Absence of association between host genetic mutations in the ORAI1 gene and COVID-19 fatality

Abstract

The calcium ion channel ORAI1 has emerged as a promising therapeutic target for the Coronavirus Disease 19 (COVID-19)-associated pneumonia, and a pharmacological inhibitor of ORAI1 has now reached clinical trials for severe COVID-19 pneumonia. Whether ORAI1 itself is associated with an increased risk for severe COVID-19 presentation is still unknown. Here, we employed genetic association analysis to investigate the potential association of host genetic polymorphisms of ORAI1 with the risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and its associated COVID-19 fatality in UK Biobank participants from white British background. The analysis showed no significant association between ORAI1 variants and COVID-19 positivity or fatality, despite the well-established roles of ORAI1 in immune response and inflammation and the success of ORAI1 inhibition in clinical trials. Our results suggest that the host genetic polymorphisms of ORAI1 are unlikely to be implicated in the broad variability in symptoms severity among afflicted patients.

UK biobank: Enhanced assessment of the epidemiology and long-term impact of coronavirus disease-2019

“…For example, the calcium ion channel gene ORAI1 is known for its role in immune response, inflammation, platelet activation and thrombus formation, and was therefore considered as a potential drug target for COVID-19. However, a UK Biobank study found that genetic variants within ORAI1 were not associated with severe COVID-19 (Shawer et al, 2022) consistent with observational analyses that found no association between calcium channel blocker use and COVID-19 outcomes (Alsagaff et al, 2021). Other analyses using UK Biobank data have reported that the ApoE e4/e4 genotype (which not only affects lipoprotein function but also moderates macrophage inflammatory phenotypes) increases the risk of severe COVID-19, independently of pre-existing dementia, cardiovascular disease and type 2 diabetes (Kuo et al, 2020).…”