A review of: El-Omar EM, Carrington M, Chow W-H, et al. 2000 Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398–402.

The World Health Organization has classified the bacterium Helicobacter pylori as a class 1 carcinogen. Initial evidence in support of this initiative came from epidemiologic studies that associated colonization of the human stomach with H. pylori and the resulting chronic-active gastritis with both gastric adenocarcinomas and gastric lymphomas. Although not every epidemiologic study has documented such a relationship, a meta-analysis of 19 studies with 2491 patients and 3959 controls provides support for at least a modest association (summary odds ratios in the range of 1.9, 95% confidence intervals = 1.3–2.8) (1). Experimental animal studies support this relationship. The development of gastric atrophy, intestinal metaplasia, and invasive adenocarcinoma in the stomachs of Mongolian gerbils infected with H. pylori provide the most compelling data indicating that this organism is an etiologic agent in gastric cancer (2).

H. pylori infection in humans is acquired during the childhood years, particularly in settings of socioeconomic deprivation and family overcrowding. Once acquired, the infection is usually life-long unless specific eradication therapy is provided. Seroprevalence studies in a variety of study groups indicate that half of the world's human population is infected with the gastric pathogen. Nevertheless, only a small subset of infected individuals will develop a disease complication during their lifetime. For instance, it has been estimated that less than 0.1% of infected individuals will develop gastric cancer.

Considerable current research interest has focused on determining whether the subset of individuals who develop disease complications relate to bacterial virulence factors, confounding environmental exposures, or host responses to infection. Initial epidemiologic studies reported that H. pylori strains harboring a pathogenicity island (a 35-kilobase transmissible element inserted into the bacterial genome) are more common in infected patients developing gastric cancers compared to community and age-matched controls infected with a strain deficient in the pathogenicity island. However, these findings have not been replicated by other investigators.

The current study by El-Omar and colleagues provides evidence indicating that the host response to gastric infection may influence disease outcome. Two specific polymorphisms in the interleukin-1 gene cluster were associated with the development of gastric atrophy and gastric cancer in Europeans (Scotland and Poland). The provocative findings are plausible because allelic variations in the interleukin-1 genes have been associated with disease outcome in other diseases including, for example, chronic inflammatory bowel disease (3).

A potential explanation for the reported association is provided by the enhanced pro-inflammatory activity observed with specific interleukin-1 beta-polymorphisms. In response to chronic H. pylori colonization, an inhibition of acid secretion by elevated levels of interleukin-1 beta could promote the development of gastric atrophy, which is an initial step in the pathway leading to carcinogenesis in the stomach.

These findings should now prompt other investigators to determine whether the findings can be extended to other human populations. Such findings may well explain why persons living in Africa rarely develop disease complications despite a very high rate of H. pylori infection. Genotyping also could be employed in the future to define those individuals at highest risk of developing disease complications and, therefore, would benefit most from eradication of H. pylori from the stomach.

Intervention studies are now underway to determine if eradication of H. pylori infection in humans will prevent the development of gastric lymphomas and gastric adenocarcinomas. These studies are awaited with anticipation because the results will impact greatly on whether to intervene and treat the infection in asymptomatic adults or children, and in particular, those with a family history of gastric cancer or who reside in a geographic region where the prevalence of gastric cancer is high.