TY - JOUR
T1 - Identification of genetic loci associated with Helicobacter pylori serologic status
AU - Mayerle, Julia
AU - Den Hoed, Caroline M.
AU - Schurmann, Claudia
AU - Stolk, Lisette
AU - Homuth, Georg
AU - Peters, Marjolein J.
AU - Capelle, Lisette G.
AU - Zimmermann, Kathrin
AU - Rivadeneira, Fernando
AU - Gruska, Sybille
AU - Vol̈zke, Henry
AU - De Vries, Annemarie C.
AU - Vol̈ker, Uwe
AU - Teumer, Alexander
AU - Van Meurs, Joyce B.J.
AU - Steinmetz, Ivo
AU - Nauck, Matthias
AU - Ernst, Florian
AU - Weiss, Frank Ulrich
AU - Hofman, Albert
AU - Zenker, Martin
AU - Kroemer, Heyo K.
AU - Prokisch, Holger
AU - Uitterlinden, Andre G.
AU - Lerch, Markus M.
AU - Kuipers, Ernst
PY - 2013/5/8
Y1 - 2013/5/8
N2 - 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.
AB - 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.
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U2 - 10.1001/jama.2013.4350
DO - 10.1001/jama.2013.4350
M3 - Article
C2 - 23652523
AN - SCOPUS:84877261831
SN - 0098-7484
VL - 309
SP - 1912
EP - 1920
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 18
ER -
