Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti-Helicobacter pylori IgG Titers.

Suk Yee Lam, Michiel C Mommersteeg, Bingting Yu, Linda Broer, Manon C W Spaander, Fabian Frost, Stefan Weiss, Henry Völzke, Markus M Lerch, Ben Schöttker, Yan Zhang, Hannah Stocker, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C Wood, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Russell P Tracy, Edmond K Kabagambe, Marcis Leja, Janis Klovins, Raitis Peculis, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, André Uitterlinden, Ernst J Kuipers, Gwenny M Fuhler, Georg Homuth, Maikel P Peppelenbosch

Journal: Gastroenterology 2022;162(6):1705-1715

PMID: 35031300

Free Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND & AIMS

A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus.

METHODS

The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants.

RESULTS

The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; β = -0.267 ± SE 0.034; P = 4.42 × 10) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels.

CONCLUSIONS

The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Address: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany.; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.; Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.; USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA.; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.; Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.; Laboratory for Clinical Biochemistry Research, University of Vermont College of Medicine, Colchester, Vermont, USA.; Division of Academics, Ochsner Health, New Orleans, Louisiana, USA.; Institute of Clinical and Preventive Medicine, Faculty of Medicine, University of Latvia, Riga, Latvia.; Latvian Biomedical Research and Study Center, Riga, Latvia.; Rīga Stradiņš University, Riga, Latvia.; Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.; Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: [email protected].

DOI: 10.1053/j.gastro.2022.01.011

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MeSH Terms: Antibodies, Bacterial, Cytokines, Genome-Wide Association Study, Helicobacter Infections, Helicobacter pylori, Humans, Immunoglobulin G, Stomach Neoplasms, Toll-Like Receptor 1