Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms.
OBJECTIVE
Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users.


METHODS
This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects.


RESULTS
Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < .001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004).


CONCLUSIONS
CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.
Geriatric Unit, Department of Medical Sciences, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. alberto.pilotto@operapadrepio.it
Alberto
A
Pilotto
Davide
D
Seripa
Marilisa
M
Franceschi
Carlo
C
Scarcelli
Donatella
D
Colaizzo
Elvira
E
Grandone
Valeria
V
Niro
Angelo
A
Andriulli
Gioacchino
G
Leandro
Francesco
F
Di Mario
Bruno
B
Dallapiccola
D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D000068579:Celecoxib; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000009:adverse effects / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects / Q000378:metabolism; D016017:Odds Ratio; D010437:Peptic Ulcer / Q000139:chemically induced* / Q000150:complications / Q000201:enzymology / Q000235:genetics; D010438:Peptic Ulcer Hemorrhage / Q000201:enzymology / Q000235:genetics*; D010894:Piroxicam / Q000009:adverse effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles / Q000009:adverse effects / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; D013449:Sulfonamides; D010894:Piroxicam; D004008:Diclofenac; D009288:Naproxen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000068579:Celecoxib; D007052:Ibuprofen