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Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large‐scale genome‐wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11‐12 (rs6490061,  P  =   3.20 × 10 −8  with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549,  P  =   8.11 × 10 −10  with an OR of 1.109). rs6490061 is located at intron 19 of the   CUX 2  gene, and its expression was suppressed by  Helicobacter pylori  infection. rs2376549 is included within the gene cluster of   DEFB   families that encode antibacterial peptides. We also found a significant association of rs7849280 in the   ABO   gene locus on 9q34.2 ( P  =   2.64 × 10 −13  with an OR of 1.148).   CUX 2  and   ABO   expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 ( P  =   0.0153 and 8.00 × 10 −11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21