T300A SNP Association with COVID-19 Severity Norfolk Cohort and UK Biobank

Autophagy is an innate pathway associated with protection from virus infection. Our previous work has found that mutations in the autophagy protein ATG16L1 has a profound effect on influenza virus infection of mice. In this study we investigate the effect the ATG16L1 polymorphism in the pathogenesis of COVID-19 in humans.  ATG16L1 consists of two domains, an N-terminal CCD and C-terminal WD repeat domain separated by an extended, unstable linker region.  A common SNP, T300A (rs2241880), in the linker region is thought to encode a caspase 3 site allowing the removal of the WD domain.  The T300A SNP is associated with increased risk of inflammatory diseases, such as Crohn’s disease. In this study, we investigated the association in humans between ATG16L1 T300A SNP, and clinical symptoms of COVID-19 in both a local Norfolk cohort and two large UK biobank cohorts.  T300A homozygotes showed decreased frequency of some symptoms in all 3 cohorts and were protected against mild but not severe COVID-19 infection.  In the severe group T300A homozygotes showed increased fever, chest pain and shortness of breath.  In addition, T300A homozygotes have reduced anti-viral antibody production.  This may be due to the involvement of ATG16L1 T300A in antigen presentation through LC3- associated phagocytosis.