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

The Biobank Japan Project, FinnGen Consortium, Seyedeh M. Zekavat, Shu Hong Lin, Alexander G. Bick, Aoxing Liu, Kaavya Paruchuri, Chen Wang, Md Mesbah Uddin, Yixuan Ye, Zhaolong Yu, Xiaoxi Liu

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1012-1024
Number of pages13
JournalNATURE MEDICINE
Volume27
Issue number6
DOIs
Publication statusPublished - Jun 2021
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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