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. TracyEdmond 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

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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 × 10−15) 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.

Original languageEnglish
Pages (from-to)1705-1715
Number of pages11
JournalGastroenterology
Volume162
Issue number6
DOIs
Publication statusPublished - Jan 2022
Externally publishedYes

Keywords

  • Bacteria
  • Immunity
  • Serology
  • Single-Nucleotide Polymorphism
  • Genome-Wide Association Study
  • Toll-Like Receptor 1/genetics
  • Stomach Neoplasms/genetics
  • Humans
  • Immunoglobulin G
  • Antibodies, Bacterial
  • Helicobacter pylori
  • Cytokines/genetics
  • Helicobacter Infections/diagnosis

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