Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study

Abstract

The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280–508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.

Azathioprine-induced severe pancytopenia: A serious complication in a patient with normal TPMT activity

“…is study also included a patient developing severe myelosuppression despite having a wild-type genotype for all three genes implicated. [10] As azathioprine is a common immunomodulator and commonly used in many autoimmune diseases, the rare occurrence of life-threatening cytopenia in these patients remains a possibility and should be treated aggressively with broad-spectrum antibiotics and growth factor support. Hb and platelet count should also be maintained at the desired level with transfusion of blood products as and when required.…”

Azatioprin u liječenju bolesnika s ulceroznim kolitisom

“…Stoga, za pripadnike različitih rasa i regija doziranje tiopurina ne bi smjelo biti jednako. 28 Najproučavaniji geni su ITPA, TPMT i NUDT15. Prema rezultatima pojedinih istraživanja, mutacije ITPA gena nisu povezane s pojavom mijelosupresije.…”

“…Zbog navedenoga, preporučljivo je učiniti genotipizaciju TPMT gena prije početka liječenja tiopurinima. 28 Rezultati istraživanja provedenog na kineskim bolesnicima ukazuju na znatnu povezanost polimorfizma gena NUDT15 (415C > T), te epistatičke interakcije između alela ITPA (94C > A) i NUDT15 (415C > T) s pojavom AZA-inducirane mijelosupresije. Posljedično, polimorfizam NUDT15 (415C > T) smatra se prediktorom pojave AZA-inducirane mijelosupresije u kineskih bolesnika, te je stoga, prije započinjanja liječenja azatioprinom, u njih preporučljivo učiniti genotipizaciju navedenih alela.…”

“…Rizik od pojave mijelosupresije u homozigotnih nositelja mutacije gena NUDT (415C > T) pokazao se izrazito velikim, te se u takvih bolesnika preporučuje izbjegavanje primjene azatioprina tijekom liječenja. 28 Osim toga, valja napomenuti kako je nedavno otkriveno da je polimorfizam jednog nukleotida (rs264708) povezan s povećanim rizikom od pojave pankreatitisa u homozigotnih bolesnika. 24 Učestalosti pojedinih nuspojava na liječenje AZAom u bolesnika s UC-om prikazane su u Tablici 3.…”

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art

“…Thiopurine methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) are enzymes involved in thiopurine metabolism, and genetic polymorphisms in these enzymes are associated with thiopurine-related toxicities [ 23 – 25 ]. Testing of genetic polymorphisms has been implemented in clinical practice, especially in leukemia and IBD [ 26 ].…”