Chromosomal changes in white blood cells increase risk of severe infections

Elderly couple

With age comes an increased risk of many infections. The mechanisms connecting aging and weakened immunity, however, have remained unclear.

A new study has identified a category of genetic markers in white blood cells which makes individuals more susceptible to diverse infections.

The study, conducted by a team of researchers from Yale, the Broad Institute of Harvard and MIT, and the National Cancer Institute (NCI), was published June 7 in the journal Nature Medicine.

As people age, genetic errors begin to accumulate during the process of cell division. For the study, researchers explored whether one category of these emerging genetic variants in white blood cells — called mosaic chromosomal alterations, or mCAs — played a role in increased infection risk.

After analyzing genetic and clinical data from nearly 800,000 individuals around the world, the researchers discovered that people with mCAs were nearly three times more likely to develop sepsis, and two times more likely to get pneumonia. Associations with other infections — including digestive system infections and urinary tract infections — were also observed.

The study also found a correlation between mCAs and COVID-19 severity in patients during the first wave of the pandemic in New York in early 2020. Among the COVID-19 patients in the study, 6% of mild cases and 17% of severe cases had mCAs.

This work was largely motivated by the rush of research at the onset of the COVID-19 pandemic, when the first identified risk factor for a severe COVID-19 infection was age,” said lead author (Seyedeh) Maryam Zekavat, an MD-PhD student in Yale’s Computational Biology and Bioinformatics program. “When I saw that mCAs were associated with COVID-19 hospitalization, I then broadened out to other infections and was astounded to see that this is a common theme across many infections, with the strongest effect estimates being for severe infections such as sepsis and pneumonia.”

Zekavat is advised by Hongyu Zhao, department chair and Ira V. Hiscock Professor of Biostatistics at Yale, and corresponding author Pradeep Natarajan of the Broad Institute of Harvard and MIT and Massachusetts General Hospital.

The risk factors for sepsis and pneumonia — severe infections often requiring hospitalization — were even higher if patients had a prior solid cancer diagnosis. This finding suggests that mCAs are an important common risk factor for both cancer and infection, and could be a marker of immune system deficiency.

The authors say that screening for mCAs could help identify individuals at increased risk for infection who might benefit from preventive measures.

The study helps us understand one biological link between age and infection risk,” said Zekavat. “Hopefully the findings will also help physicians identify individuals at increased risk of severe infections, and tailor prophylactic therapies for those with these genetic markers.”

Natarajan says that their findings will be relevant in a post-COVID 19 world, too. “I think it's important for us to continue to understand who is at risk for severe infections — and the way that we assess that risk today is largely just by age,” Natarajan said. “This work helps us refine that much more, and may help in future public health efforts when thinking about quarantines and distancing and prophylactic medicines; and then, for new pandemics, prioritizing early access to vaccines.”

Mitchell J. Machiela of the National Cancer Institute, Giulio Genovese of the Broad Institute of Harvard and MIT, and Natarajan are co-senior authors of the paper.

Zekavat and Shu-Hong Lin of the NCI are co-lead authors.

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