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

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 naïve-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.

Periodontal Disease Increases the Host Susceptibility to COVID-19 and its Severity: A Mendelian Randomization Study (preprint)

Background: Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity.Methods: Summary statistics of COVID-19 susceptibility and severity was retrieved from the COVID-19 Host Genetics Initiative and used as outcomes in this study. As for exposures, Single Nucleotide Polymorphisms (SNPs) with genome-wide significant variants from genome wide association study (GWAS) of PD were included in the MR analysis. Inverse-variance weighted (IVW) method was employed as the main approach to analyzing the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations.Findings: The MR estimates showed that PD was markedly associated with a higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017) and weighted median method (OR = 1.029, P = 0.024). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW: OR = 1.025, P = 0.039; weighted median, OR = 1.030, P = 0.027). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19.Interpretation: This study provides genetic evidence on the possible causality of periodontal disease accounting for the host susceptibility to COVID-19 and its severity, thereby highlighting the importance of disease prevention and oral/periodontal healthcare for general wellbeing during the pandemic and beyond.Funding Information: This work was supported by the Natural Science Foundation of Zhejiang Province (LY18H160050, LQ20H140002), Medical and Health Science and Technology Planning Project of Zhejiang Province (2018KY518), National Natural Science Foundation of China (31771390, 81972261, 32070151), Wenzhou Science and Technology Bureau (ZY2020007, 2020Y0536, Y20190147).Declaration of Interests: The authors declare that no competing interests exist.Ethics Approval Statement: This study only used publicly available data and the relevant ethical approval can be found in the corresponding studies referenced in the Methods section.