Abstract 1229: Clonal hematopoiesis of indeterminate potential (CHIP), centenarians and age-related cardiovascular risk: Is TET2 the culprit

Abstract

Abstract Background. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related hematological condition, that has been associated with an increased risk of hematological malignancies and of overall mortality. This excess mortality in subjects with CHIP seems to be related to an increased risk of cardiovascular atherosclerotic diseases (Jaiswal S, NEJM 2014). Our aim was to analyze the prevalence of CHIP in patients with Coronary Artery Disease (CAD) and in a group of selected ultra-centenarians ((age >105 years), since no data hasve been produced until now in such a peculiar population of “super-controls” (Garagnani P, Aging 2013). Methods. We performed whole-exome sequencing (WES) from peripheral-blood cells DNA in 99 patients with angiographically proven severe CAD from the Verona Heart Study (Girelli D, NEJM 2000;), and 79 semisupercentenarians (age >105 years). The mean coverage varied from 30x to 100x (higher in centenarians). We analyzed somatic mutations predicted to alter function in 6 key genes (TET2, ASXL1, DNMT3A, JAK2, PPM1D, TP53), selected as the most frequently detected in CHIP according to literature. Results. The prevalence of CHIP in CAD patients was 18.2%, similarly to the increased prevalence detected in other CAD populations (Jaiswal S, NEJM 2017). On the other hand, CHIP was rare in centenarians (prevalence of 2.5%), a result that contradicts the expected exponential increase of CHIP observed after the age of 70 years in previous studies. This result suggested a kind of “survival bias”, that indirectly supports the pathogenic role of age-related CHIP. An utterly fascinating finding was in the frequency of driver mutations in CAD subjects with CHIP: the majority (85%) of CAD patients presented mutations in TET2. Conclusions. Our outcomes add further insights to the nature of CHIP, which could be seen as a preleukemic condition that also leads to an intrinsic odd of cardiovascular events. The Our outcomes add further insights to the recent hypothesis that links CHIP to an increased risk of cardiovascular disease. The study results raise the question over a possible many-sided clinical and biological significance of CHIP that might depend on the driver mutation. In particular, we propose that TET2-driven CHIP is the most responsible for the higher cardiovascular risk, consistently with the pro-atherosclerotic role of this gene in mouse models (Fuster JJ, Science 2017, Jaiswal S, NEJM 2017). Citation Format: Luca Bertamini, Claudia Sala, Nicola Martinelli, Cristina Papayannidis, Cristina Giuliani, Giovanni Malerba, Paolo Garagnani, Maria Abbondanza Pantaleo, Michele Cavo, Oliviero Olivieri, Giovanni Martinelli, Claudio Franceschi, Domenico Girelli. Clonal hematopoiesis of indeterminate potential (CHIP), centenarians and age-related cardiovascular risk: Is TET2 the culprit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1229.