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

Abstract

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. 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. 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. 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.