Specific Immune Phenotypes Protect Individuals Against COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

Identifying the host factors influencing the COVID-19 outcome is critical to overcome the global pandemic. The associations between immune phenotypes and the risk of COVID-19 are still poorly understood. We sought to systematically evaluate the causal impact of multiple immune cell traits on COVID-19 susceptibility and its severity using two-sample Mendelian randomization (MR). Genetic variants associated with each immune phenotypes at P < 5×10-8 from genome-wide association studies (GWAS). The GWAS statistics of COVID-19 is from COVID-19 Host Genetics Initiative. Susceptibility and severity were defined as COVID-19 positive and hospitalization versus population controls, respectively. Inverse-variance weighted (IVW) method was used as the main MR analysis, and comprehensive sensitivity analyses were conducted for estimating the robustness. The MR estimates showed that genetically predicted high expression of BAFF-R on B cell was strongly associated with a lower risk of COVID-19 severity. In addition, BAFF-R expression on B cell subsets showed consistent causal relationship with COVID-19 severity, such as its expression on transitional B cell and naive-mature B cell. Evidence from all sensitivity analyses further supported these associations. In MR analysis for COVID-19 susceptibility, we observed a highly consistent protective role of BAFF-R expression, although the P value was not significant. Moreover, in multivariable MR analyses, adjusting for the effects of other B cell biomarkers displayed similar MR findings. This study provides genetic evidence that the genetically high expression of BAFF-R on B cells decreases the risk of COVID-19 severity.