Identification of genetic loci associated with Helicobacter pylori serologic status

JAMA. 2013 May 8;309(18):1912-20. doi: 10.1001/jama.2013.4350.


Importance: Helicobacter pylori is a major cause of gastritis and gastroduodenal ulcer disease and can cause cancer. H. pylori prevalence is as high as 90% in some developing countries but 10% of a given population is never colonized, regardless of exposure. Genetic factors are hypothesized to confer H. pylori susceptibility.

Objective: To identify genetic loci associated with H. pylori seroprevalence in 2 independent population-based cohorts and to determine their putative pathophysiological role by whole-blood RNA gene expression profiling.

Design, setting, and participants: Two independent genome-wide association studies (GWASs) and a subsequent meta-analysis were conducted for anti-H. pylori IgG serology in the Study of Health in Pomerania (SHIP) (recruitment, 1997-2001 [n = 3830]) as well as the Rotterdam Study (RS-I) (recruitment, 1990-1993) and RS-II (recruitment, 2000-2001 [n = 7108]) populations. Whole-blood RNA gene expression profiles were analyzed in RS-III (recruitment, 2006-2008 [n = 762]) and SHIP-TREND (recruitment, 2008-2012 [n = 991]), and fecal H. pylori antigen in SHIP-TREND (n = 961).

Main outcomes and measures: H. pylori seroprevalence.

Results: Of 10,938 participants, 6160 (56.3%) were seropositive for H. pylori. GWASs identified the toll-like receptor (TLR) locus (4p14; top-ranked single-nucleotide polymorphism (SNP), rs10004195; P = 1.4 × 10(-18); odds ratio, 0.70 [95% CI, 0.65 to 0.76]) and the FCGR2A locus (1q23.3; top-ranked SNP, rs368433; P = 2.1 × 10(-8); odds ratio, 0.73 [95% CI, 0.65 to 0.81]) as associated with H. pylori seroprevalence. Among the 3 TLR genes at 4p14, only TLR1 was differentially expressed per copy number of the minor rs10004195-A allele (β = -0.23 [95% CI, -0.34 to -0.11]; P = 2.1 × 10(-4)). Individuals with high fecal H. pylori antigen titers (optical density >1) also exhibited the highest 25% of TLR1 expression levels (P = .01 by χ2 test). Furthermore, TLR1 exhibited an Asn248Ser substitution in the extracellular domain strongly linked to the rs10004195 SNP.

Conclusions and relevance: GWAS meta-analysis identified an association between TLR1 and H. pylori seroprevalence, a finding that requires replication in nonwhite populations. If confirmed, genetic variations in TLR1 may help explain some of the observed variation in individual risk for H. pylori infection.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Bacterial
  • Case-Control Studies
  • Cohort Studies
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Germany / epidemiology
  • Helicobacter Infections / epidemiology
  • Helicobacter Infections / genetics*
  • Helicobacter pylori / isolation & purification*
  • Humans
  • Male
  • Middle Aged
  • Netherlands / epidemiology
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Seroepidemiologic Studies
  • Toll-Like Receptor 1 / genetics*
  • Young Adult


  • Antigens, Bacterial
  • Toll-Like Receptor 1