Polymorphisms in fatty-acid-metabolism-related genes are associated with colorectal cancer risk.

Birgit Hoeft, Jakob Linseisen, Lars Beckmann, Karin Müller-Decker, Federico Canzian, Anika Hüsing, Rudolf Kaaks, Ulla Vogel, Marianne U Jakobsen, Kim Overvad, Rikke D Hansen, Sven Knüppel, Heiner Boeing, Antonia Trichopoulou, Yvoni Koumantaki, Dimitrios Trichopoulos, Franco Berrino, Domenico Palli, Salvatore Panico, Rosario Tumino, H B Bueno-de-Mesquita, Fränzel J B van Duijnhoven, Carla H van Gils, Petra H Peeters, Vanessa Dumeaux, Eiliv Lund, José M Huerta Castaño, Xavier Muñoz, Laudina Rodriguez, Aurelio Barricarte, Jonas Manjer, Karin Jirström, Bethany Van Guelpen, Göran Hallmans, Elizabeth A Spencer, Francesca L Crowe, Kay-Tee Khaw, Nick Wareham, Sophie Morois, Marie-Christine Boutron-Ruault, Françoise Clavel-Chapelon, Veronique Chajes, Mazda Jenab, Paolo Boffetta, Paolo Vineis, Traci Mouw, Teresa Norat, Elio Riboli, Alexandra Nieters, Carcinogenesis 31, 466-72 (2010)


Colorectal cancer (CRC) is the third most common malignant tumor and the fourth leading cause of cancer death worldwide. The crucial role of fatty acids for a number of important biological processes suggests a more in-depth analysis of inter-individual differences in fatty acid metabolizing genes as contributing factor to colon carcinogenesis. We examined the association between genetic variability in 43 fatty acid metabolism-related genes and colorectal risk in 1225 CRC cases and 2032 controls participating in the European Prospective Investigation into Cancer and Nutrition study. Three hundred and ninety two single-nucleotide polymorphisms were selected using pairwise tagging with an r(2) cutoff of 0.8 and a minor allele frequency of >5%. Conditional logistic regression models were used to estimate odds ratios and corresponding 95% confidence intervals. Haplotype analysis was performed using a generalized linear model framework. On the genotype level, hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), phospholipase A2 group VI (PLA2G6) and transient receptor potential vanilloid 3 were associated with higher risk for CRC, whereas prostaglandin E receptor 2 (PTGER2) was associated with lower CRC risk. A significant inverse association (P < 0.006) was found for PTGER2 GGG haplotype, whereas HPGD AGGAG and PLA2G3 CT haplotypes were significantly (P < 0.001 and P = 0.003, respectively) associated with higher risk of CRC. Based on these data, we present for the first time the association of HPGD variants with CRC risk. Our results support the key role of prostanoid signaling in colon carcinogenesis and suggest a relevance of genetic variation in fatty acid metabolism-related genes and CRC risk.