Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection

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

“…Genetic determinants of mLOY have shown associations with X-chromosome loss in women as well as with mCA (both autosomal and X chromosome). 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.…”

“…In line with this, a recent study showed that this PRS for mLOY was also associated with X chromosome and autosomal mCA in a large cohort of participants from 5 biobanks including the UK biobank. 10 Given this background, we hypothesized that the genetic loci associated with mLOY, through a predisposition to an increased general genomic instability, are of plausible relevance for processes that affect brain recovery after stroke. We therefore investigated this PRS for mLOY for association with functional outcome after ischemic stroke.…”

The vicious and virtuous circles of clonal hematopoiesis

“…Two articles published in this issue of Nature Medicine link novel etiological and context-specific clinical features to CH. Dharan et al present chronic infection with human immunodeficiency virus (HIV) as a novel etiology for CH, characterized by specific gene associations and clonal dynamics 2 , whereas Zekavat et al demonstrate the association of mCAs with a wide range of infections, including infection with the coronavirus SARS-CoV-2 3 . Key to the connection between these manuscripts is the self-perpetuating circle of inflammation and clonal expansion.…”

“…Zekavat et al studied the association between mCAs and risk of infection among 768,762 people 3 . They found expanded autosomal mCAs to be significantly associated with diverse infections, including respiratory, gastrointestinal and genitourinary infections, as well as with elevated lymphocyte counts.…”

“…Thus, repeated or sustained exposure to inflammatory stimuli might leave them at a competitive advantage. The studies presented in this issue 2,3 describe the role of CH as both a driver of inflammation (primary CH) and its consequence (secondary CH). This could be conceptualized chronologically as follows: low-grade inflammation initially promotes clonal expansion of certain mutant HSPCs that, as the clone size increases, further promotes inflammation in a vicious circle that ultimately compromises organ function.…”