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

Zekavat, Seyedeh M.; Lin, Shu-Hong; Bick, Alexander; A, Liu; Paruchuri, Kaavya; Wang, Chen; Uddin, Md Mesbah; Ye, Yixuan; Yu, Zhaolong; Liu, Xiaoxi; Kamatani, Yoichiro; Bhattacharya, Romit; Pirruccello, James P.; Pampana, Akhil; Loh, Po−Ru; Kohli, Puja; McCarroll, Steven A.; Kiryluk, Krzysztof; Neale, Benjamin M.; Ionita‐Laza, Iuliana; Engels, Eric A.; Brown, Derek; Smoller, Jordan W.; Green, Robert C.; Karlson, Elizabeth W.; Lebo, Matthew S.; Ellinor, Patrick T.; Weiss, Scott T.; Daly, Mark J.; Terao, Chikashi; Zhao, Hongyu; Ebert, Benjamin L.; Reilly, Muredach P; Ganna, Andrea; Machiela, Mitchell J.; Genovese, Giulio; Natarajan, Pradeep

doi:10.1038/s41591-021-01371-0

Cited by 125 publications

(85 citation statements)

References 48 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

et al. 2021

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Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03–1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08–1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95–1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2021

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“…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.…”

Section: The Vicious and Virtuous Circles Of Clonal Hematopoiesismentioning

confidence: 99%

“…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.…”

Section: The Vicious and Virtuous Circles Of Clonal Hematopoiesismentioning

confidence: 99%

“…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.…”

Section: The Vicious and Virtuous Circles Of Clonal Hematopoiesismentioning

confidence: 99%

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