Polymorphisms in fatty-acid-metabolism-related genes are associated with colorectal cancer risk.
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.
Hoeft
Birgit
B
German Cancer Research Center, Heidelberg, Germany.
Linseisen
Jakob
J
Beckmann
Lars
L
Müller-Decker
Karin
K
Canzian
Federico
F
Hüsing
Anika
A
Kaaks
Rudolf
R
Vogel
Ulla
U
Jakobsen
Marianne U
MU
Overvad
Kim
K
Hansen
Rikke D
RD
Knüppel
Sven
S
Boeing
Heiner
H
Trichopoulou
Antonia
A
Koumantaki
Yvoni
Y
Trichopoulos
Dimitrios
D
Berrino
Franco
F
Palli
Domenico
D
Panico
Salvatore
S
Tumino
Rosario
R
Bueno-de-Mesquita
H B
HB
van Duijnhoven
Fränzel J B
FJ
van Gils
Carla H
CH
Peeters
Petra H
PH
Dumeaux
Vanessa
V
Lund
Eiliv
E
Huerta Castaño
José M
JM
Muñoz
Xavier
X
Rodriguez
Laudina
L
Barricarte
Aurelio
A
Manjer
Jonas
J
Jirström
Karin
K
Van Guelpen
Bethany
B
Hallmans
Göran
G
Spencer
Elizabeth A
EA
Crowe
Francesca L
FL
Khaw
Kay-Tee
KT
Wareham
Nick
N
Morois
Sophie
S
Boutron-Ruault
Marie-Christine
MC
Clavel-Chapelon
Françoise
F
Chajes
Veronique
V
Jenab
Mazda
M
Boffetta
Paolo
P
Vineis
Paolo
P
Mouw
Traci
T
Norat
Teresa
T
Riboli
Elio
E
Nieters
Alexandra
A
D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005060:Europe / Q000453:epidemiology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D054520:Group III Phospholipases A2 / Q000235:genetics; D054522:Group VI Phospholipases A2 / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018078:Receptors, Prostaglandin E / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012907:Smoking / Q000453:epidemiology; D050916:TRPV Cation Channels / Q000235:genetics
D005227:Fatty Acids; D009363:Neoplasm Proteins; C545644:PTGER2 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D050916:TRPV Cation Channels; C459445:TRPV3 protein, human; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D054520:Group III Phospholipases A2; D054522:Group VI Phospholipases A2; C484163:PLA2G3 protein, human; C516475:PLA2G6 protein, human