Polymorphisms in inflammatory pathway genes and their associations with colorectal cancer risk

B Frank; M Hoffmeister; N Klopp; T Illig; J Chang-Claude; H Brenner

doi:10.1055/s-0030-1266457

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Polymorphisms in inflammatory pathway genes and their associations with colorectal cancer risk

B Frank ¹, M Hoffmeister ¹, N Klopp ², T Illig ², J Chang-Claude ³, H Brenner ¹

¹Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
²Institute of Epidemiology, Research Centre for Environment and Health, Neuherberg, Germany
³Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

Abstract

Introduction: Chronic inflammation is a well-established risk factor for colorectal cancer (CRC), and various inflammatory bowel diseases, such as chronic ulcerative colitis and Crohn's disease, predispose to CRC. Conclusive evidence for the significance of inflammation during neoplastic progression comes from studies of cancer risk among long-term users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), which indicate that the regular NSAID use significantly reduces risk of CRC. The aim of this study was to test the hypothesis that polymorphisms in genes regulating inflammatory processes modulate CRC risk. Material and Methods: In a large population-based case-control study, we evaluated the associations of selected, putative functional candidate SNPs, PRODH R185W (rs4819756), PTGS1 R8W (rs1236913), PTGS1 G213G (rs5788), UBD I68T (rs2076485) and UBD S160C (rs8337), with CRC risk. Genomic DNA of 1795 patients and 1805 control individuals from the German DACHS study were used for genotyping, applying Sequenom's MassARRAY System (Sequenom, USA). Unconditional logistic regression was applied to estimate odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs), adjusted for age and sex, using dominant and co-dominant models. Results: PTGS1 G213G was significantly associated with an increased CRC risk (OR=1.19; 95% CI, 1.03–1.39; P=0.02), comparing minor allele carriers with major allele homozygotes. This estimate was consistent across locations and stages of CRC (range of ORs, 1.15–1.20). Carriage of the minor allele of UBD I68T was significantly associated with advanced stages of CRC and with CRC below 65 years of age (OR, 1.23; 95% CI, 1.04–1.45; P=0.02 and OR, 1.32; 95% CI, 1.05–1.67; P=0.02, respectively). Conclusion: Our results support a role of genetic variability in inflammatory pathway genes and colorectal carcinogenesis. Replication in further large epidemiologic studies and functional analyses are warranted to confirm this preliminary evidence.