A prospective study of genetic polymorphisms in the cytochrome P-450 2C9 enzyme and the risk for distal colorectal adenoma.
OBJECTIVE
Regular aspirin use is associated with a reduced risk for colorectal adenoma, whereas smoking increases risk. The cytochrome P-450 (CYP) 2C9 (CYP2C9) enzyme is involved in the metabolism of several drugs, including possibly aspirin, and such carcinogens as smoking-related polycyclic aromatic hydrocarbons. Genetic variation in this enzyme may modulate the influence of aspirin and smoking on adenoma risk.


METHODS
We examined the risk for incident distal colorectal adenoma according to CYP2C9 genotype, aspirin use, and smoking in a prospective nested case-control study of women.


RESULTS
Among 394 cases and 396 controls, women with at least 1 variant CYP2C9 allele had a significantly greater risk for adenoma (multivariate odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15; P = 0.007). Although women who used aspirin regularly (>/=2 standard tablets/wk) experienced a lower risk for adenoma compared with non-regular users, the effect was similar irrespective of genotype. Women who smoked >20 pack-years had an OR of adenoma of 1.50 (95% CI, 1.07-2.12; P = 0.02) compared with those who smoked </=20 pack-years. Among women with at least 1 variant allele who smoked >20 pack-years, the OR of adenoma was 2.50 (95% CI, 1.44-4.38; P = 0.001) compared with women with no variant alleles who smoked </=20 pack-years.


CONCLUSIONS
Polymorphisms in the CYP2C9 enzyme are associated with elevated risk for colorectal adenoma. This observation does not appear to be related to modification of the effect of aspirin on adenoma risk, but may be associated with differential metabolism of environmental carcinogens.
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Andrew T
AT
Chan
Gregory J
GJ
Tranah
Edward L
EL
Giovannucci
David J
DJ
Hunter
Charles S
CS
Fuchs
D000236:Adenoma / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001241:Aspirin / Q000627:therapeutic use*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012306:Risk; D012907:Smoking / Q000009:adverse effects*
C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D001241:Aspirin