Steponaitiene Ruta, Kupcinskas Juozas, Survilaite Santa, Varkalaite Greta, Jonaitis Laimas, Kiudelis Gediminas, Denapiene Goda, Valantinas Jonas, Skieceviciene Jurgita, Kupcinskas Limas
Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Adv Med Sci. 2016 Mar;61(1):135-40. doi: 10.1016/j.advms.2015.09.008. Epub 2015 Dec 10.
Inter-individual thiopurine metabolism variability can influence treatment outcomes in inflammatory bowel disease (IBD) patients. Genetic polymorphisms in thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) were linked with toxicity of azathioprine (AZA). The aim of the study was to investigate frequencies of TPMT and ITPA polymorphisms in Lithuanian IBD patients and analyze their association with AZA-related adverse events.
MATERIALS/METHODS: Polymorphisms in TPMT (TPMT*2,*3B,*3C,*3A) and ITPA (rs1127354, rs7270101) genes were determined using PCR-RFLP and TaqMan(®) genotyping assays. 551 consecutive Lithuanian IBD patients were genotyped. The use of AZA and its side effects were assessed retrospectively according to hospital medical records.
Frequencies of TPMT3A, TPMT3B and TPMT3C alleles were 3.1%, 0.5% and 0.1%, respectively. TPMT2 genetic variant was not detected in the study group. The distribution of minor alleles for ITPA rs1127354 and rs7270101 polymorphisms was 9.9% and 10.5%, respectively. AZA was prescribed in 82 patients and it provoked myelotoxicity in 11%, hepatotoxicity in 6.1%, dyspepsia in 6.1%, and pancreatitis in 3.6% of cases. Among patients who had AZA-related myelotoxicity, 11.1% were TPMT compound heterozygous, 44.4% had heterozygous genotype (P<0.01). Frequencies of ITPA minor alleles were similar among the patients with and without AZA-related side effects.
Frequencies of TPMT and ITPA variant alleles in Lithuanian IBD group were similar to those observed in the Northern-Eastern Europe Caucasian populations. Polymorphisms in TPMT might be associated with myelotoxicity and leukopenia in AZA treated patients, while ITPA variant alleles appear not to be linked with treatment-related side effects.
个体间硫嘌呤代谢的变异性会影响炎症性肠病（IBD）患者的治疗效果。硫嘌呤甲基转移酶（TPMT）和肌苷三磷酸焦磷酸酶（ITPA）的基因多态性与硫唑嘌呤（AZA）的毒性有关。本研究的目的是调查立陶宛IBD患者中TPMT和ITPA基因多态性的频率，并分析它们与AZA相关不良事件的关联。
材料/方法：使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和TaqMan®基因分型检测法测定TPMT（TPMT*2、*3B、*3C、*3A）和ITPA（rs1127354、rs7270101）基因的多态性。对551例连续的立陶宛IBD患者进行基因分型。根据医院病历回顾性评估AZA的使用情况及其副作用。
TPMT3A、TPMT3B和TPMT3C等位基因的频率分别为3.1%、0.5%和0.1%。研究组未检测到TPMT2基因变异。ITPA rs1127354和rs7270101多态性的次要等位基因分布分别为9.9%和10.5%。82例患者使用了AZA，其中11%发生骨髓毒性，6.1%发生肝毒性，6.1%发生消化不良，3.6%发生胰腺炎。在发生AZA相关骨髓毒性的患者中，11.1%为TPMT复合杂合子，44.4%为杂合基因型（P<0.01）。发生和未发生AZA相关副作用的患者中ITPA次要等位基因的频率相似。
立陶宛IBD组中TPMT和ITPA变异等位基因的频率与在东北欧白种人群中观察到的频率相似。TPMT基因多态性可能与AZA治疗患者的骨髓毒性和白细胞减少有关，而ITPA变异等位基因似乎与治疗相关副作用无关。
