Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals.

B acterial, environmental, population related, and individual host factors are major determinants of the outcome of H pylori infection. 2 Many bacterial virulence genes— including the pathogenicity island cagA, the s1m1 vacA alleles, babA2, sabA, and oipA—have been associated with a higher degree of gastric mucosal inflammation, intestinal metaplasia, gastric or duodenal ulcer, gastric adenocarcinoma, and MALToma. 3–7 H pylori triggers and maintains gastric mucosal inflammation by different mechanisms, which are partly strain dependent and partly strain independent. T and B lymphocyte activation and infiltration of the gastric mucosa depend on H pylori antigen processing. The number of infiltrating polymorphonuclear cells varies depending on the virulence of the infecting strain, being much greater when infections are caused by cagA positive strains. 5 7–9 The inflammatory cells infiltrating H pylori infected gastric mucosa produce a pattern of proinflammatory cytokines. 11 High mucosal levels of mononuclear cytokines (IL8, IL6, IL1b, tumour necrosis factor a (TNFa), and interferon c (IFNc)) and lymphocytic derived cytokines (IL2, IL2R) have been described in H pylori infected patients. H pylori infection also induces the production of IL12, a heterodimeric proinflammatory protein that triggers the production of IFNc and favours the differentiation of T helper 1 (Th1) cells, 18 which, in H pylori infected mucosa, prevail over Th2 cells. 16 19 The ability of IL12 to induce Th1 is one of the biological bases of the importance of this cytokine in resisting most bacteria, including H pylori, and also intracellular protozoa and fungal pathogens. 20 21 Cellular sources of IL12 in response to infections are mainly dendritic cells and phagocytes. The two subunits of IL12—p35 and p40—are encoded by different genes, named IL12A and IL12B respectively, which are unrelated and are located on separate chromosomes (3p12–q13.2 and 5q31–33). Host cytokine gene polymorphisms may be as important as exogenous stimuli in influencing the amount of cytokines produced and consequently the pattern and severity of inflammation. 22–26 IL12 gene polymorphisms in particular have been observed to affect autoimmune diabetes and atopic and non-atopic asthma. Both IL12A and IL12B have a polymorphic dinucleotide repeat region (CT for IL12A and TG-TA for IL12B) in introns 6 and 4, respectively (Gene bank accession numbers: AF404773 for IL12A and AY008847 for IL12B), which might affect the amount of the synthesised cytokine. No data have been reported on the possible influence of IL12A and IL12B polymorphisms on H pylori infection and its outcome. Our aims in the present study were, first, to use denaturating high performance liquid chromatography (DHPLC) to screen the promoters and the coding sequences of IL12A and IL12B in order to identify any single nucleotide polymorphisms (SNPs); second, to analyse the SNPs identified, together with the number of CT and TG-TA dinucleotide repeats (variable number tandem repeats (VNTR)) of IL12A intron 6 and IL12B intron 4 in patients with or without H pylori infection; and third, to verify the association, if any, between the IL12 gene polymorphisms studied and the outcome of H pylori infection (gastric adenocarcinoma in particular).