Abstract A10: IL1B haplotypes and risk of gastric precancerous lesions in African Americans and Caucasians in New Orleans

Gastric cancer is one of the most common cancers in the world and the second leading cause of death due to cancer. Infection with Helicobacter pylori (H. pylori) is the factor most commonly associated with this disease. It is currently believed that the interaction of bacterial and host factors is what determines the risk of gastritis and eventually the development of cancer. African Americans have one of the highest incidence and mortality from gastric cancer, while white people have the lowest. Gastric cancer is the result of a cascade of multiple inflammatory events initiated after the H. pylori infection which leads to the development of active gastritis and the infiltration of inflammatory cells to the gastric mucosa without damaging the architecture of the tissue, a process known as non-atrophic gastritis (NAG). Host factors, including diet, may condition the development of multifocal atrophic gastritis (MAG) with loss of gastric glands and the development of fibrotic tissue. MAG progresses to MAG with intestinal metaplasia (MAG-IM) in which some areas of the gastric tissue acquire phenotypical characteristics of intestinal cells. This is considered the final inflammatory stage which is followed by the development of dysplasia and finally cancer. The inflammatory process is mediated by cytokines produced in response to the H. pylori infection. The production of cytokines is regulated, among other things, by the presence of single nucleotide polymorphisms (SNP) at the DNA level. Our initial report showed that SNPs in the interleukin (IL) 1B gene (IL1B) are associated with the presence of MAG. However, because of the complexity of the inflammatory response we believe that it likely involves many more cytokines and SNPs. We then studied the frequencies of halploytpes in eight cytokine genes, including IL1B, IL6, IL8, IL10, tumor necrosis alpha (TNF), transforming growth factor beta (TGFB), cyclooxygenase 2 (PTGS2) and arginase 1 (ARG1) genes, and their association with gastric inflammatory stages in 569 African and Caucasian Americans attending the Gastroenterology Service for upper abdominal complaints in New Orleans, LA. We found that African American individuals not only had significantly higher frequency of MAG (with and without intestinal metaplasia) than Caucasian individuals, but also higher frequency of infection with H. pylori, especially cagA-positive H. pylori strains. Interestingly, we found one haplotype in the IL1B gene (IL1B-511T/-31C/+3954T) associated with the presence of MAG-IM/dysplasia only in the African American group. Of note, that specific haplotype was not found in our Caucasian population. Additional analysis suggested the presence of differential genetic blocks in the cytokine genes included in this study between African Americans and Caucasians.

Altogether, our data suggest the presence of “inflammatory genetic blocks” differentially distributed between African Americans and Caucasians. These “blocks” may determine the differential inflammatory response to injurious agents like H. pylori, the result of which is associated with tissue damage.

Genetic markers of disease have become a necessity to identify individuals at risk for developing more aggressive disease. Our results are really promising in achieving that goal, even though they must be confirmed with larger number of patients and controls.