Germline risk of clonal haematopoiesis

Abstract

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke

“… 10 , 15 Furthermore, several of the genetic variants that predispose men to mLOY (in particular those involved in the DNA damage response and telomere maintenance pathway) also predispose to other CH subtypes in both sexes (i.e., mCAs and CH of indeterminate potential [CHIP]). 1 In line with these results, genetic determinants of mLOY have shown to be associated with diabetes mellitus and nonhematologic cancers in both men and women, as well as age at menopause in women. 9 , 14 Given previous support for associations between several subtypes of CH and age-related diseases including cardiovascular disease, a mechanism through CH might explain the present observed association between the PRS for mLOY and functional outcome after ischemic stroke.…”

Loss of Y and clonal hematopoiesis in blood—two sides of the same coin?

“…Recent studies suggest that LOY in leukocytes could confer direct physiological effects through LOY-associated transcriptional effects affecting global gene expression, and acting as a biomarker of genomic instability in somatic tissue [ 5 , 7 ]. Considering the similarities in age-related prevalence and disease risks conferred by LOY and CHIP, it is of considerable interest to determine whether the two phenomena co-exist or might occur in a mutually exclusive manner [ 15 ]. Of note, a recent study revealed a co-occurrence of LOY and CHIP in bone-marrow cells derived from patients referred for clinical bone-marrow evaluation [ 11 ].…”

Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease

“…Genetic association studies have repeatedly shown that CHIP has polygenic and inherited risk [122]. Its associations with the TERT locus have been replicated in numerous clinical trials.…”