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Publication Detail

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

Authors: Zekavat, Seyedeh M; Lin, Shu-Hong; Bick, Alexander G; Liu, Aoxing; 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; Ionita-Laza, Iuliana; Engels, Eric A; Brown, Derek W; Smoller, Jordan W; Green, Robert; Karlson, Elizabeth W; Lebo, Matthew; Ellinor, Patrick T; Weiss, Scott T; Daly, Mark J; Biobank Japan Project; FinnGen Consortium; Terao, Chikashi; Zhao, Hongyu; Ebert, Benjamin L; Reilly, Muredach P; Ganna, Andrea; Machiela, Mitchell J; Genovese, Giulio; Natarajan, Pradeep

Published In Nat Med, (2021 06)

Abstract: Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

PubMed ID: 34099924 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Aged; Aged, 80 and over; Aging/genetics*; Aging/pathology; Biological Specimen Banks; Chromosome Aberrations; Communicable Diseases/complications; Communicable Diseases/genetics*; Communicable Diseases/microbiology; Digestive System Diseases/epidemiology; Digestive System Diseases/genetics; Digestive System Diseases/microbiology; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Hematologic Neoplasms/complications; Hematologic Neoplasms/genetics; Hematologic Neoplasms/microbiology; Humans; Male; Middle Aged; Mosaicism; Pneumonia/epidemiology; Pneumonia/genetics*; Pneumonia/microbiology; Risk Factors; Sepsis/epidemiology; Sepsis/genetics*; Sepsis/microbiology; Urogenital Abnormalities/epidemiology; Urogenital Abnormalities/genetics; Urogenital Abnormalities/microbiology; Young Adult

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