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COVID-19 Genetic Analysis Leads to Host Blood Proteins Suspected of Influencing Disease Outcomes

NEW YORK – A research team from the UK, Austria, Sweden, and Denmark used a genomics-based approach to come up with a list of blood proteins that may contribute to severe COVID-19 cases.

That set included an ABO blood type-related protein, consistent with prior research going back as far as the early days of the pandemic suggesting certain blood types could impact susceptibility to SARS-CoV-2 infection.

"Our research replicates findings of blood markers previously associated with COVID-19 and prioritizes additional blood markers for risk prediction of severe forms of COVID-19," co-senior authors Christopher Hübel and Gerome Breen, with King's College London's Institute of Psychiatry, Psychology, and Neuroscience and the UK National Institute for Health Research, and their colleagues wrote, adding that "we pinpoint druggable targets potentially implicated in disease pathology."

As they reported in PLOS Genetics on Thursday, members of the COVID Clinical Neuroscience Study Consortium searched for blood proteomic contributors to severe COVID-19 cases that required hospitalization or led to patient death or the need for respiratory support. Using available data from prior genome-wide association studies, along with Mendelian randomization analyses, the researchers came up with genetic proxies for thousands of blood proteins to find those making causal contributions to such outcomes.

"Together, our findings support previous findings and identify novel blood markers associated with a severe COVID-19 phenotype," the authors reported, "indicating possible avenues to develop prognostic biomarkers and therapeutics for COVID-19."

The team's approach led to more than a dozen potential associations, including six proteins linked to at least one of the severe COVID-19 outcomes and another eight blood proteins that appeared to protect against severe forms of disease when found at high levels.

"What we have done in our study is provide a shortlist for the next stage of research," Breen said in a statement, noting that the study opens a "potentially important avenue for further research to better understand the mechanisms behind COVID-19 with an ultimate aim of developing new treatments but potentially also preventative therapies."

Increased levels of three blood proteins — SELL, SELE, and PECAM-1 — corresponded with protection from severe COVID-19 in general, for example. Bumped up blood levels of the remaining five proteins were linked to either lower hospitalization risk or with a reduced risk of requiring respiratory support or of death.

Among half a dozen blood proteins showing apparent associations with enhanced risk of severe disease, the team flagged a chromosome 9 gene called ABO that codes for an enzyme that determines an individual's ABO blood group.

"Our study does not link [a] precise blood group with risk of severe COVID-19, but since previous research has found that the proportion of people who are group A is higher in COVID-19-positive individuals, this suggests that blood group A is a more likely candidate for follow-up studies," Hübel said in a statement.

The results also implicated high blood levels of the GCNT4, CD207, RAB14, or C1GALT1C1 proteins in increased risk of hospitalization and respiratory support or death, the team noted, while increased levels of the fatty acid hydrolase enzyme FAAH2 was linked to hospitalization alone in individuals infected with SARS-CoV-2.

"It is important to note that, in our analyses, we did not identify typical canonical immune proteins," the authors wrote. "This suggests that with a larger database of proteins we can pinpoint non-canonical immunomodulatory proteins relevant to disease pathophysiology."