Genetic variants of UGT1A6 influence risk of colorectal adenoma recurrence.
OBJECTIVE
The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia.


METHODS
We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial.


RESULTS
Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively).


CONCLUSIONS
These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma.
Hubner
Richard A
RA
Section of Cancer Genetics, Institute of Cancer Research, Sutton, United Kingdom and Division of Epidemiology and Public Health, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom.
Muir
Kenneth R
KR
Liu
Jo-Fen
JF
Logan
Richard F A
RF
Grainge
Matthew
M
Armitage
Nicholas
N
Shepherd
Vic
V
Popat
Sanjay
S
Houlston
Richard S
RS
D000236:Adenoma / Q000235:genetics* / Q000517:prevention & control; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000517:prevention & control; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase; D001241:Aspirin