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Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines' toxicity and efficacy
Author(s) -
PALMIERI O.,
LATIANO A.,
BOSSA F.,
VECCHI M.,
D’INCÀ R.,
GUAGNOZZI D.,
TONELLI F.,
CUCCHIARA S.,
VALVANO M. R.,
LATIANO T.,
ANDRIULLI A.,
ANNESE V.
Publication year - 2007
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/j.1365-2036.2007.03421.x
Subject(s) - itpa , thiopurine methyltransferase , azathioprine , medicine , mercaptopurine , ulcerative colitis , gastroenterology , single nucleotide polymorphism , pyrophosphatase , pharmacology , genotype , immunology , disease , gene , biology , biochemistry , enzyme , hepatitis c virus , virus , ribavirin
Summary Aim To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn’s disease and ulcerative colitis. Methods In 422 consecutive patients (250 with Crohn’s disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy. Results Seventy‐three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) ( P < 0.001); no correlation with other ADRs and efficacy of therapy was found. Conversely, the frequency of inosine triphosphate pyrophosphatase and HPRT1 risk genotypes was not significantly different in patients with ADRs (included leucopenia). Non‐responders had an increased frequency of inosine triphosphate pyrophosphatase risk genotypes ( P = 0.03). Conclusions The majority of azathioprine/mercaptopurine‐induced ADRs and efficacy of therapy are not explained by the investigated gene polymorphisms. The combined evaluation of all three genes enhanced the correlation with leucopenia (43.5% vs. 23% in controls) ( P = 0.008), at the expense of a reduced accuracy (60%).