PHILADELPHIA- A collection of human DNA variants tied to more severe cases of COVID-19 are also associated with other serious medical conditions such as those dealing with blood clots and faulty inflammatory responses, according to a new study. A summary of this analysis, which came from stored genetic data from 600,000 people, was published today in PLOS Genetics.
"This work provided invaluable insights into the genetic architecture of COVID-19 risk factors and disease complications, a pressing need as the pandemic continues," said the study's lead author, Anurag Verma, PhD, an instructor in Translational Medicine and Human Genetics at the Perelman School of Medicine at the University of Pennsylvania. "The balance between the associations that we uncovered will be important as more therapies for COVID-19 are considered."
Data used in this study came from the Million Veteran Program, which was established by the United States Department of Veterans Affairs. It is among the largest and most diverse biobanks (repositories of genetic information used for research) in the world, making it ideal for examining the various pieces of DNA that could be exploited by COVID-19.
With the variants associated with severe COVID-19 in hand, the researchers then began to see whether any other health conditions were more likely to be associated with them. To do this, they analyzed roughly 1,500 "phenotypes," meaning the identifiable traits of a disease, which could be gleaned from an electronic health record.
"One thing that stood out to us was the high number of immune-mediated conditions that shared genetic architecture with severe manifestations of COVID-19," said the study's co-senior author, Katherine Liao, MD, MPH, a rheumatologist in the Department of Medicine at Brigham and Women's Hospital, VA Boston Healthcare System, and an associate professor of Medicine and Biomedical Informatics at Harvard Medical School.
Variants that had been associated with more severe COVID-19 in the ABO locus, a term meaning a gene's position on a chromosome, were found to also be associated with the most other conditions. Patients with these variants were 33 percent more likely to have conditions like venous embolism and thrombosis, which both involve blood clots.
When analyzing 67 different respiratory conditions, 11 had significant associations with variants in the MUC5B locus. Those with variants in this location were almost three times as likely to have idiopathic fibrosing alveolitis, a condition marked by the build-up of scar tissue in the lungs.
However, some of the genetic variants associated with worse COVID-19 were actually associated with not having some conditions, including some respiratory and autoimmune conditions. Variants in CRHR1 locus were associated with a 16 percent decrease in the odds of pulmonary fibrosis, which also causes scarring in the lungs, and variants in TYK2's locus reduced odds of a patient having psoriasis or lupus.
"The nature of the associations brought to light how the SARS-CoV-2 virus pushes on a pressure point in the human immune system. The immune system is performing a constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process, attacking itself," said Liao.
Some differences in association were seen when genetic ancestry was taken into account. The odds of someone having neutropenia - a condition in which a patient has a low count of the white blood cells used by the body's immune system - were 29 percent higher in those with African genetic ancestry who had variants in the LMNA locus. Those with European genetic ancestry who had the same variants did not share a higher association.
"What we found challenges some assumptions that were made about COVID-19 and some of those who we believed to be at risk," Verma said. "Our research also highlights the risks some people might have because of their DNA. This demonstrates the value and impact that linking genetic variations with electronic health record data in biobanks has when it comes to public health responses, both in the current pandemic and future crises."
Funding for this study was provided by the Department of Veterans Affairs' Million Veteran Program (MVP035). Co-authors of the study were also supported by National Institutes of Health (R01 AA026302, P30 DK0503060, P30 AR072577).
