PIWI-like proteins contribute to the onset and progression of carcinogenesis. Whether single nucleotide polymorphisms (SNPs) in the PIWI-like 1 (PIWIL1) gene affect the morbidity and mortality of gastric cancer (GC) remains unclear. To investigate the efficacy of PIWIL1 SNPs genotype on the morbidity and mortality of GC and its interaction within PIWIL1 gene SNPs variation and between elevated plasma glucose. We conducted a case-control study that contained 216 GC patients and 204 cancer-free controls to compare differential expression of PIWIL1 SNPs. PIWIL1 gene rs1106042 AA and AG genotypes were associated with significantly reduced GC risk (odds ratio [OR]: 0.15 and 0.26,  < 0.001 and  = 0.016), and rs10773771 CT+CC type significantly increased cancer risk (OR: 1.54  = 0.037). We observed strong associations between rs10773771 and pathological type ( = 0.012), rs11703684, and invasion depth ( = 0.012). We noticed significant gene-gene interaction between rs1106042 and rs10773771 ( = 0.0107). Interaction between the copresence of rs1106042 GG plus hyperglycemia was also significant (relative excess risk due to interaction: 28.78, attributable proportion due to interaction: 68.2%, synergy index: 3.32). Patients with rs1892723 TT and rs1892722 GG+GA type had better survival ( = 0.030 and  = 0.048). rs10773771 CT+CC was associated with GC risk increase, rs1106042 AA and AG function as a protective factor. rs1892723 CT+TT and rs1892722 AA type may portend a poor prognosis. Elevated fasting plasma glucose will significantly increase the risk of PIWIL gene rs1106042 GG carcinogenesis by multiplicative interaction.

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