Refereed journal article or data article (A1)

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




List of AuthorsZekavat 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., The Biobank Japan Project, Terao Chikashi, Zhao Hongyu, Ebert Benjamin L., Reilly Muredach P., Ganna Andrea, Machiela Mitchell J., Genovese Giulio, Natarajan Pradeep; FinnGen Consortium

PublisherSpringer Nature

Publication year2021

JournalNature Medicine

Journal name in sourceNATURE MEDICINE

Journal acronymNAT MED

Volume number27

Issue number6

Start page1012

End page1024

Number of pages28

ISSN1078-8956

eISSN1546-170X

DOIhttp://dx.doi.org/10.1038/s41591-021-01371-0

Self-archived copy’s web addresshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245201/


Abstract

The burden of mosaic chromosomal alterations in blood-derived DNA, a type of clonal hematopoiesis, is associated with an increased risk for diverse types of infections, including sepsis and pneumonia.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 x 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 x 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 x 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 x 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 x 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.


Last updated on 2022-27-10 at 12:30