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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Genome-Wide Association Study
Pylorus
Atrophy
Prostate
Stomach
Stem Cells
Antigens
Single Nucleotide Polymorphism
Helicobacter pylori
Genome
Serum
Precancerous Conditions
Pepsinogen A
Genetic Loci
Stomach Neoplasms
Japan
Cohort Studies
Research
Genes

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Hishida, A., Ugai, T., Fujii, R., Nakatochi, M., Wu, M. C., Ito, H., ... 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
Hishida, Asahi ; Ugai, Tomotaka ; Fujii, Ryosuke ; Nakatochi, Masahiro ; Wu, Michael C. ; Ito, Hidemi ; Oze, Isao ; Tajika, Masahiro ; Niwa, Yasumasa ; Nishiyama, Takeshi ; Nakagawa-Senda, Hiroko ; Suzuki, Sadao ; Koyama, Teruhide ; Matsui, Daisuke ; Watanabe, Yoshiyuki ; Kawaguchi, Takahisa ; Matsuda, Fumihiko ; Momozawa, Yukihide ; Kubo, Michiaki ; Naito, Mariko ; Matsuo, Keitaro ; Wakai, Kenji. / GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy. In: Carcinogenesis. 2019 ; Vol. 40, No. 5. pp. 661-668.
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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.",
author = "Asahi Hishida and Tomotaka Ugai and Ryosuke Fujii and Masahiro Nakatochi and Wu, {Michael C.} and Hidemi Ito and Isao Oze and Masahiro Tajika and Yasumasa Niwa and Takeshi Nishiyama and Hiroko Nakagawa-Senda and Sadao Suzuki and Teruhide Koyama and Daisuke Matsui and Yoshiyuki Watanabe and Takahisa Kawaguchi and Fumihiko Matsuda and Yukihide Momozawa and Michiaki Kubo and Mariko Naito and Keitaro Matsuo and Kenji Wakai",
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Hishida, A, Ugai, T, Fujii, R, Nakatochi, M, Wu, MC, 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, Naito, M, Matsuo, K & Wakai, K 2019, 'GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy', Carcinogenesis, vol. 40, no. 5, pp. 661-668. https://doi.org/10.1093/carcin/bgz016

GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy. / Hishida, Asahi; Ugai, Tomotaka; Fujii, Ryosuke; Nakatochi, Masahiro; Wu, Michael C.; Ito, Hidemi; Oze, Isao; Tajika, Masahiro; Niwa, Yasumasa; Nishiyama, Takeshi; Nakagawa-Senda, Hiroko; Suzuki, Sadao; Koyama, Teruhide; Matsui, Daisuke; Watanabe, Yoshiyuki; Kawaguchi, Takahisa; Matsuda, Fumihiko; Momozawa, Yukihide; Kubo, Michiaki; Naito, Mariko; Matsuo, Keitaro; Wakai, Kenji.

In: Carcinogenesis, Vol. 40, No. 5, 04.07.2019, p. 661-668.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GWAS analysis reveals a significant contribution of PSCA to the risk of Heliobacter pylori-induced gastric atrophy

AU - Hishida, Asahi

AU - Ugai, Tomotaka

AU - Fujii, Ryosuke

AU - Nakatochi, Masahiro

AU - Wu, Michael C.

AU - Ito, Hidemi

AU - Oze, Isao

AU - Tajika, Masahiro

AU - Niwa, Yasumasa

AU - Nishiyama, Takeshi

AU - Nakagawa-Senda, Hiroko

AU - Suzuki, Sadao

AU - Koyama, Teruhide

AU - Matsui, Daisuke

AU - Watanabe, Yoshiyuki

AU - Kawaguchi, Takahisa

AU - Matsuda, Fumihiko

AU - Momozawa, Yukihide

AU - Kubo, Michiaki

AU - Naito, Mariko

AU - Matsuo, Keitaro

AU - Wakai, Kenji

PY - 2019/7/4

Y1 - 2019/7/4

N2 - 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.

AB - 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.

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