EFCAB4B (CRACR2A) genetic variants associated with COVID-19 fatality

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021). Severe COVID-19 is characterised in part by vascular thrombosis and cytokine storms due to increased plasma concentrations of factors secreted from endothelial and T-cells. Here, using patient data recorded in the UK Biobank, we demonstrate the importance of variations in Rab46 (CRACR2A) and clinical outcomes. Using logistic regression analysis, we determined that three single nucleotide polymorphisms (SNPs) in the gene EFCAB4B cause missense variations in Rab46, which are associated with COVID-19 fatality independently of risk factors. All three SNPs cause changes in amino acid residues that are highly conserved across species, indicating their importance in protein structure and function. Two SNPs, rs17836273 (A98T) and rs36030417 (H212Q), cause amino acid changes in important functional domains: the EF-hand and coiled-coil domain respectively. By using molecular modelling, we suggest that the substitution of threonine at position 98 causes structural changes in the EF-hand calcium binding domain. Rab46 is a Rab GTPase that plays regulates both regulating endothelial cell secretion and T-cell cytokine signalling and this study supports the hypothesis that genetic variations in Rab46 plays a role in COVID-19 severity.