Abstract B73: Body mass index modifies the association between SMAD7 polymorphism rs4939827 and colorectal cancer risk

Abstract

Introduction: SMAD7 inhibits the activity of transforming growth factor beta (TGF-β), an anti-inflammatory molecule that acts as a tumor suppressor and might be important for colorectal cancer incidence. We investigated the association between the risk of colorectal cancer and two common polymorphisms in SMAD7 (rs4939827, rs4464148) previously identified in GWAS as potentially associated with colorectal cancer. We further investigated these relationships across strata of environmental factors related to inflammation, including non-steroidal anti-inflammatory drug (NSAID) use and body mass index (BMI).Methods: Incident cases of invasive colorectal cancer diagnosed from 1997-2002 in Caucasian, post-menopausal women residing in 13 counties in western Washington State were identified from SEER reports. Community-based controls were randomly selected from population lists, matched on 5-year age intervals to the cases. Women completed a baseline interview and provided a blood or buccal sample, which was genotyped for rs4939827 and rs4464148. Logistic regression was used to generate odds ratios (OR) and 95% confidence intervals (CI) for the association between SMAD7 polymorphisms and colorectal cancer risk. Interaction terms for body mass index (BMI) and non-steroidal anti-inflammatory drug (NSAID) use were included in logistic regression models to investigate potential effect modification.Results: We did not observe evidence for any association between rs4464148 and colorectal cancer risk. However, the minor allele for rs4939827 (C allele) was associated with a significantly decreased risk of colorectal cancer overall (CT: OR: 0.81; 95% CI 0.62-1.06; CC OR: 0.73; 95% CI 0.53-1.01), p-trend=0.05. We observed significant heterogeneity for the association between rs4939827 and colorectal cancer (p-interaction=0.02) according to body mass index. Reductions in colorectal cancer risk associated with rs4939827 were limited to only non-obese women. No differences in the association of either SMAD7 polymorphism with colorectal cancer according to NSAID use were observed.Conclusion: Our results support a role for genetic variation in SMAD7 in altering colorectal cancer risk among women. SMAD7 likely alters the risk of colorectal carcinogenesis through its regulatory role in the TGF-β pathway, which is involved in both cellular proliferation and inflammation. Our findings also suggest that exogenous and modifiable risk factors that affect inflammation, such as body mass index, may have the potential to alter the association between endogenous factors such as SMAD7 and colorectal cancer.Citation Information: Cancer Prev Res 2010;3(12 Suppl):B73.