NUDT 15基因多态性与巯嘌呤类药物耐受性及其所致白细胞减少的研究进展
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摘要
目的综述NUDT 15基因多态性与巯嘌呤类药物耐受性及其所致白细胞减少的研究,以期为巯嘌呤类药物在临床中的应用提供参考。方法检索国内外相关文献,进行整理和综合分析。结果研究人群主要集中在亚洲,大多为韩国和日本人,在中国儿童急性淋巴细胞白血病患者中仅有2个人群的研究,在中国炎症性肠病患者中有3个相关研究。大多数研究显示在亚洲人群中NUDT 15 c.415 C>T位点突变与巯嘌呤类药物的耐受性及相关白细胞减少有关,此外多个在炎症性肠患者群中的研究发现c.415 C>T纯合突变可能与严重脱发有关。结论大多数研究显示亚洲人群NUDT 15 c.415C>T位点突变与巯嘌呤类药物的耐受性及相关白细胞减少有关,该位点的测定可能会优化巯嘌呤类药物在临床中的应用,但其他NUDT 15基因位点突变相关的研究较少,还需要进一步探究。
OBJECTIVE To review researches on the association between NUDT 15 polymorphism and tolerance of thiopurine, thiopurine-induced leukopenia, hoping which can provide some help for its better clinical application. METHODS Searched domestic and foreign related literature, organized and comprehensive analyzed. RESULTS The people studied were mainly Asian, especially Korean and Japanese. However, there was only two studies in child acute lymphoblastic leukemia and 3 studies in inflammatory bowel disease in China. Most studies revealed that NUDT 15 c.415 C>T mutation was strongly associated with intolerance of thiopurines and thiopurine-induced leukopenia especially in Asians. Besides, several studies in inflammatory bowel disease also found that patients with c.415 C>T homozygous mutation were easier to develop severe hair loss. CONCLUSION Most studies have revealed that NUDT 15 c.415 C>T mutation is strongly associated with intolerance of thiopurines and thiopurine-induced leukopenia especially in Asians. Genotyping c.415 C>T genotype might provide help for a better clinical reaction. Whereas, researches on NUDT 15 other variants is few and need to explore further their.
OBJECTIVE To review researches on the association between NUDT 15 polymorphism and tolerance of thiopurine, thiopurine-induced leukopenia, hoping which can provide some help for its better clinical application. METHODS Searched domestic and foreign related literature, organized and comprehensive analyzed. RESULTS The people studied were mainly Asian, especially Korean and Japanese. However, there was only two studies in child acute lymphoblastic leukemia and 3 studies in inflammatory bowel disease in China. Most studies revealed that NUDT 15 c.415 C>T mutation was strongly associated with intolerance of thiopurines and thiopurine-induced leukopenia especially in Asians. Besides, several studies in inflammatory bowel disease also found that patients with c.415 C>T homozygous mutation were easier to develop severe hair loss. CONCLUSION Most studies have revealed that NUDT 15 c.415 C>T mutation is strongly associated with intolerance of thiopurines and thiopurine-induced leukopenia especially in Asians. Genotyping c.415 C>T genotype might provide help for a better clinical reaction. Whereas, researches on NUDT 15 other variants is few and need to explore further their.
引文
[1]中华医学会儿科学分会血液学组.儿童急性淋巴细胞白血病诊疗建议(第四次修订)[J].中华儿科杂志,2014,52(9):641-644.
[2]中华医学会儿科学分会血液学组.儿童非霍奇金淋巴瘤诊疗建议[J].中华儿科杂志,2011,49(3):186-192.
[3]MATSUOKA K,KOBAYASHI T,UENO F,et al.Evidence-based clinical practice guidelines for inflammatory bowel disease[J].J Gastroenterol,2018,53(3):305-353.
[4]MOON W,LOFTUS E J.Review article:recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease[J].Aliment Pharmacol Ther,2016,43(8):863-883.
[5]KAKUTA Y,KINOUCHI Y,SHIMOSEGAWA T.Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia:prospects for clinical application of NUDT15 genotyping[J].J Gastroenterol,2018,53(2):172-180.
[6]NEURATH M F,KIESSLICH R,TEICHGRABER U,et al.6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease[J].Clin Gastroenterol Hepatol,2005,3(10):1007-1014.
[7]POPPE D,TIEDE I,FRITZ G,et al.Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J].J Immunol,2006,176(1):640-651.
[8]KARNER S,SHI S,FISCHER C,et al.Determination of6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes:novel targets for thiopurine therapy?[J].Ther Drug Monit,2010,32(2):119-128.
[9]ROBERTS R L,BARCLAY M L.Update on thiopurine pharmacogenetics in inflammatory bowel disease[J].Pharmacogenomics,2015,16(8):891-903.
[10]MEI L,ONTIVEROS E P,GRIFFITHS E A,et al.Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy[J].Blood Rev,2015,29(4):243-249.
[11]YANG S K,HONG M,BAEK J,et al.A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia[J].Nat Genet,2014,46(9):1017-1020.
[12]YANG J J,LANDIER W,YANG W,et al.Inherited NUDT15variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia[J].J Clin Oncol,2015,33(11):1235-1242.
[13]KRISHNAMURTHY P,SCHWAB M,TAKENAKA K,et al.Transporter-mediated protection against thiopurine-induced hematopoietic toxicity[J].Cancer Res,2008,68(13):4983-4989.
[14]TANAKA Y,NAKADATE H,KONDOH K,et al.Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia[J].Pharmacogenomics J,2018,18(2):275-280.
[15]TAKAGI Y,SETOYAMA D,ITO R,et al.Human MTH3(NUDT18)protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates:comparison with MTH1and MTH2[J].J Biol Chem,2012,287(25):21541-21549.
[16]VALERIE N C,HAGENKORT A,PAGE B D,et al.NUDT15hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine[J].Cancer Res,2016,76(18):5501-5511.
[17]SINGH M,BHATIA P,KHERA S,et al.Emerging role of NUDT15 polymorphisms in 6-mercaptopurine metabolism and dose related toxicity in acute lymphoblastic leukaemia[J].Leuk Res,2017,62:17-22.
[18]MORIYAMA T,NISHII R,PEREZ-ANDREU V,et al.NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity[J].Nat Genet,2016,48(4):367-373.
[19]EMBI-EBI.Ensembl Project[EB/OL].[2018-04-01].http://asia.ensembl.org/index.html.
[20]汤燕静,陈儒,张然然,等.中国汉族急性淋巴细胞白血病患儿NUDT15基因多态性与巯嘌呤治疗耐受性的关系[C].第十三届江浙沪儿科学术会议暨2016年浙江省医学会儿科学学术年会论文汇编.湖州:2016.
[21]LIANG D C,YANG C P,LIU H C,et al.NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia[J].Pharmacogenomics J,2015,16(6):536-539.
[22]TANAKA Y,KATO M,HASEGAWA D,et al.Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia[J].Br JHaematol,2015,171(1):109-115.
[23]SUZUKI H,FUKUSHIMA H,SUZUKI R,et al.Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age[J].J Hum Genet,2016,61(9):797-801.
[24]YI E S,CHOI Y B,CHOI R,et al.NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels in children with acute lymphoblastic leukemia[J].Cancer Res Treat,2018,50(3):872-882.
[25]中华医学会消化病学分会炎症性肠病学组.建立全国通用的炎症性肠病诊治过程的关键性质量控制指标的共识意见[J].中华炎性肠病杂志:中英文,2017,1(1):12-19.
[26]ZHU X,WANG X D,CHAO K,et al.NUDT15polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn’s disease[J].Aliment Pharmacol Ther,2016,44(9):967-975.
[27]ASADA A,NISHIDA A,SHIOYA M,et al.NUDT15R139C-related thiopurine leukocytopenia is mediated by6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease[J].J Gastroenterol,2016,51(1):22-29.
[28]KAKUTA Y,NAITO T,ONODERA M,et al.NUDT15R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD[J].Pharmacogenomics J,2015,16(3):280-285.
[29]CHAO K,WANG X,CAO Q,et al.Combined Detection of NUDT15 variants could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease:a multicenter analysis[J].Inflamm Bowel Dis,2017,23(9):1592-1599.
[30]SATO T,TAKAGAWA T,KAKUTA Y,et al.NUDT15,FTO,and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases[J].Intest Res,2017,15(3):328-337.
[31]LEE J H,KIM T J,KIM E R,et al.Measurements of6-thioguanine nucleotide levels with TPMT and NUDT15genotyping in patients with Crohn’s disease[J].PLoS One,2017,12(12):e188925.
[32]WANG H H,HE Y,WANG H X,et al.Comparison of TPMTand NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease[J].World J Gastroenterol,2018,24(8):941-948.
[33]SUTIMAN N,CHEN S,LING K L,et al.Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients[J].Pharmacogenomics,2017,19(1):31-43.
[34]LEE Y J,HWANG E H,PARK J H,et al.NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease[J].Eur J Gastroenterol Hepatol,2016,28(4):475-478.
[35]AILING Z,JING Y,JINGLI L,et al.Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects:a case report[J].J Clin Pharm Ther,2016,41(5):572-574.
[36]周琰,吴炯,郭玮,等.NUDT15基因突变致巯唑嘌呤治疗克罗恩病并发严重骨髓抑制1例[J].复旦学报(医学版),2017,44(4):542-544.
[2]中华医学会儿科学分会血液学组.儿童非霍奇金淋巴瘤诊疗建议[J].中华儿科杂志,2011,49(3):186-192.
[3]MATSUOKA K,KOBAYASHI T,UENO F,et al.Evidence-based clinical practice guidelines for inflammatory bowel disease[J].J Gastroenterol,2018,53(3):305-353.
[4]MOON W,LOFTUS E J.Review article:recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease[J].Aliment Pharmacol Ther,2016,43(8):863-883.
[5]KAKUTA Y,KINOUCHI Y,SHIMOSEGAWA T.Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia:prospects for clinical application of NUDT15 genotyping[J].J Gastroenterol,2018,53(2):172-180.
[6]NEURATH M F,KIESSLICH R,TEICHGRABER U,et al.6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease[J].Clin Gastroenterol Hepatol,2005,3(10):1007-1014.
[7]POPPE D,TIEDE I,FRITZ G,et al.Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins[J].J Immunol,2006,176(1):640-651.
[8]KARNER S,SHI S,FISCHER C,et al.Determination of6-thioguanosine diphosphate and triphosphate and nucleoside diphosphate kinase activity in erythrocytes:novel targets for thiopurine therapy?[J].Ther Drug Monit,2010,32(2):119-128.
[9]ROBERTS R L,BARCLAY M L.Update on thiopurine pharmacogenetics in inflammatory bowel disease[J].Pharmacogenomics,2015,16(8):891-903.
[10]MEI L,ONTIVEROS E P,GRIFFITHS E A,et al.Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy[J].Blood Rev,2015,29(4):243-249.
[11]YANG S K,HONG M,BAEK J,et al.A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia[J].Nat Genet,2014,46(9):1017-1020.
[12]YANG J J,LANDIER W,YANG W,et al.Inherited NUDT15variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia[J].J Clin Oncol,2015,33(11):1235-1242.
[13]KRISHNAMURTHY P,SCHWAB M,TAKENAKA K,et al.Transporter-mediated protection against thiopurine-induced hematopoietic toxicity[J].Cancer Res,2008,68(13):4983-4989.
[14]TANAKA Y,NAKADATE H,KONDOH K,et al.Interaction between NUDT15 and ABCC4 variants enhances intolerability of 6-mercaptopurine in Japanese patients with childhood acute lymphoblastic leukemia[J].Pharmacogenomics J,2018,18(2):275-280.
[15]TAKAGI Y,SETOYAMA D,ITO R,et al.Human MTH3(NUDT18)protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates:comparison with MTH1and MTH2[J].J Biol Chem,2012,287(25):21541-21549.
[16]VALERIE N C,HAGENKORT A,PAGE B D,et al.NUDT15hydrolyzes 6-thio-deoxyGTP to mediate the anticancer efficacy of 6-thioguanine[J].Cancer Res,2016,76(18):5501-5511.
[17]SINGH M,BHATIA P,KHERA S,et al.Emerging role of NUDT15 polymorphisms in 6-mercaptopurine metabolism and dose related toxicity in acute lymphoblastic leukaemia[J].Leuk Res,2017,62:17-22.
[18]MORIYAMA T,NISHII R,PEREZ-ANDREU V,et al.NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity[J].Nat Genet,2016,48(4):367-373.
[19]EMBI-EBI.Ensembl Project[EB/OL].[2018-04-01].http://asia.ensembl.org/index.html.
[20]汤燕静,陈儒,张然然,等.中国汉族急性淋巴细胞白血病患儿NUDT15基因多态性与巯嘌呤治疗耐受性的关系[C].第十三届江浙沪儿科学术会议暨2016年浙江省医学会儿科学学术年会论文汇编.湖州:2016.
[21]LIANG D C,YANG C P,LIU H C,et al.NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia[J].Pharmacogenomics J,2015,16(6):536-539.
[22]TANAKA Y,KATO M,HASEGAWA D,et al.Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia[J].Br JHaematol,2015,171(1):109-115.
[23]SUZUKI H,FUKUSHIMA H,SUZUKI R,et al.Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age[J].J Hum Genet,2016,61(9):797-801.
[24]YI E S,CHOI Y B,CHOI R,et al.NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels in children with acute lymphoblastic leukemia[J].Cancer Res Treat,2018,50(3):872-882.
[25]中华医学会消化病学分会炎症性肠病学组.建立全国通用的炎症性肠病诊治过程的关键性质量控制指标的共识意见[J].中华炎性肠病杂志:中英文,2017,1(1):12-19.
[26]ZHU X,WANG X D,CHAO K,et al.NUDT15polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn’s disease[J].Aliment Pharmacol Ther,2016,44(9):967-975.
[27]ASADA A,NISHIDA A,SHIOYA M,et al.NUDT15R139C-related thiopurine leukocytopenia is mediated by6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease[J].J Gastroenterol,2016,51(1):22-29.
[28]KAKUTA Y,NAITO T,ONODERA M,et al.NUDT15R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD[J].Pharmacogenomics J,2015,16(3):280-285.
[29]CHAO K,WANG X,CAO Q,et al.Combined Detection of NUDT15 variants could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease:a multicenter analysis[J].Inflamm Bowel Dis,2017,23(9):1592-1599.
[30]SATO T,TAKAGAWA T,KAKUTA Y,et al.NUDT15,FTO,and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases[J].Intest Res,2017,15(3):328-337.
[31]LEE J H,KIM T J,KIM E R,et al.Measurements of6-thioguanine nucleotide levels with TPMT and NUDT15genotyping in patients with Crohn’s disease[J].PLoS One,2017,12(12):e188925.
[32]WANG H H,HE Y,WANG H X,et al.Comparison of TPMTand NUDT15 polymorphisms in Chinese patients with inflammatory bowel disease[J].World J Gastroenterol,2018,24(8):941-948.
[33]SUTIMAN N,CHEN S,LING K L,et al.Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients[J].Pharmacogenomics,2017,19(1):31-43.
[34]LEE Y J,HWANG E H,PARK J H,et al.NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn’s disease[J].Eur J Gastroenterol Hepatol,2016,28(4):475-478.
[35]AILING Z,JING Y,JINGLI L,et al.Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects:a case report[J].J Clin Pharm Ther,2016,41(5):572-574.
[36]周琰,吴炯,郭玮,等.NUDT15基因突变致巯唑嘌呤治疗克罗恩病并发严重骨髓抑制1例[J].复旦学报(医学版),2017,44(4):542-544.