CACNA1E, C4BPA is causally associated with gastric cancer: A Mendelian randomization study

Abstract

Background: Gastric cancer (GC) is influenced by several risk factors such as smoking and high intake of cured foods. However, the effect of some molecules on incidence of GC have not been demonstrated. In this study, Single-Variable Mendelian Randomization (SVMR) and Multi-Variable Mendelian Randomization (MVMR) were utilized for estimating the causal association between calcium voltage-gated channel subunit alpha 1E (CACNA1E), C4b binding protein alpha (C4BPA) and GC. Methods: The Genome-Wide Association Study (GWAS) ids for GC and exposure factors were derived from Integrative Epidemiology Unit (IEU) Open GWAS database. Including 6563 GC samples and 195,745 control samples, and there were 8,885,324 Single Nucleotide Polymorphisms (SNPs) for GC. The sample size for CACNA1E was 31,684, and the number of SNPs was 18,413. The sample size for C4BPA was 14,263, and the number of SNPs was 15,879. The SVMR studies were conducted to estimate the risk of CACNA1E and C4BPA in GC using MR Egger, weighted median, inverse variance weighted (IVW), simple mode and weighted mode. Importantly, IVW was the most major method. In addition, sensitivity analysis was conducted to assess the reliability of MR results, which mainly consisted of the heterogeneity, horizontal pleiotropy and Leave-One-Out (LOO). Finally, the MVMR analysis was carried out. Results: The SVMR indicated that CACNA1E and C4BPA are causally related to GC, with C4BPA (P=0.006, OR=1.032) as a risk factor and CACNA1E (P=0.005, OR=0.827) as a protective factor. The reliability of SVMR results was demonstrated by sensitivity analysis. The MVMR analysis was consistent with the outcome of SVMR, implicating C4BPA as a cause of GC, whereas CACNA1E is a protective factor against GC. Conclusion: A causal relationship between CACNA1E, C4BPA and GC was confirmed by our study, and increased C4BPA expression elevates the prevalence of GC and vice versa for CACNA1E.