk of MI at 5 years, especially in those not carrying a mLOY. CHIP and mLOY are highly prevalent in elderly subjects, but none of them separately increase inflammation, atherosclerosis or MI incidence in an important manner. mLOY do not modulate the inflammation, atherosclerosis burden or atherothrombotic risk associated with CHIP, but CHIP may accelerate the occurrence of MI when not associated with mLOY.