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Prepublished online as a Blood First Edition Paper on April 3, 2003; DOI 10.1182/blood-2002-12-3803.
Submitted December 17, 2002
Accepted March 22, 2003
Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and anti-oxidative capacity
Sara Rollinson, Adam P Levene, Fiona K Mensah, Philippa L Roddam, James M Allan, Tim C Diss, Eve Roman, Andrew Jack, Kenneth MacLennan, Michael F Dixon, and Gareth J Morgan*
Epidemiology and Genetics Unit, Algernon Firth Building, University of Leeds, Leeds, United Kingdom
Epidemiology and Genetics Unit, Margaret Smith Building, University of Leeds, Leeds, United Kingdom
Molecular Biology Unit, Histopatholgy Department, Royal Free and University College Medical School, London, United Kingdom
Academic Unit of Pathology, University of Leeds, Leeds, United Kingdom
* Corresponding author; email: GarethM{at}pathology.leeds.ac.uk.
Gastric marginal zone lymphoma (GMZL) is strongly associated with Helicobacter pylori (H. pylori) infection, which induces an inflammatory response, subsequently resulting in the generation of DNA-damaging reactive oxygen species (ROS). The extent of damage will depend upon the severity of inflammation, the cellular antioxidant capacity, and the integrity of cellular DNA repair mechanisms. Interleukin-1 (IL-1) gene cluster polymorphisms have been shown to be important mediators of inflammation, while polymorphisms in the glutathione S-transferase GST T1 and GST M1 genes are believed to affect cellular antioxidant capacity. We aimed to determine whether polymorphisms at the IL-1 and GST T1 and GST M1 loci modulate the risk of developing GMZL. Archived peripheral blood and biopsy samples were collected for a historical series of 66 GMZL cases; while blood samples from 163 healthy controls were collected for use as a comparison series. Genotypes were determined for GST T1, GST M1, IL-1 RN, and IL-IB-31 using PCR based techniques. For the cases where H. pylori status could be determined, infection was found in 86.0%, while the prevalence of H. pylori infection in the control population was found to be 37.4%. The IL-1 RN genotype was significantly associated with risk of GMZL, (OR 5.51, 95% CI 2.16-14.07) for the IL-1 RN 2/2 genotype compared to the IL-1 RN 1/1. The IL-1B-31 genotype was not to be associated with GMZL risk. The GST T1 null genotype was strongly associated with risk of GMZL (OR 9.51, 95% CI 4.57-19.81), whereas the GST M1 null genotype was not associated with risk of GMZL. Evidence was found of effect modification between the IL-1 RN, and GST T1 genotypes (p=0.02). The combination of IL-1 RN 2/2 and GST T1 null genotype was most strongly associated with risk of GMZL (OR 32.29, 95% CI 6.92-150.63). These results support the hypothesis that the risk of developing GMZL is influenced by inter-individual variation in inflammatory response, modulating the immune response to H. pylori infection, and anti-oxidative capacity determining the body's ability to detoxify ROS generated in the immune response.
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