Introduction Chronic inflammation plays a key role in the pathogenesis of many cancers but its role in colorectal neoplasia (CRN) is not clear. Our aim was to investigate the effect of cytokine gene polymorphisms and circulating cytokine levels on risk of CRN in North East Scotland, which has a high incidence of colon cancer.
Methods Subjects underwent a complete bowel cancer screening colonoscopy and were free of IBD. Blood-derived DNA was used to genotype polymorphisms in the IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes using 5′ nuclease taqman assays. Serum high-sensitivity C-reactive protein (Hs-CRP) and plasma levels of six cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10 and TNF-α) were measured. Subjects with adenomas with or without cancer (cases) were compared against subjects with no evidence of adenoma or cancer (controls). For Hs-CRP and plasma cytokines, levels were divided into tertiles and compared against each other. χ2 test was used for comparing cases and controls. Logistic regression analysis adjusting for gender was used and odds ratios (OR) with 95% CI were calculated.
Results For the genetic study, a total of 295 cases were compared with 398 controls. Mean age of the cases was 64.4 years compared to 62.3 years in controls (p<0.01) and males were overrepresented in the cases (66.1% vs 53.3% in controls, p<0.001). Regular use of NSAID was more common among controls compared to cases (p<0.0001). The pro-inflammatory IL-1B-31 C*C genotype increased the risk of having an adenoma by 1.9-fold compared to the IL-1B-31 T*T genotype (95% CI 1.2 to 3.0). Among subjects with adenoma, the pro-inflammatory IL8-251-A*A genotype increased the risk of having a high-risk lesion (cancer, large adenoma, or multiple adenomas) compared to the IL-8-251 T*T + T*A genotypes (OR 3.4, 95% CI 1.7 to 7.0). None of the other polymorphisms showed any significant associations. Having a Hs-CRP level in the highest tertile compared to the lowest two tertiles increased the risk of having an adenoma by 1.6-fold (95% CI 1.0 to 2.6) and cancer by 2.1-fold (95% CI 0.9 to 5.0). Among subjects with adenomas, having an IL-8 plasma level in the highest tertile compared to the lowest two tertiles doubled the risk of having a high-risk lesion.
Conclusion Proinflammatory cytokine gene polymorphisms in IL-1B increase the risk of developing adenomas while those in the IL-8 increase the risk of progression to advanced lesions. Hs-CRP and IL-8 levels predict presence and severity of CRN. Along with the NSAID findings, our data point to inflammation as an underlying pathogenetic mechanism in this cancer.
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