Role ofCD14Promoter Polymorphisms inHelicobacter pyloriInfection–Related Gastric Carcinoma

Abstract

Genetic variation in CD14 may affect CD14 expression and susceptibility to Helicobacter pylori infection-related cancers. This study examined functional single nucleotide polymorphisms (SNP) in the CD14 promoter and their associations with risk of developing gastric carcinoma in relation to H. pylori infection. Thirty individual DNAs were sequenced to identify variants, and the function of the variants was examined by reporter gene assays. Genotypes and haplotypes were analyzed in 470 patients and 470 controls, and odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression. Serologic H. pylori antibody and soluble CD14 (sCD14) levels were measured by ELISA. Two SNPs (-651C>T and -260C>T) were identified, of which the -260CT and -260TT genotypes were associated with elevated risk of gastric carcinoma (OR, 1.77; 95% CI, 1.09-2.85 and OR, 1.95; 95% CI, 1.20-3.16, respectively). Haplotype analysis suggested a synergistic effect of the two SNPs (OR for the T(-651)-T(-260) haplotype, 3.39 versus OR for the C(-651)-T(-260) haplotype, 1.45; P = 0.02), which is consistent with reporter gene assays. A multiplicative joint effect between H. pylori infection and -260C>T polymorphism was observed (OR for the presence of both -260TT genotype and H. pylori infection, 4.03; 95% CI, 1.80-9.04). Patients had significantly higher sCD14 than controls (1,866 +/- 2,535 ng/mL versus 1,343 +/- 2,119 ng/mL; P < 0.001), and this difference was associated with the CD14 -260 polymorphism and H. pylori infection. Functional polymorphism in CD14 is associated with greater risk of H. pylori-related gastric carcinoma, which might be mediated by elevated sCD14.