title: Identification of genetic loci associated with Helicobacter pylori serologic status.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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
  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.
authors: Department of Medicine A, University Medicine Greifswald, Greifswald, Germany.
authors: Julia
authors: J
authors: Mayerle
authors: Caroline M
authors: CM
authors: den Hoed
authors: Claudia
authors: C
authors: Schurmann
authors: Lisette
authors: L
authors: Stolk
authors: Georg
authors: G
authors: Homuth
authors: Marjolein J
authors: MJ
authors: Peters
authors: Lisette G
authors: LG
authors: Capelle
authors: Kathrin
authors: K
authors: Zimmermann
authors: Fernando
authors: F
authors: Rivadeneira
authors: Sybille
authors: S
authors: Gruska
authors: Henry
authors: H
authors: Völzke
authors: Annemarie C
authors: AC
authors: de Vries
authors: Uwe
authors: U
authors: Völker
authors: Alexander
authors: A
authors: Teumer
authors: Joyce B J
authors: JB
authors: van Meurs
authors: Ivo
authors: I
authors: Steinmetz
authors: Matthias
authors: M
authors: Nauck
authors: Florian
authors: F
authors: Ernst
authors: Frank-Ulrich
authors: FU
authors: Weiss
authors: Albert
authors: A
authors: Hofman
authors: Martin
authors: M
authors: Zenker
authors: Heyo K
authors: HK
authors: Kroemer
authors: Holger
authors: H
authors: Prokisch
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Markus M
authors: MM
authors: Lerch
authors: Ernst J
authors: EJ
authors: Kuipers
authors: Ernst
authors: E
authors: Kuipers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000942:Antigens, Bacterial; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D016481:Helicobacter Infections / Q000453:epidemiology / Q000235:genetics*; D016480:Helicobacter pylori / Q000302:isolation & purification*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D016036:Seroepidemiologic Studies; D051194:Toll-Like Receptor 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: D000942:Antigens, Bacterial; D051194:Toll-Like Receptor 1