Abstract
Gastric cancer (GC) is a multistep complex disease involving multiple genes, and gene–gene interactions have a greater effect than a single gene in determining cancer susceptibility. This study aimed to explore the interaction of the let-7e rs8111742, miR-365b rs121224, and miR-4795 rs1002765 single nucleotide polymorphisms (SNPs) with SNPs of the predicted target gene PGC and Helicobacter pylori status in GC and atrophic gastritis (AG) risk. Three miRNA SNPs and seven PGC SNPs were detected in 2448 cases using the Sequenom MassArray platform. Two pairwise combinations of miRNA and PGC SNPs were associated with increased AG risk (let-7e rs8111742 – PGC rs6458238 and miR-4795 rs1002765 – PGC rs9471643). Singly, miR-365b rs121224 and PGC rs6912200 had no effect individually but in combination they demonstrated an epistatic interaction associated with AG risk. Similarly, let-7e rs8111742 and miR-4795 rs1002765 SNPs interacted with H. pylori infection to increase GC risk (rs8111742: Pinteraction = 0.024; rs1002765: Pinteraction = 0.031, respectively). A three-dimensional interaction analysis found miR-4795 rs1002765, PGC rs9471643, and H. pylori infection positively interacted to increase AG risk (Pinteraction = 0.027). Also, let-7e rs8111742, PGC rs6458238, and H. pylori infection positively interacted to increase GC risk (Pinteraction = 0.036). Furthermore, both of these three-dimensional interactions had a dosage–effect correspondence (Ptrend < 0.001) and were verified by MDR. In conclusion, the miRNAs SNPs (let-7e rs8111742 and miR-4795 rs1002765) might have more superior efficiency when combined with PGC SNPs and/or H. pylori for GC or AG risk than a single SNP on its own.
Highlights
Single nucleotide polymorphisms (SNPs) are potential predicting biomarkers of cancer risk, they have limited use for multistage complex diseases involving multiple genes [1,2,3]
We previously investigated associations of three miRNA polymorphisms with seven pepsinogen C (PGC) polymorphisms affecting the risk of Gastric cancer (GC) and atrophic gastritis (AG) in a Chinese population
We found that the let-7e rs8111742 – PGC rs6458238 – H. pylori three-way combination had a positive interaction with GC risk (Pinteraction = 0.036, interaction index = 15.69), while the miR-4795 rs1002765 – PGC rs9471643 – H. pylori three-way combination had a positive interaction with AG risk (Pinteraction = 0.027, interaction index = 4.02; Table 5)
Summary
Single nucleotide polymorphisms (SNPs) are potential predicting biomarkers of cancer risk, they have limited use for multistage complex diseases involving multiple genes [1,2,3]. Several studies have reported that gene–gene interactions are more important than single genes in promoting cancer susceptibility [3,4,5]. In epistasis, which is a phenomenon that consists of the effect of complex interactions, is greater than the main effects of any single susceptibility gene [5, 7]. Several studies have simultaneously screened miRNA SNPs and target gene SNPs, and interactions between specific pairs to promote carcinogenic effect have been identified [9]
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