Mosaic Chromosomal Alterations Increase the Risk of Diverse Infections

Mosaic chromosomal alterations (mCAs)—clonal structural somatic alterations in leukocytes—are well established to increase the risk of hematological malignancy. Because these genetic variants increase in abundance with age, researchers posited they may play a role in the age-related diminishment of immune function.

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Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center and investigator in the Cardiovascular Research Center at Massachusetts General Hospital, and Giulio Genovese, of the Cardiovascular Disease Initiative of the Broad Institute of Harvard and MIT, collaborated with Mitchell J. Machiela, ScD, MPH, of the National Cancer Institute, in supervising an international team to examine this question.

In Nature Medicine, the researchers present evidence that mCAs are a marker of diminished immunity and confer susceptibility to a range of infections, including sepsis and pneumonia. Furthermore, COVID-19 patients who had mCAs were predisposed to more severe disease.

Associations of mCAs with Infections

The genome-wide association study included multiethnic data on 768,762 unrelated individuals from the UK Biobank, Mass General Brigham Biobank, FinnGen, BioBank Japan and Columbia University Biobank. Across the genome, the presence of any mCA was associated with incident infections across a wide range of organ systems (HR, 1.06; P=8.6 × 10⁻⁸).

The associations were stronger for expanded mCA clones (those present in at least 10% of peripheral leukocyte DNA), particularly expanded autosomal mCAs. Carriers of expanded autosomal mCAs were at increased risk of:

• Sepsis—HR, 2.68 (P=3.1 × 10⁻²⁸)
• Pneumonia—HR, 1.76 (P=2.3 × 10⁻¹⁵)
• Respiratory infections in general—HR, 1.36 (P=3.8 × 10⁻¹⁰)
• Digestive infections—HR, 1.51 (P=2.2 × 10⁻⁹)
• Genitourinary infections—HR, 1.25 (P=3.7 × 10⁻⁴)

The associations between expanded autosomal mCAs and sepsis or respiratory system infections were stronger in patients who had cancer before infection than in those with no cancer history. That interaction was driven by solid tumors, not hematologic cancers.

Screening for expanded mCA clones, particularly in individuals who develop solid cancer, may help identify patients at high risk of infection who might benefit from targeted treatment.

Association of mCAs with COVID-19 Severity

Data on 719 patients with COVID-19 were available from the UK Biobank. After adjustment for age, sex, smoking status and principal components of ancestry, expanded autosomal mCAs were associated with a doubled risk of COVID-19 hospitalization (OR, 2.17; P=0.02). When the UK data were meta-analyzed with information on 14 COVID-19 patients from FinnGen, the OR was 2.44 (P=0.004).

The researchers also studied 871 COVID-19 patients from the Columbia University Biobank. Expanded autosomal mCAs were detected in:

• 6% of patients with mild disease (not requiring hospitalization, n=52)
• 14% of patients with moderate disease (requiring hospitalization but not intubation and not fatal, n=440)
• 17% of patients with severe disease (fatal and/or required intubation and mechanical ventilation, n=379)

Adjusted for age, sex and self-reported ancestry, expanded autosomal mCAs were associated with these ordinal outcomes with an OR of 1.52 (P=0.03). Awareness of the COVID-19 risk associated with mCAs may help with prioritizing prophylactic interventions for individual patients and evaluating response to immunization.

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