Abstract 36: Genetic variability in MRP4 (ABCC4), ibuprofen use, and colorectal cancer risk in the Colon Cancer Family Registry

Introduction: MRP4 (encoded by ABCC4), a member of the C subfamily of ATP-binding cassette (ABC) transporters, moves pro-inflammatory prostaglandins (PGs) through membranes while consuming ATP. Several studies point to a strong link between MRP4-mediated transport of PGs and colorectal cancer (CRC). This study is the first to explore associations between a comprehensive set of polymorphisms covering the full range of genetic variation in ABCC4 and CRC risk. Additionally, we investigated interactions between ABCC4 polymorphisms and NSAID use (specifically ibuprofen, a known potent inhibitor of MRP4) on the risk of CRC. Methods: Using a case-unaffected sibling control design, which included 1,584 incident CRC cases and 2,516 sibling controls from the Colon Cancer Family Registry (CCFR), we investigated the role of 97 ABCC4 tagSNPs (MAF>5%) independently and in combination with ibuprofen use on risk of CRC. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusting for age and sex; ibuprofen-interaction analyses were additionally adjusted for BMI, smoking, and physical activity. Results: One tagSNP (rs9556466 (intron 1, G>A)) was statistically significantly associated with higher CRC risk after correcting for multiple comparisons (ORhet=1.41; 95% CI 1.17-1.69, pglobal=0.0005, padj=0.035). Four tagSNPs in total were statistically significantly associated (nominal p-value≤0.05) with higher risk of rectal cancer (rs9556466, rs2274403 (intron 9, A>G), rs12019639 (upstream of ABCC4, T>C), and rs1678405 (intron 13, T>C); three tagSNPs were associated with lower risk of rectal cancer (rs4773866 (intron 1, G>A), rs9524855 (intron 4, A>G), and rs7329514 (intron 1, G>A)); and one SNP was associated with higher risk of colon cancer (rs9556466). Additionally, ibuprofen use modified CRC risk: four tagSNPs showed 1.4 to 2-fold lower CRC risk among current ibuprofen users who carried the variant allele (rs4148455 (intron 3, G>A), rs1751005 (intron 13, C>T), rs4773843 (intron 10, C>T), and rs9524821 (intron 9, G>A)), whereas one tagSNP was associated with higher risk of colorectal cancer among current ibuprofen users carrying the variant allele (rs1614102 (intron 26, G>A)). Conclusion: These findings suggest that genetic variation in ABCC4 is associated with CRC risk, and that genotype may differentially modify the association between ibuprofen use and CRC risk. The SNPs identified here may be useful in designing