Abstract
BackgroundThe 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.MethodsThe 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.ResultsCarriers 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).ConclusionTwo 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.
Highlights
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)
Carriers of the variant allele of MDR1 G-rs3789243-A were at 1.52-fold (95% confidence interval (CI): 1.12-2.06) higher risk of colorectal cancer (CRC) than homozygous carriers of the wild type allele (Table 2)
COX-2 and BRCP polymorphisms were not associated with CRC risk (Table 2)
Summary
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). Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality in the Western World, with great impact on the life quality for the affected persons Both genetic and life-style factors contribute to the pathogenesis, and gene-environmental interactions may modulate cancer risk. The ATP-binding cassette (ABC) transporters P-glycoprotein (encoded by the Multidrug Resistance 1 (MDR1/ ABCB1) gene) and Breast Cancer Resistance Protein (BCRP, encoded by the BCRP/ABCG2 gene) are abundant in the intestine [5]. They transport a diverse spectrum of substrates from the enterocytes into the intestinal lumen, thereby restricting the exposure to these potentially harmful substances [6]. P-glycoprotein preferentially transports large hydrophobic molecules, while BCRP is able to transport both hydrophobic and large anionic compounds, e.g. conjugates, the substrate specificities have been shown to be overlapping [7]
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