rs762855 single nucleotide polymorphism modulates the risk for diffuse-type gastric cancer in females: a genome-wide association study in the Korean population

Background: Intestinal-type gastric cancer (IGC) and diffuse-type gastric cancer (DGC) exhibit different prevalence rates between sexes. While environmental factors like Helicobacter pylori infection and alcohol consumption contribute to these differences, they do not fully account for them, suggesting a role for host genetic factors. Methods: We conducted a meta-analysis to explore associations between single nucleotide polymorphisms (SNPs) and the risk of IGC or DGC. The analysis included the SNUBH cohort (998 participants: 159 DGCs, 303 IGCs, 4,962,361 variants) and the GC_HC cohort (6,233 participants: 389 DGCs, 405 IGCs, 4,541,617 variants). Significant variants were validated in the SNUBH2_AA cohort (5,511 participants: 40 DGCs, 49 IGCs, 3,668,632 variants). Results: The meta-analysis identified that rs762855 (chr4:3,074,795; hg19) is significantly associated with DGC risk in females (OR [95% CI]: 1.758 [1.438–2.150], P = 3.91 × 10^–8), a finding replicated in the SNUBH2_AA datasets (OR [95% CI]: 3.356 [1.031–10.92], P = 4.43 × 10^–2). Gene-set and transcriptomic analyses revealed that the Myb/SANT DNA Binding Domain Containing 1 (MSANTD1) gene is significantly linked to DGC susceptibility in females. In addition, Mendelian randomization analyses suggested that increased serum total protein and non-albumin protein (NAP) levels elevate DGC risk in females (P < 0.05), but not in males. Conclusion: The rs762855 SNP, MSANTD1, and serum NAP levels are associated with DGC risk in Korean females.