A Comprehensive Assessment of the Causal Relationship between Atopic Conditions and Pancreatic Cancer Risk: A Two-Sample Mendelian Randomization Study

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BACKGROUND: Observational studies consistently report reduced pancreatic ductal adenocarcinoma (PDAC) risk among individuals with atopic conditions (asthma and rhinitis); however, the underlying biological mechanism remains unclear. This Mendelian randomization (MR) study investigated the potential causal relationship between atopy and PDAC by leveraging multiple genome-wide association studies (GWAS) and individual-level PDAC data. METHODS: A two-sample MR analysis was conducted, leveraging genetic variants as instrumental variables for atopic conditions extracted from genomic repositories in approach 1 and from four large-scale atopy-specific GWAS in approach 2. Single-nucleotide polymorphism-PDAC association estimates were obtained from PanGenEU GWAS. The primary analysis employed the inverse variance weighted method. Sensitivity analyses (MR-Egger, weighted median, and leave-one-out) were conducted to evaluate pleiotropy and robustness. Additional immunoglobulin E (IgE)-stratified MR analysis was conducted among individuals with biomarker data to explore endotype-specific causality. RESULTS: There was no clear evidence of a causal association between asthma or rhinitis and PDAC risk [odds ratioasthma (ORasthma) range: 0.90-1.07; ORrhinitis range: 0.80-0.98)]. Sensitivity analyses showed no directional pleiotropy. IgE-stratified analyses exhibited null results for asthma and a modest but insignificant inverse trend for rhinitis among individuals with low IgE sensitization. CONCLUSIONS: This MR study found no evidence supporting a causal protective effect of atopy on PDAC risk. Other factors may modulate the protective effect reported in the observational studies. Atopic endotypes exhibit heterogeneous genetic architectures, warranting further investigation into endotype-specific mechanisms. IMPACT: These findings shift causal PDAC research toward atopic endotypes.

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