A frequent Toll-like receptor 1 gene polymorphism affects NK- and T-cell IFN-γ production and is associated with Helicobacter pylori-induced gastric disease.
BACKGROUND
Helicobacter pylori infects approximately 50% of the world population. Among the infected individuals, only 10-20% develop peptic ulcers and <3% progress to gastric cancer (GC). Th1-predominant immune responses have been suggested to underlie H. pylori-induced gastric diseases. However, the reason for a strong inter-individual variation of susceptibility and course of the disease is currently far from being understood. It has been shown that H. pylori stimulates the host's Toll-like receptor (TLR) 2/1 complex. Furthermore, the single nucleotide polymorphism (SNP) I602S of TLR1 alters the inflammatory cytokine response of monocytes. Therefore, we hypothesized an association of this TLR1 SNP with H. pylori-mediated gastric pathologies.


METHODS
Subjects with different TLR1 genotypes were analyzed for their IFN-γ response of NK- and T-cells. We further genotyped 548 patients with gastric diseases for this SNP and compared patients with gastritis with those having ulcer, and patients with high-risk gastritis versus patients with GC.


RESULTS
Homozygous 602S allele carriers exhibited impaired in vitro IFN-γ responses to the TLR2/1 agonist Pam(3) CSK(4). The TLR1 I602S SNP is significantly associated with GC (p = .002) and gastric ulcer (p = .051). Odds ratios showed significantly reduced risk regarding GC and peptic ulcer for the homozygous mutated genotype. The odds ratios were 0.4 (95% CI, 0.22-0.72) and 0.588 (95% CI, 0.35-1.00), respectively.


CONCLUSIONS
In conclusion, our results suggest that the nonfunctional TLR1 602S/S genotype is associated with a reduced risk of H. pylori-induced gastric diseases, probably via diminished Th1 responses.
Institute of Medical Immunology CVK, Charité-University Medical Center, Berlin, Germany.
Chin-An
CA
Yang
Carmen
C
Scheibenbogen
Sandra
S
Bauer
Christoph
C
Kleinle
Thomas
T
Wex
Jan
J
Bornschein
Peter
P
Malfertheiner
Stephan
S
Hellmig
Ralf R
RR
Schumann
Lutz
L
Hamann
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005838:Genotype; D016481:Helicobacter Infections / Q000276:immunology / Q000473:pathology*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013272:Stomach Diseases / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology
D051194:Toll-Like Receptor 1; D007371:Interferon-gamma