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Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection
Seyedeh M Zekavat1,2,3, Shu-Hong Lin4, Alexander G Bick2,5
1Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
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.
Insights
Mosaic chromosomal alterations (mCAs) are linked to increased infection risk in aging individuals. These genetic changes in blood DNA indicate impaired immunity, predisposing to sepsis, pneumonia, and other infections.
Area of Science:
- Genetics
- Immunology
- Gerontology
Background:
- Aging is the primary risk factor for infectious diseases, yet the underlying biological mechanisms remain unclear.
- Mosaic chromosomal alterations (mCAs), detected in blood DNA, are associated with clonal hematopoiesis, abnormal blood cell counts, and increased mortality.
- mCAs have been linked to various health issues, but their direct role in infectious disease susceptibility was not fully understood.
Purpose of the Study:
- To investigate the association between mosaic chromosomal alterations (mCAs) and the risk of developing diverse infections.
- To identify genetic loci associated with expanded mCAs and their potential role in immune function.
Main Methods:
- Analysis of mCAs in DNA from 768,762 individuals across five biobanks, excluding those with hematological cancer at DNA acquisition.
- Statistical analysis to determine the association between expanded autosomal mCAs and incident infections using hazard ratios (HR) and confidence intervals (CI).
- Genome-wide association study (GWAS) to identify genetic loci linked to expanded mCAs and assess their enrichment at immune cell regulatory sites.
Main Results:
- Expanded autosomal mCAs were significantly associated with an increased risk of diverse infections (HR 1.25, P = 1.8 × 10-7).
- Specific infections showed strong associations, including sepsis (HR 2.68), pneumonia (HR 1.76), digestive system infections (HR 1.51), and genitourinary infections (HR 1.25).
- A GWAS identified 63 loci associated with expanded mCAs, many located at transcriptional regulatory sites relevant to immune cells.
Conclusions:
- Mosaic chromosomal alterations (mCAs) are a significant risk factor for various infections, highlighting a novel link between genetic instability and immune defense.
- mCAs serve as a potential biomarker for impaired immunity in aging populations.
- The findings suggest that mCAs contribute to increased susceptibility to infections, underscoring the importance of understanding age-related genetic changes in immune health.
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