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Background  The xenobiotic transporters, Multidrug Resistance 1  (MDR1/ABCB1)  and Breast Cancer Resistance Protein  (BCRP/ABCG2)  may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness.  The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use.    Methods  The following polymorphisms were analyzed; a synonymous  MDR1  C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional  BCRP  C421A (rs2231142), the two  COX-2  A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the  COX-2  T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study.    Results  Carriers of the variant allele of  MDR1  intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of  MDR1  C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these  MDR1  polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous  MDR1  C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02).  COX-2  and  BCRP  polymorphisms were not associated with CRC risk. There was interaction between NSAID use and  MDR1  C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively).    Conclusion  Two polymorphisms in  MDR1  were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that  MDR1  polymorphisms affect the relationship between meat and CRC risk.

bmc cancer

Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study