Refereed journal article or data article (A1)

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




List of Authors: Zekavat SM, Lin SH, Bick AG, Liu AX, Paruchuri K, Wang C, Uddin MM, Ye YX, Yu ZL, Liu XX, Kamatani Y, Bhattacharya R, Pirruccello JP, Pampana A, Loh PR, Kohli P, McCarroll SA, Kiryluk K, Neale B, Ionita-Laza I, Engels EA, Brown DW, Smoller JW, Green R, Karlson EW, Lebo M, Ellinor PT, Weiss ST, Daly MJ, Terao C, Zhao HY, Ebert BL, Reilly MP, Ganna A, Machiela MJ, Genovese G, Natarajan P; FinnGen Consortium

Publisher: Springer Nature

Publication year: 2021

Journal: Nature Medicine

Journal name in source: NATURE MEDICINE

Journal acronym: NAT MED

Volume number: 27

Issue number: 6

Number of pages: 28

ISSN: 1078-8956

eISSN: 1546-170X

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

Self-archived copy’s web address: https://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 2022-04-02 at 15:28