Genome-wide Mendelian randomization and single-cell RNA sequencing analyses identify the causal effects of glucocorticoids on inflammatory disorders of breast

Background Inflammatory disorders of breast(IDB) is a common reason for glucocorticoids(GCs) treatment in women. However, there are no studies elucidating the relationship between GCs and the risk of IDB in general population. Therefore, we employed Mendelian randomization (MR) to explore the causal associations between GCs and IDB. Methods A two-sample MR analysis was performed using the summary statistics sourced from the largest genome-wide association studies(GWAS) conducted in GCs, glucocorticoid receptor-related mRNAs(GRs) and IDB. Inverse-variance weighting (IVW), MR‒Egger, and weighted median (WM) were further supported by several sensitivity analyses. Metascape and Single-cell RNA sequencing(scRNA-Seq) were used to analyze the functions and distribution of GRs. Results We detected causal genetic associations between GCS and IDB (OR, 1.22 (95% CI, 1.019– 1.462), P = 0.021). Further WM measure (OR, 1.294 (95% CI, 1.002– 1.671), P = 0.048) also showed similar results. No causal association was found between GCs and Childbirth-Associated Breast Infections. ScRNA-Seq confirmed that GRs were expressed in almost all immune cells, but more highly expressed in macrophages. The expression quantitative trait locus (eQTL) data suggest that NR1I3 is a high-risk factor for IDB. Conclusions We are the first to use MR analysis to explore the causal relationships between GCs and IDB, revealing an increased risk of IDB with GCs. These may caused by the highly expressed GRs on macrophages in breast tissue.