Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease

Abstract

Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed "clonal hematopoiesis of indeterminate potential," in coronary artery disease. Such mutations typically occur in DNMT3A, TET2, ASXL1, and JAK2. Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.

Keywords: cardiovascular disease; clonal hematopoiesis; coronary artery disease; genetics; inflammation.

Figure 1.. Dynamic genomic model of coronary artery disease.

Large-effect single rare disruptive coding variants, such as LDLR putative loss-of-function variants, are a well-recognized monogenic factors for coronary artery disease. Over the last decade, advances in common trait / common variant genetics continue to refine the polygenic contribution of coronary artery disease, as estimated through coronary artery disease polygenic risk scores. More recently, population-based next-generation sequencing studies that use blood DNA estimated the age-related prevalence of clonal hematopoiesis of indeterminate potential, as indicated by the presence of clonally expanded leukemogenic variants among asymptomatic adults. Subsequent studies then demonstrated the contribution of clonal hematopoiesis of indeterminate potential to coronary artery disease. Figure made with BioRender.com.

Figure 2.. The NLRP3 inflammasome connects TET2 clonal hematopoiesis of indeterminate potential with coronary artery disease.

Multiple lines of evidence support this connection. (1) Atherogenic mice with a subsequent of hematopoietic stem cells deficient of Tet2 versus wild-type have greater reduction of supravalvular aortic atherosclerosis from NLRP3 inflammasome inhibition versus placebo. The activated NLRP3 inflammasome leads to a cascade of enhanced IL-1B and IL-6 signaling, and was connected to atherosclerosis previously but only recently with greater relevance in this context. (2) The common IL6R p.Asp358Ala variant was previously associated with a modest reduction of coronary artery disease odds in the general population. In the UK Biobank, individuals with TET2 or DNMT3A clonal hematopoiesis of indeterminate potential (CHIP) compared to those without had a great reduction in cardiovascular disease event rates with IL6R p.Asp358Ala versus wild-type. (3) The CANTOS trial previously showed that individuals with coronary artery disease and increased high-sensitivity C-reactive protein had a moderate reduction in major adverse cardiovascular disease events when given canakinumab (monoclonal antibody directed at IL-1B) versus placebo. In a non-prespecified post hoc analysis of CANTOS, individuals with TET2 CHIP appeared to have a much larger reduction in major adverse cardiovascular disease events from canakinumab vs placebo compared to others. Figure made with BioRender.com.