No Genetic Causal Relationship between COVID-19 and Herpes Zoster: A Bidirectional Mendelian Randomization Analysis

Yuan Cao,1,* Xinhua Hu,1,* Jun Li,1,2 Yumin Zheng3 1Department of Neurology, People’s Hospital of Xinjin District, Chengdu, Sichuan, People’s Republic of China; 2Department of Urology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China; 3Department of Neurology, Shanghai Civil Aviation Hospital/Gubei Branch of Ruijin Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yumin Zheng, Department of Neurology, Shanghai Civil Aviation Hospital/Gubei Branch of Ruijin Hospital, Shanghai, People’s Republic of China, Email [email protected] Jun Li, Department of Urology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, People’s Republic of China, Email [email protected]: Increased incidences of herpes zoster (HZ) have been reported among COVID-19 patients, but the underlying causal mechanisms remain unclear. Inspired by an atypical case of HZ in a COVID-19 patient, we conducted a bidirectional Mendelian randomization (MR) analysis to investigate potential causal relationships.Patients and Methods: The genetic statistics were extracted from the COVID19-hg GWAS meta-analyses and the IEU GWAS database. MR analyses were performed using the inverse-variance weighted (IVW) method as the primary approach, with MR-Egger, weighted median, simple mode, and weighted mode methods as supplementary strategies. Heterogeneity and pleiotropy were assessed using Cochran’s Q test, MR-Egger intercept, and MR-PRESSO analysis, while outliers were evaluated with MR-radial plots.Results: The MR analysis did not support a significant causal relationship between COVID-19 and HZ. In the forward analysis, the IVW method revealed no significant associations between COVID-19 susceptibility (β = − 0.053, SE = 0.182, P = 0.77), hospitalization (β = 0.060, SE = 0.069, P = 0.38), or severity (β = 0.015, SE = 0.048, P = 0.75) and HZ. Similarly, the reverse analysis showed no significant effect of HZ on COVID-19 susceptibility (β = 0.006, SE = 0.006, P = 0.33), hospitalization (β = − 0.012, SE = 0.012, P = 0.32), or severity (β = − 0.015, SE = 0.020, P = 0.46). Sensitivity analyses confirmed these findings, showing no substantial heterogeneity or horizontal pleiotropy.Conclusion: Our findings provide no evidence of a causal relationship between genetic predisposition to COVID-19 and the risk of HZ reactivation. The observed clinical association may be attributable to non-genetic factors, such as immune suppression or stress related to COVID-19 and its treatment. Further studies are warranted to explore these alternative mechanisms and improve clinical management of HZ in the context of COVID-19.Keywords: herpes zoster, shingles, COVID-19, Mendelian randomization