{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:42:39Z","timestamp":1792284159596,"version":"4.4.0"},"posted":{"date-parts":[[2026,3,30]]},"group-title":"Gastroenterology","reference-count":101,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Helicobacter pylori<\/jats:italic>\n                  (\n                  <jats:italic>H. pylori<\/jats:italic>\n                  ) 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\n                  <jats:italic>H. pylori<\/jats:italic>\n                  infection, many genetic factors underlying host response to\n                  <jats:italic>H. pylori<\/jats:italic>\n                  remain unidentified. Moreover, although\n                  <jats:italic>H. pylori<\/jats:italic>\n                  infection has been implicated in a range of extra-gastric diseases, whether these associations share a common genetic architecture remains unclear. We performed a genome-wide association study (GWAS) of anti-\n                  <jats:italic>H. pylori<\/jats:italic>\n                  IgG antibody titers, a composite host phenotype reflecting susceptibility to persistent infection and subsequent immune activation, followed by gene-based and pathway analyses, involving up to 140,863 individuals. This included 56,967 individuals in the discovery phase and 68,211 in the replication phase from Japanese cohorts, together with an additional 15,685 from European populations in a cross-ancestry meta-analysis. We reveal significant associations between IgG titers 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\n                  <jats:italic>CCDC80<\/jats:italic>\n                  ,\n                  <jats:italic>NFKBIZ<\/jats:italic>\n                  ,\n                  <jats:italic>TIFA<\/jats:italic>\n                  ,\n                  <jats:italic>PSCA<\/jats:italic>\n                  , and\n                  <jats:italic>TRAF3<\/jats:italic>\n                  . Mendelian randomization (MR) analyses revealed directionally consistent associations between genetic liability to higher anti\u2013\n                  <jats:italic>H. pylori<\/jats:italic>\n                  IgG levels and a range of diseases, including immune-mediated diseases such as type 1 diabetes, Hashimoto\u2019s disease, atopic dermatitis, as well as quantitative traits like body height and weight. These genetic findings support the interpretation that host genetic determinants of response to\n                  <jats:italic>H. pylori<\/jats:italic>\n                  , particularly those mediated through HLA class II, form part of a shared immunogenetic architecture associated with susceptibility to multiple immune-related diseases.\n                <\/jats:p>","DOI":"10.64898\/2026.03.27.26349357","type":"posted-content","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T16:05:20Z","timestamp":1774886720000},"source":"Crossref","is-referenced-by-count":1,"title":["Genome-wide association and Mendelian randomization analyses of host response to\n                  <i>Helicobacter pylori<\/i>\n                  infection implicate HLA polymorphisms and immune-mediated diseases"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-2971","authenticated-orcid":false,"given":"Tomoki","family":"Kyosaka","sequence":"first","affiliation":[{"name":"Graduate School of Medicine, Tohoku University, Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9076-0710","authenticated-orcid":false,"given":"Akira","family":"Narita","sequence":"additional","affiliation":[{"name":"Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9789-245X","authenticated-orcid":false,"given":"Jerzy K","family":"Kulski","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4229-4137","authenticated-orcid":false,"given":"Aye Ko Ko","family":"Minn","sequence":"additional","affiliation":[{"name":"RIKEN Center for Advanced Intelligence Project, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-1412","authenticated-orcid":false,"given":"Akimitsu","family":"Miyake","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Tohoku University, Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9229-2200","authenticated-orcid":false,"given":"Yurii","family":"Kotsar","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Tohoku University, Sendai, Japan"},{"name":"RIKEN Center for Advanced Intelligence Project, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoga","family":"Hiraide","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Tohoku University, Sendai, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-0574","authenticated-orcid":false,"given":"Takafumi","family":"Ojima","sequence":"additional","affiliation":[{"name":"RIKEN Center for Advanced Intelligence Project, Tokyo, Japan"},{"name":"Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan"},{"name":"Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-4837","authenticated-orcid":false,"given":"Masahiro","family":"Nakatochi","sequence":"additional","affiliation":[{"name":"Public Health Informatics Unit, Department of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7486-3146","authenticated-orcid":false,"given":"Shinichi","family":"Namba","sequence":"additional","affiliation":[{"name":"Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan"},{"name":"Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4799-8782","authenticated-orcid":false,"given":"Taiki","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-9759","authenticated-orcid":false,"given":"Yoichi","family":"Sutoh","sequence":"additional","affiliation":[{"name":"Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan"},{"name":"Division of Biomedical Information Analysis, Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3939-9480","authenticated-orcid":false,"given":"Yu","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0011-123X","authenticated-orcid":false,"given":"Linda","family":"Broer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1502-8888","authenticated-orcid":false,"given":"Fabian","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Medicine A, University Medicine Greifswald, Greifswald, 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