Mutually reinforcing relationship between Sjögren’s syndrome and lung adenocarcinoma: insights from Mendelian randomisation, single-cell, and transcriptomic analyses

Abstract Increasing evidence suggests an association between Sjögren’s syndrome (SS) and multiple cancers; however, the causal relationships and regulatory mechanisms remain unclear. Using European genome-wide association study data, we employed Mendelian randomisation (MR) and meta-analysis to explore the SS-cancer causality. Bidirectional two-sample MR revealed that SS increased the risk of colorectal (odds ratio (OR) = 1.08) and lung cancers (OR = 1.15), whereas lung (OR = 3.03) and female genital cancers (OR = 6.59) were found to elevate the risk of SS. Co-localisation analysis confirmed bidirectional causality between SS and lung cancer. Summary data-based MR identified HLA-DPB2 as a hub gene, with single-cell RNA and mRNA analyses suggesting its role in memory B cells regulation via MHC-II ligands and lung carcinogenesis. This study demonstrates a mutually positive association between SS and lung cancer, implicating HLA-DPB2 as a potential regulatory gene and offering novel insights into the relationship between SS and cancer, especially lung cancer.