Identification of Genetic Loci Associated With Helicobacter pylori Serologic Status

• Published in: JAMA : the journal of the American Medical Association Vol. 309; no. 18; pp. 1912 - 1920
• Main Authors: Mayerle, Julia, den Hoed, Caroline M, Schurmann, Claudia, Stolk, Lisette, Homuth, Georg, Peters, Marjolein J, Capelle, Lisette G, Zimmermann, Kathrin, Rivadeneira, Fernando, Gruska, Sybille, Völzke, Henry, de Vries, Annemarie C, Völker, Uwe, Teumer, Alexander, van Meurs, Joyce B. J, Steinmetz, Ivo, Nauck, Matthias, Ernst, Florian, Weiss, Frank-Ulrich, Hofman, Albert, Zenker, Martin, Kroemer, Heyo K, Prokisch, Holger, Uitterlinden, Andre G, Lerch, Markus M, Kuipers, Ernst
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 08.05.2013
• Subjects: Adult; Aged; Aged, 80 and over; Antigens, Bacterial; Bacteria; Bacterial diseases; Bacterial diseases of the digestive system and abdomen; Bacterial infections; Biological and medical sciences; Case-Control Studies; Cohort Studies; Female; Gene expression; General aspects; Genetic Loci; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Germany - epidemiology; Helicobacter Infections - epidemiology; Helicobacter Infections - genetics; Helicobacter pylori - isolation & purification; Human bacterial diseases; Humans; Infectious diseases; Male; Medical sciences; Middle Aged; Netherlands - epidemiology; Polymorphism, Single Nucleotide; Prevalence; Risk assessment; Seroepidemiologic Studies; Systematic review; Toll-Like Receptor 1 - genetics; Young Adult; Netherlands; Germany; Infection; Medicine; Association; Spirillales; Helicobacter pylori; Spirillaceae; Bacteriosis; Bacteria; Genetics; Identification; Serology
• ISSN: 0098-7484; 1538-3598
• 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.