- 學位論文
台灣ITPA基因缺失多態性之發生率
Detecting the frequencies of inosine triphosphate pyrophosphatase gene polymorphisms in Taiwan.
摘要
大約有37%的病人在使用azathiopurine 治療時會出現藥物毒性反應，其中大約50%的病人可經由檢測TPMT的多態性而預測得，而在最近的研究顯示ITPA基因與azathiopurine的毒性有關聯。ITPA是一種催化ITP代謝為IMP的酵素。ITPA基因缺失是一種常見的遺傳疾病，它的特徵是ITP會不正常的累積在紅血球中。ITPA基因有缺失的病患在使用thiopnrine類藥物6-mercaptopurine或其前趨藥物時，都有可能產生毒性。ITPA基因缺失在病理上的機轉仍未明確。在下面描繪了ITPA基因的結構特性，它有8個exon並檢測其5個單核甘酸的多態性。包括不影響ITPA活性的(138-G->A,561G-A,708G-A)及會影響的(94-C->A,IVS2+21A->C)。在本研究中，我們檢驗了100位一般民眾的ITPA多態性發生率，在台灣人中94C>A的對偶因發率為0.17(白種人為0.06)。IVS2+21A>C多能性發生率為0(白種人為0.13)，而138G>A,561G>A,708G>A。在台灣人中的多態性分別為0.395，047及0.16。而除了138G>A外，這個研究顯示台灣ITPA 缺失的情形高於白種人。這些資料可提供未來計劃檢驗的病患使用azathiopurine治療時發生嚴重毒性風險的研究時的基礎。
並列摘要
Drug adverse reaction from azathioprine treatment affects up to 37% of patients. Thiopurine methyltransferase (TPMT) polymorphisms will prospectively identify approximately 10% of patients. Recently, a polymorphism in the inosine triphosphate pyrophosphatase gene (ITPA) has been associated with severe azathioprine toxicity. The enzyme inosine triphosphate pyrophosphatase catalyses the pyrophosphohydrolysis of ITP to IMP. Inosine triphosphate pyrophosphohydrolase deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes. A deficiency of ITPase may occur adverse reactions to therapy with the thiopurine drug 6-mercaptopurine (6-MP) and its prodrug azathioprine. The genetic basis and pathological mechanism of ITPase deficiency are unknown. Below have characterized the genomic structure of the ITPA gene, showing that it has eight exons. Five single nucleotide polymorphisms (SNP) were identified, three silent (138G-->A, 561G-->A, 708G-->A) and two associated with ITPase deficiency (94C-->A, IVS2+21A-->C).In this study, we examine the frequencies of ITPA polymorphisms in 100 healthy taiwanese individuals. The allele frequency of the 94C > A variant in the Taiwnese sample was 0.17 (Caucasian allele frequency 0.06).The IV2 + 21A > C polymorphism was 0 (Caucasian allele frequency 0.130). Allele frequencies of the 138G > A, 561G > A and 708G > A polymorphisms were 0.395, 0.47 and 0.16 respectively in the Taiwanese population, and with the exception of the 138G > A polymorphism, this study reveal that Taiwanese allele frequencies is higher than Caucasians. This data provides a foundation on which prospective studies can be planned to identify patients at risk for severe toxicity from azathioprine therapy.