Genetic liability to critically ill COVID-19 increased risk of HER2-positive breast cancer through the immune pathway: A Mendelian randomization study

The clinical management of patients with both coronavirus disease 2019 (COVID-19) and breast cancer remains a complex and unresolved issue that despite extensive discussion has not reached a consensus. In contemporary literature, the association between COVID-19 and HER2-positive breast cancer has received minimal attention. Genetic instruments for severe acute respiratory syndrome coronavirus 2 infection (N = 2,597,856), hospitalized COVID-19 (N = 2,095,324), and critically ill COVID-19 (N = 1,086,211) were obtained from the COVID-19 Host Genetics Initiative genome-wide association study (GWAS) meta-analysis. A total of 103,530 HER2-positive breast cancer cases from GWAS were enrolled in our study. The summary GWAS statistics of 731 immune cells (N = 3757) were obtained from the MRCEU open database. Causal associations were evaluated by applying Mendelian randomization (MR) including inverse variance weighting, MR-Egger regression, and weighted-median analysis. Sensitivity analyses were employed, including Cochran Q test, MR-Egger intercept test, MR Pleiotropy Residual Sum and Outlier, and leave-one-out analysis, to examine the robustness of these findings. Genetic liability to critically ill COVID-19 was significantly causally associated with the increased risk of HER2-positive breast cancer (odds ratios = 1.086, 95% confidence intervals = 1.015-1.162, P = .016). No causal associations between severe acute respiratory syndrome coronavirus 2 infection or hospitalized COVID-19 and HER2-positive breast cancer were observed. Additionally, genetic liabilities to critically ill COVID-19 were significantly positively associated with 9 immune cells. IgD- CD27- AC and CD27 on IgD+ CD38- unsw mem (memory B cells) were identified as potential mediators of the causal relationship between critically ill COVID-19 and HER2-positive breast cancer. Genetic liability to critically ill COVID-19 is associated with an increased risk of HER2-positive breast cancer possibly through the immune pathway. Future studies are essential to elucidate the mechanisms underlying this causal relationship, aiming to develop therapeutic strategies to mitigate the immune cell-mediated impact on HER2-positive breast cancer risk.