Genetic architecture shared between severity of COVID-19 and other health problems

Researchers in the United States have identified a shared genetic architecture between the severity of coronavirus disease 2019 (COVID-19) and other health issues.

Using data from the electronic health record and genomic data from Veterans Affairs (VA), the Million Veteran Program (MVP) and the United Kingdom Biobank (UKBB), the team identified conditions associated with risk factors of severe COVID-19.

The study found that phenotypes associated with poor outcomes for COVID-19, such as thrombotic complications, also shared genetic variants associated with severe COVID-19.

Among respiratory conditions, only idiopathic pulmonary fibrosis and asthma shared genetic risk factors with severe disease, with no observed association for chronic obstructive pulmonary disease.

Corporal Michael Crescenz’s Anurag Verma at VA Medical Center in Philadelphia and colleagues also found that variants associated with severe COVID-19 were associated with a reduced risk of autoimmune inflammatory conditions such as psoriasis and rheumatoid arthritis.

The team says the divergent association between severe COVID-19 and autoimmune inflammatory conditions underscores the importance of balancing immune tolerance and immunodeficiency when considering therapeutic targets for COVID therapies -19.

A pre-printed version of the research paper is available on the medRxiv* server, while the article is subject to peer review.

What did the study involve?

Certain pre-existing health conditions are known to increase the risk of severe COVID-19 and death.

Genetic variants associated with severe illness or hospitalization due to COVID-19 have been identified in genome-wide association studies of the COVID-19 Host Genetics Initiative.

The team performed a phenome-wide association study (PheWAS) on 48 genetic variants associated with critical COVID-19 and 39 variants associated with hospitalization of COVID-19.

Among 455,683 MVP participants (mean age 68), Verma and colleagues tested genetic variants associated with severe COVID-19 for associations between 1,559 phenotypes, as well as 353,365 UK Biobank participants and 1,064 phenotypes.

Two genetic variants (rs550057, rs505922) at the locus of the ABO blood group system were associated with the highest number of phenotypes for health problems, with the most significant increases in the risk of venous embolism (27% increase) and thrombosis (31%).

“Genetic variations in ABO are an established risk factor for the severity of COVID-19,” the team says. “Patients with blood group A have a higher risk of requiring mechanical ventilation and a prolonged stay in intensive care compared to patients with blood group O.”

These same variations in ABO are known to be associated with several blood clotting disorders in hospitalized COVID-19 patients, including deep vein thrombosis and pulmonary embolism.

Conceptual model of the relationship between TYK2 (rs34536133) with a reduced risk of psoriasis, psoriatic arthritis, rheumatoid arthritis and simultaneously an increased risk of severity of COVID-19.

Conceptual model of the relationship between TYK2 (rs34536133) with a reduced risk of psoriasis, psoriatic arthritis, rheumatoid arthritis and simultaneously an increased risk of severity of COVID-19.

What about other conditions?

Of more than 60 respiratory conditions tested, only idiopathic pulmonary fibrosis and asthma shared variants with severe COVID-19.

A single nucleotide polymorphism (SNP) rs74956615 at the PTB-binding ribonucleoprotein locus 1 (RAVER1) was associated with a 29% and 22% reduced risk for autoimmune diseases psoriasis and rheumatoid arthritis, respectively.

The study also found that a known functional missense in the tyrosine kinase 2 (Tyk2) variant (SNP rs34536443) in the region exhibited the highest binding imbalance with rs74956615, suggesting that this variant resulted in the majority of the risk reduced.

The team says recent studies looking at potentially important pathways for the progression of COVID-19 have highlighted TYK2 and its downstream signaling pathway via type 1 interferons as a potential target for treatment.

“The existing literature may help explain the dual association between a reduced risk of autoimmune diseases such as psoriasis and RA and an increased risk of severe COVID via TYK2,” the researchers write.

The TYK2 enzyme plays a vital role in the inflammatory response and in type 1 interferon signaling – part of the innate immune response that blocks the spread of a virus from infected cells to uninfected cells, explains the team.

What are the implications of the study?

“In this large-scale PheWAS, we have identified a shared genetic architecture between variants associated with severe COVID-19 and other complex conditions using data from MVP, one of the largest and most diverse biobanks in the world. world, with replication in UKBB, ”writes Verma and colleagues.

Researchers say the divergent association between severe COVID-19 and autoimmune inflammatory conditions underscores the importance of balancing immune tolerance and immunodeficiency.

“This balance will be important when considering therapeutic targets for COVID-19 therapies where the pathways can control both inflammation and the host’s viral response,” they write.

“In addition, our results suggest that the PheWAS approach may be a useful tool to identify clinical factors related to emerging infectious diseases regarding severity or complications when genomic data is available,” the team explains.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behaviors, or be treated as established information.

About Alma Ackerman

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