Clonal Hematopoiesis of Indeterminate Potential (CHIP) in Patients with Coronary Artery Disease and in Centenarians. Further Clues Linking Chip with Cardiovascular Risk

Background. Age-related clonal hematopoiesis of indeterminate potential (CHIP), a relatively common condition in elderly people, has been associated with an increased risk of hematological neoplasms, and, to a greater extent, of overall mortality. Earlier this year, Jaiswal and colleagues have suggested that excess mortality in subjects with CHIP is related to an increased risk of cardiovascular diseases, and provided a convincing model linking TET2 mutations to a pro-inflammatory state favoring the development of atherosclerotic plaques.

Aims. We sought to replicate the recent findings of an increased prevalence of CHIP in patients with Coronary Artery Disease (CAD), by studying patients enrolled in the Verona Heart Study. We were also interested in studying a group of selected ultra-centenarians (mean age 105.6 ± 2.0 years), as the prevalence of CHIP has been previously reported to increase linearly with age until near 90 years, but no data have been produced until now in such a peculiar population of "super-controls".

Methods. We analyzed whole-exome sequencing (WES) data from peripheral-blood cells DNA in 99 patients with angiographically proven severe CAD, and 79 centenarians. The mean coverage varied from 30x to 100x (maximum in centenarians). We focused on somatic mutations predicted to alter the protein function in 6 genes (TET2, ASXL1, DNMT3A, JAK2, PPM1D, TP53) ,known to be key players in the development of CHIP.

Results. The prevalence of CHIP in CAD patients was 18.2%, a figure reproducing the increased prevalence in other CAD populations recently reported by Jaiswal and colleagues. By contrast, the prevalence of CHIP in centenarians was only 2.5%, a figure in clear countertrend with respect to the linear increase of CHIP observed until the age of 90 years in previous studies. This suggested a kind of "survival bias" indirectly supporting the pathogenic role of age-related CHIP. Interestingly, the majority (85%) of the driver mutations in CAD patients occurred in TET2, consistently with the pro-atherosclerotic role of this gene in mouse models.

Conclusions. Our results add further to the recent hypothesis that links CHIP to an increased risk of cardiovascular disease.