Abstract

Helicobacter pylori (H. pylori) infects the gastric epithelium of approximately half of the global population, and is a well-known risk factor for developing gastric cancer. Despite the clinical significance of H. pylori infection, many genetic factors that contribute to susceptibility remain unidentified. While it is well-established that H. pylori infection can result in gastritis and peptic ulcers, which may progress to gastric cancer, its causal link to other diseases remains unclear. We performed the genome-wide association study (GWAS) for anti-H. pylori IgG antibody titers, which were validated as a surrogate marker for H. pylori infection by the correlation with clinical traits, followed by gene-based and pathway analyses, involving up to 140,863 individuals. This included 56,967 in the discovery phase, and 68,211 in the replication phase from Japanese cohorts, and an additional 15,685 from European populations in a cross-ancestry meta-analysis. We reveal significant associations between H. pylori infection and polymorphisms in the Human Leukocyte Antigen (HLA) class II region within the Major Histocompatibility Complex (MHC), as well as genes related to innate immunity, including CCDC80, NFKBIZ, TIFA, PSCA, and TRAF3. Mendelian randomization (MR) analysis revealed that genetic liability to H. pylori infection has both positive and negative causal relationships with a variety of diseases, including autoimmune-related diseases such as Type 1 diabetes, Hashimoto’s disease, atopic dermatitis, as well as traits like body height and weight. These genetic findings strongly support the notion that genetic liability to H. pylori infection influences not only gastrointestinal diseases, but also a broader spectrum of health issues, thereby providing valuable insights for public health strategies and personalized medicine approaches.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by the Japan Agency for Medical Research and Development (AMED) (JP23ek0410113) to Y.O. and G.T., Programs for Bridging the gap between R&D and the IDeal society (society 5.0) and Generating Economic and social value (BRIDGE) (JPJ012525) to G.T., the Japan Society for the Promotion of Science (JSPS) KAKENHI (25K00278 and 22K13523) to T.Kyosaka and A.M., Japan Science and Technology Agency (JST) Moonshot R&D (JPMJMS2023) to J.T. and G.T., the RIKEN Center for Advanced Intelligence Project "Genome Statistical Analysis Using Machine Learning and Artificial Intelligence Technologies" to G.T., and the Tohoku Kaihatsu Memorial Foundation to T.Kyosaka and A.M. This work was also supported by the National Cancer Center Research and Development Fund (28-A-19, 31-A-18, and 2022-A-20). The TMM project's supercomputer and integrated database dbTMM were supported by AMED grant numbers JP21tm0424601 and JP21tm0124005, respectively. The HERPACC Study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (Priority Areas of Cancer: 17015018; Innovative Areas: 221S0001) and JSPS KAKENHI (JP16H06277[CoBiA], JP26253041, JP20K10463, JP23K16316, and JP24K02697), as well as a Grant-in-Aid for the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare (MHLW) of Japan. The JPHC Study was supported by the National Cancer Center Research and Development Fund (23-A-31[toku], 26-A-2, 29-A-4, 2020-J-4, and 2023-J-4), and a Grants-in-Aid for Cancer Research from MHLW of Japan (from 1989 to 2010). The J-MICC Study was supported by Grants-in-Aid for Scientific Research from MEXT (Priority Areas of Cancer: 17015018; Innovative Areas: 221S0001) and JSPS KAKENHI (JP16H06277 and JP22H04923[CoBiA]). It was also partially funded by the BBJ Project from AMED (since April 2015) and by MEXT (from April 2003 to March 2015). The Yamagata Study was supported by AMED (20ck0106561h0001 and 24ck0106887h0002) and JSPS KAKENHI (JP23K07454).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Informed consent for participation was obtained for all study subjects and approval was given by the Institutional Review Boards of Tohoku University (TMM Project), National Cancer Center (JPHC), Aichi Cancer Center (J-MICC, HERPACC), and Yamagata University (Yamagata Study).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Summary statistics for the GWAS of H. pylori infection generated in this study will be made publicly available through the jMorp database (https://jmorp.megabank.tohoku.ac.jp/) in connection with publication of this work. Most of the GWAS summary statistics used as outcome datasets in the Mendelian randomization analyses are available through BioBank Japan PheWeb (https://pheweb.jp/), whereas the remaining summary statistics are derived from controlled-access datasets governed by cohort-specific ethical and institutional restrictions and can be accessed upon reasonable request to the respective data access committees. European ancestry GWAS summary statistics for anti-H. pylori IgG antibody titers from Lam et al. (2022) are not publicly available and were obtained under a data-sharing agreement; access must be requested directly from the original authors. Individual-level genotype and phenotype data from the participating Japanese cohorts cannot be publicly shared due to privacy, ethical, and regulatory restrictions. All remaining data supporting the findings of this study are available within the article and its Supplementary Information.

https://jmorp.megabank.tohoku.ac.jp/

https://pheweb.jp/

AbbreviationsBBBioBank JapanCCDC80Coiled-coil domain containing 80GWASgenome-wide association studyFHSFramingham Heart StudyHERPACCHospital-based Epidemiologic Research Program at Aichi Cancer CenterHLAhuman leukocyte antigenIMMIwate Tohoku Medical Megabank organizationIVWinverse-variance weightedJ-MICCJapan Multi-Institutional Collaborative Cohort StudyJPHCJapan Public Health Centre-based Prospective StudyLDlinkage disequilibriumMAFminor allele frequencyMESAMulti-Ethnic Study of AtherosclerosisMHCmajor histocompatibility complexMRMendelian randomizationNFKBIZNF-kappa-B inhibitor zetaNF-κBnuclear factor-kappa BORodds ratioPCprincipal componentPSCAprostate stem cell antigenrggenetic correlationRSRotterdam StudySHIPStudy of Health in PomeraniaSNPsingle nucleotide polymorphismT1DType 1 diabetesT2DType 2 diabetesTIFATRAF interacting protein with forkhead associated domainTLRToll-Like receptorTRAF3Tumor necrosis factor receptor-associated factor 3TMMTohoku Medical MegabankToMMoTohoku Medical Megabank Organization (Miyagi prefecture)