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Million Veteran Program Study Links Genetic Variants Related to Severe COVID-19 to Other Conditions

NEW YORK – Genetic variants implicated in risk for severe COVID-19 also contribute to several complex diseases, including diabetes and cardiovascular disease, new research from the Million Veteran Program suggests.

"We had a unique opportunity to scan thousands of conditions documented before the COVID-19 pandemic," first author Anurag Verma, a researcher affiliated with the VA Medical Center in Philadelphia and the University of Pennsylvania, said in a statement. "We gained insights into the genetic architecture of COVID-19 risk factors and disease complication."

As they reported in PLOS Genetics on Thursday, the researchers performed a phenome-wide association study (PheWAS) searching for other complex conditions with ties to dozens of genetic variants. Those variants had previously been implicated in severe COVID-19 through genome-wide association studies by the COVID-19 Host Genetics Initiative. The set included 42 hospitalization-related variants and almost three dozen variants linked to critical illness after SARS-CoV-2 infection.

"The PheWAS of genetic variants reported to associate with severe COVID-19 demonstrated shared genetic architecture between COVID-19 severity and known underlying risk factors for both severe COVID-19 and poor COVID-19 outcomes, rather than susceptibility to other viral infections," the authors reported, adding that "only few respiratory conditions had shared genetic conditions with severe COVID-19."

Using genotyping profiles and clinical data from electronic health records spanning almost 1,600 clinical conditions or phenotypes for 658,582 individuals in the Million Veteran Program, the team found that variants related to severe COVID-19 were associated with several conditions, including those already implicated in poor outcomes after SARS-CoV-2 infection such as type 2 diabetes or cardiovascular conditions ranging from venous embolism or thrombosis to ischemic heart disease.

Variants at the ABO blood group locus that were associated with severe COVID-19 had the most widespread phenotypic ties in the PheWAS, the researchers reported, and showed particularly strong associations to venous embolism and thrombosis.

They also unearthed variants that were linked to almost a dozen respiratory conditions or lung traits. While some variants that bumped up severe COVID-19 risk were linked to lung conditions, the risk of other lung or respiratory conditions such as pulmonary fibrosis was lower in the presence of variants related to severe COVID-19.

Similarly, at least some of the variants that are overrepresented in individuals at risk of severe SARS-CoV-2 infection, including TYK2 gene variants, appeared to protect against autoimmune conditions such as psoriasis, systemic lupus erythematosus, and rheumatoid arthritis.

The authors noted that "[d]ivergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions, both respiratory and non-respiratory, highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets."

The analysis also highlighted ancestry-related differences. In participants of African or Hispanic ancestry, for example, the team saw ties between severe COVID-19 risk and neutropenia, a condition marked by particularly low neutrophil white blood cell levels that puts individuals at increased infection risk.

"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," co-senior and co-corresponding author Katherine Liao, a researcher affiliated with the VA Boston Healthcare System, Harvard Medical School, and Brigham and Women's Hospital, said in a statement.

"The nature of the associations brought to light how the SARS-CoV-2 virus pushes on a pressure point in the human immune system," Liao explained, "and its constant balancing act of fighting infection while maintaining enough control so that it does not also become an autoimmune process, attacking self."

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