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Combinations of Cytochrome P450 Gene Polymorphisms Enhancing the Risk for Sporadic Colorectal Cancer Related to Red Meat Consumption

¹ Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, France; ² Institut des Maladies de l'Appareil Digestif et CIC Institut National de la Sante et de la Recherche Medicale and ³ Service d'Hépato-Gastroentérologie, CHU de Nantes; ⁴ Laboratoire de Biomathématiques-Biostatistique, Faculté de Pharmacie, Université de Nantes; ⁵ Biofortis Nantes; ⁶ Laboratoire d'Informatique de Nantes Atlantique, Université de Nantes; ⁷ Service d'Hépato-Gastroentérologie, CHD de La Roche-Sur-Yon, France; ⁸ Centre d'Examen de Santé, La Roche-Sur-Yon; ⁹ Association des Gastroentérologues de Vendée, Challans, France; and ¹⁰ Centre d'Examen de Santé de Saint-Nazaire, France

Requests for reprints: Sébastien Küry, Laboratoire d'Etude de l'ADN, Faculté de Médecine de Nantes, 1 rue Gaston Veil, 44035 Nantes Cedex, France. Phone: 33-240-41-29-69. E-mail: Sebastien.Kury{at}univ-nantes.fr

Susceptibility to sporadic colorectal cancers (CRC) is generally thought to be the sum of complex interactions between environmental and genetic factors, all of which contribute independently, producing only a modest effect on the whole phenomenon. However, to date, most research has concealed the notion of interaction and merely focused on dissociate analyses of risk factors to highlight associations with CRC. By contrast, we have chosen a combinative approach here to explore the joint effects of several factors at a time. Through an association study based on 1,023 cases and 1,121 controls, we examined the influence on CRC risk of environmental factors coanalyzed with combinations of six single nucleotide polymorphisms located in cytochrome P450 genes (c.–163A>C and c.1548T>C in CYP1A2, g.–1293G>C and g.–1053C>T in CYP2E1, c.1294C>G in CYP1B1, and c.430C>T in CYP2C9). Whereas separate analyses of the SNPs showed no effect on CRC risk, three allelic variant combinations were found to be associated with a significant increase in CRC risk in interaction with an excessive red meat consumption, thereby exacerbating the intrinsic procarcinogenic effect of this dietary factor. One of these three predisposing combinations was also shown to interact positively with obesity. Provided that they are validated, our results suggest the need to develop robust combinative methods to improve genetic investigations into the susceptibility to CRC. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1460–7)