No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype.
BACKGROUND
CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer.


METHODS
Individual and combined associations of NSAIDs and CYP2C9*2 and *3 variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions.


RESULTS
There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an CYP2C9 variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy.


CONCLUSIONS
Both NSAID use and CYP2C9*2 and/ or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.
Siemes
C
C
Department of Epidemiology and Biostatistics, Erasmus University Medical Centre, Rotterdam, the Netherland.
Eijgelsheim
M
M
Dieleman
J P
JP
van Schaik
R H N
RH
Uitterlinden
A G
AG
van Duijn
C M
CM
Hofman
A
A
Coebergh
J W W
JW
Stricker
B H Ch
BH
Visser
L E
LE
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases