GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy

Asahi Hishida, Tomotaka Ugai, Ryosuke Fujii, Masahiro Nakatochi, Michael C. Wu, Hidemi Ito, Isao Oze, Masahiro Tajika, Yasumasa Niwa, Takeshi Nishiyama, Hiroko Nakagawa-Senda, Sadao Suzuki, Teruhide Koyama, Daisuke Matsui, Yoshiyuki Watanabe, Takahisa Kawaguchi, Fumihiko Matsuda, Yukihide Momozawa, Michiaki Kubo, Mariko NaitoKeitaro Matsuo, Kenji Wakai

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Abstract

Although recent genome-wide association studies (GWASs) have identified genetic variants associated with Helicobacter pylori (HP)-induced gastric cancer, few studies have examined the genetic traits associated with the risk of HP-induced gastric precancerous conditions. This study aimed to elucidate genetic variants associated with these conditions using a genome-wide approach. Data from four sites of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study were used in the discovery phase (Stage I); two datasets from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center 2 (HERPACC2) study were used in the replication phases (Stages II and III) and SKAT (SNP-set Kernel Association Test) and single variant-based GWASs were conducted for the risks of gastric atrophy (GA) and severe GA defined by serum pepsinogen (PG) levels, and PG1 and PG1/2 ratios. In the gene-based SKAT in Stage I, prostate stem cell antigen (PSCA) was significantly associated with the risks of GA and severe GA, and serum PG1/2 level by linear kernel [false discovery rate (FDR) = 0.011, 0.230 and 7.2 × 10-7, respectively]. The single variant-based GWAS revealed that nine PSCA single nucleotide polymorphisms (SNPs) fulfilled the genome-wide significance level (P < 5 × 10-8) for the risks of both GA and severe GA in the combined study, although most of these associations did not reach genome-wide significance in the discovery or validation cohort on their own. GWAS for serum PG1 levels and PG1/2 ratios revealed that the PSCA rs2920283 SNP had a striking P-value of 4.31 × 10-27 for PG1/2 ratios. The present GWAS revealed the genetic locus of PSCA as the most significant locus for the risk of HP-induced GA, which confirmed the recently reported association in Europeans.

Original languageEnglish
Pages (from-to)661-668
Number of pages8
JournalCarcinogenesis
Volume40
Issue number5
DOIs
Publication statusPublished - 04-07-2019

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All Science Journal Classification (ASJC) codes

  • Cancer Research

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Hishida, A., Ugai, T., Fujii, R., Nakatochi, M., Wu, M. C., Ito, H., Oze, I., Tajika, M., Niwa, Y., Nishiyama, T., Nakagawa-Senda, H., Suzuki, S., Koyama, T., Matsui, D., Watanabe, Y., Kawaguchi, T., Matsuda, F., Momozawa, Y., Kubo, M., ... Wakai, K. (2019). GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy. Carcinogenesis, 40(5), 661-668. https://doi.org/10.1093/carcin/bgz016