HRM技术在炎症性肠病患者TPMT基因多态性的检测中的应用性研究
摘要
背景:硫唑嘌呤是治疗炎症性肠病的常用免疫抑制剂,由于其严重的骨髓抑制毒副作用,已有的研究显示该药物副作用与硫嘌呤甲基转移酶(TPMT)基因突变有关。
目的:应用HRM技术检测炎症性肠病患者TPMT基因多态性,探索炎症性肠病(IBD)患者TPMT基因型与硫唑嘌呤(AZA)致骨髓抑制的关系。方法:采集了82例IBD患者和53例健康志愿者的外周血,使用QIAamp DNA Blood Minikit(德国Qiagen公司生产)提取其中的DNA,采用聚合酶链反应-高分辨熔解曲线(PCR-HRM)与Sanger法序列测定相结合的方法,检测上述人群中3种常见的TPMT突变等位基因TPMT*3A(G460A/A719G)、TPMT*3B(G460A)、TPMT*3C(A719G)。结果:临床资料:82例IBD(UC 38例/CD 42例/IC 2例),根据是否使用AZA治疗分为A、B两组。其中A组有31例患者,使用AZA的剂量为50-100mg/d,(男20/女11),平均年龄39.6(18-68)岁。健康对照组为C组(男28/女25),平均年龄41.06(23-68)岁。A组与C组、B组与C组年龄无统计学差异。TPMT基因多态性检测出了TPMT*1/*3C杂合子6例,占4.44%(6/135);IBD患者(A+B组)中TPMT*1/*3C杂合子4例,占4.88%(4/82),TPMT*3C基因频率为2.44%。健康对照者(C组)中TPMT*3C杂合子2例,占3.77%(2/53),TPMT*3C基因频率为1.89%。未检测出TPMT*3A和TPMT*3B型突变。IBD患者的4例出现骨髓抑制的患者中,1例是TPMT*1/*3C杂合子;其余3例为TPMT野生型。另外检测出了TPMT*1S(T474C)突变,IBD患者(A+B组)中TPMT*1S(T474C)纯合型占1.96%,杂合型占35.85%,基因频率为:C19.81%。健康对照组(C组)中TPMT*1S(T474C)纯合型占2.44%,杂合型占39.02%,基因频率为:C 21.95%。结论:存在基因突变的IBD患者对硫唑嘌呤不能耐受,导致骨髓抑制。然而TPMT基因突变可以解释部分AZA治疗IBD导致骨髓抑制的病例,但不能解释大部分病例。
Background:Azathioprine(AZA) is a common drug which is used to treat inflammatory bowel disease(IBD),however it may cause the myelotoxicity in some patients.Recent studies indicated that the drug adverse reaction had some relationship with the mutation of thiopurine methyltransferase (TPMT).Objective To discuss the relationship between the genotype of TPMT and AZA induced myelotoxicity in the patients with IBD.Methods Peripheral blood was collected from 82 IBD patients and 53 healthy Chinese people. Genomic DNA was isolated from these blood samples with a QIAamp DNA Blood Mini Kit(Qiagen),and three commom mutation alleles of TPMT [TPMT*3A(G460A/A719G),TPMT*3B(G460A),TPMT*3C(A719G)]were detected by polymerase chain reaction-high resolution melting and sequencing.Result Clinical data:There were 82 IBD patients(UC 38/CD 42/IC 2),who were divided into group A and B based on whether they used AZA or not.Group A was composed by 31 patients who received AZA(50-100mg/d)(male 20/female 11) whose average age was 39.6(18-68) years old.The healthy control group was group C(male28/female 25),average age 41.05(23-68).There was no significant difference between the age of either group A and C or group B and C.Six cases of heterozygote TPMT*1/*3C were detected,which accounted for 4.44%of the test population.Four cases of heterozygote TPMT*1/*3C were found in IBD patients,making genotypic frequency of the heterozygote TPMT*1/*3C 4.88%,and mutation allele frequency in these patients 2.44%. While two cases of heterozygote TPMT*1/*3C were found in healthy people, so genotypic frequency of the heterozygote TPMT*1/*3C was3.77%.Mutation allele frequency in these people was 1.89%.No TPMT*3A or TPMT*3B was found. Bone marrow suppression occurred in four of the patients who received AZA, but only one of them has the TPMT*1/*3C mutation,the others are wild-type homozygote.What's more,TPMT*1S(T474C) was also detected.In IBD patients,genotype frequency of TPMT*IS homozygote was 1.96%, heterozygote was 35.85%,and the mutant allele frequency was 19.81%.The genotype frequency of TPMT*1S homozygote was 2.44%,heterozygote was 39.02%, and the mutant allele frequency was 21.95%in the healthy people.Conclusion: Patient who has the TPMT mutation is very likely to have the bone marrow suppression.But mutantion of TPMT gene could just partially explain the AZA induced myelotoxicity.Except the gene mutation,there are many other risks could cause bone marrow expression.
目的:应用HRM技术检测炎症性肠病患者TPMT基因多态性,探索炎症性肠病(IBD)患者TPMT基因型与硫唑嘌呤(AZA)致骨髓抑制的关系。方法:采集了82例IBD患者和53例健康志愿者的外周血,使用QIAamp DNA Blood Minikit(德国Qiagen公司生产)提取其中的DNA,采用聚合酶链反应-高分辨熔解曲线(PCR-HRM)与Sanger法序列测定相结合的方法,检测上述人群中3种常见的TPMT突变等位基因TPMT*3A(G460A/A719G)、TPMT*3B(G460A)、TPMT*3C(A719G)。结果:临床资料:82例IBD(UC 38例/CD 42例/IC 2例),根据是否使用AZA治疗分为A、B两组。其中A组有31例患者,使用AZA的剂量为50-100mg/d,(男20/女11),平均年龄39.6(18-68)岁。健康对照组为C组(男28/女25),平均年龄41.06(23-68)岁。A组与C组、B组与C组年龄无统计学差异。TPMT基因多态性检测出了TPMT*1/*3C杂合子6例,占4.44%(6/135);IBD患者(A+B组)中TPMT*1/*3C杂合子4例,占4.88%(4/82),TPMT*3C基因频率为2.44%。健康对照者(C组)中TPMT*3C杂合子2例,占3.77%(2/53),TPMT*3C基因频率为1.89%。未检测出TPMT*3A和TPMT*3B型突变。IBD患者的4例出现骨髓抑制的患者中,1例是TPMT*1/*3C杂合子;其余3例为TPMT野生型。另外检测出了TPMT*1S(T474C)突变,IBD患者(A+B组)中TPMT*1S(T474C)纯合型占1.96%,杂合型占35.85%,基因频率为:C19.81%。健康对照组(C组)中TPMT*1S(T474C)纯合型占2.44%,杂合型占39.02%,基因频率为:C 21.95%。结论:存在基因突变的IBD患者对硫唑嘌呤不能耐受,导致骨髓抑制。然而TPMT基因突变可以解释部分AZA治疗IBD导致骨髓抑制的病例,但不能解释大部分病例。
Background:Azathioprine(AZA) is a common drug which is used to treat inflammatory bowel disease(IBD),however it may cause the myelotoxicity in some patients.Recent studies indicated that the drug adverse reaction had some relationship with the mutation of thiopurine methyltransferase (TPMT).Objective To discuss the relationship between the genotype of TPMT and AZA induced myelotoxicity in the patients with IBD.Methods Peripheral blood was collected from 82 IBD patients and 53 healthy Chinese people. Genomic DNA was isolated from these blood samples with a QIAamp DNA Blood Mini Kit(Qiagen),and three commom mutation alleles of TPMT [TPMT*3A(G460A/A719G),TPMT*3B(G460A),TPMT*3C(A719G)]were detected by polymerase chain reaction-high resolution melting and sequencing.Result Clinical data:There were 82 IBD patients(UC 38/CD 42/IC 2),who were divided into group A and B based on whether they used AZA or not.Group A was composed by 31 patients who received AZA(50-100mg/d)(male 20/female 11) whose average age was 39.6(18-68) years old.The healthy control group was group C(male28/female 25),average age 41.05(23-68).There was no significant difference between the age of either group A and C or group B and C.Six cases of heterozygote TPMT*1/*3C were detected,which accounted for 4.44%of the test population.Four cases of heterozygote TPMT*1/*3C were found in IBD patients,making genotypic frequency of the heterozygote TPMT*1/*3C 4.88%,and mutation allele frequency in these patients 2.44%. While two cases of heterozygote TPMT*1/*3C were found in healthy people, so genotypic frequency of the heterozygote TPMT*1/*3C was3.77%.Mutation allele frequency in these people was 1.89%.No TPMT*3A or TPMT*3B was found. Bone marrow suppression occurred in four of the patients who received AZA, but only one of them has the TPMT*1/*3C mutation,the others are wild-type homozygote.What's more,TPMT*1S(T474C) was also detected.In IBD patients,genotype frequency of TPMT*IS homozygote was 1.96%, heterozygote was 35.85%,and the mutant allele frequency was 19.81%.The genotype frequency of TPMT*1S homozygote was 2.44%,heterozygote was 39.02%, and the mutant allele frequency was 21.95%in the healthy people.Conclusion: Patient who has the TPMT mutation is very likely to have the bone marrow suppression.But mutantion of TPMT gene could just partially explain the AZA induced myelotoxicity.Except the gene mutation,there are many other risks could cause bone marrow expression.
引文
1 郑家驹.炎症性肠病药物治疗进 展胃肠病学和肝病学杂志 2006年8月第15卷第4期 347-349;
2 刘继喜,李冰,孙钢。炎性肠病患者服用硫唑嘌呤的不良反应及处理 临床消化杂志 2006年第18卷第5期 268-269;
3 A.F.Y.Al Hadithya,N.K.H.de Boerb,L.J.J.Derijksc,d,J.C.Eschere,C.J.J.Mulderb,J.R.B.J.Brouwersa,Thiopurines in inflammatory bowel disease:pharmacogenetics,therapeutic drug monitoring and clinical recommendations Digestive and Liver Disease 37(2005) 282-297
4 张波,徐小薇,李大魁 巯嘌呤甲基转移酶遗传多态性对硫唑嘌呤药动学和药效学影响的研究概况 中国药学杂志2006年6月第41卷第11期 801-803;
5 Escousse A,Guedon F,Mounie J,Rifle G,Mousson C,D'Athis P.6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.J Pharm Pharmacol.
6 LENNARD L,REES C A,LILLEYMAN J S,et al.Childhood leukemia:a relationship between intracellular 6-mercaptopurine metabolites and neutropenia[J].Br J Olin Pharmacol,1983,16:359-363.
7 LENNARD L,VAN LOON J A,LILLEYMAN J S,et al.Thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations [J].Olin Pharmacol Ther,1989,46:149-154.
8 RICHARD M.WEINSHILBOUM1 AND SUSAN L.SLADEK Mercaptopurine Pharmacogenetics:Monogenic Inheritance of Erythrocyte Thiopurine Methyltransferase Activity Am JHum Genet 1980 32:651-662;
9 Tai,H.-L.;Krynetski,E.Y.;Yates,C.R.;Loennechen,T.;Fessing,M.Y.;Krynetskaia,N.F.;Evans,W.E.:Thiopurine S-methyltransferase deficiency:two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.Am.J.Hum.Genet.58:1996.694-702;
10 Sofie Haglund,Malin Lindqvist,Sven Almer,Curt Peterson,and Jan Taipalensuul Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease Clinical Chemistry 50:2 288-295(2004)
11 Diane M.Otterness,Carol L.Szumlanski,Thomas C.Wood,and Richard M.Weinshilboum Human Thiopurine Methyltransferase Pharmacogenetics Kindred with a Terminal Exon Splice Junction Mutation That Results in Loss of Activity J.Clin.Invest.Volume 101,Number 5,March 1998,1036-1044
12 Takamitsu Sasaki,Emi Goto,Yumiko konno,Masahiro Hiratsuka and Michinao Mizugaki Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals Drug Metab.Pharacokinet.21(4):SNP25(332)-SNP29(336)(2006)
13 Hon,Y.Y.;Fessing,M.Y.;Pui,C.-H.;Relling,M.V.;Krynetski,E.Y.;Evans,W.E.:Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.Hum.Molec.Genet.8:371-376,1999.
14Collie-Duguid ES,Pritchard SC,Powrie RH,Sludden J,Collier DA,Li T,McLeod HL The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.Pharmacogenetics.1999Feb;9(1):37-42:
15 张建萍,关永源,吴珏珩.等.健康汉族人硫嘌呤甲基转移酶遗传多态性研究.癌症,2003,22(4):385-388;
16 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Huang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
17 Li-Rong Zhang a,Dong-Kui Song,Wei Zhang,Jun Zhao,Lin-jing Jia,Dong-Liang Xing Efficient screening method of the thiopurine methyltransferase polymorphisms for patients considering taking thiopurine drugs in a Chinese Han population in Henan Province(central China) Clinica Chimica Acta 376(2007) 45-51;
18 Alison J.Black,MB,ChB;Howard L.McLeod,PharmD;Hillary A.Capell,MB,ChB,MD,FRCP;Robert H.Powrie,BSc;Lloyd K.Matowe,MSc;Stuart C.Pritchard,MSc;Elaina S.R.Collie-Duguid,PhD;and David M.Reid,MB,ChB,MD,FRCP Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine.Ann Intern Med.1998Nov 1;129(9):716-8
19 COLOMBEL J F,FERRARI N,DEBUYSERE H,et al.Genotypic analysis of thiopurine S-methyltransferase in patients with Chohn's disease and severe myelosuppression during azathioprine therapy[J].Gastroenterology,2000,118:1025-1030.
20 杨程德,郭强,李挺,鲍春德,顾越英,陈顺乐 硫唑嘌呤致SLE骨髓抑制者的TPMT酶基因多态性 上海第二医科大学学报 VoL24 Suppl 2004 76-79
21 詹钟平 梁柳琴 杨岫岩 王一西 黄民 李昊 风湿病人群硫唑嘌呤代谢酶基因型与药物耐受性的关系 中华医学杂志.2007,87(25).-1734-1737
22 魏红,李成荣,李智毅,刘芳,黄民,王国兵,吴珏珩,张建萍,硫嘌呤甲基转移酶遗传多态性检测在6-MP个体化治疗中的意义 中国医院药学杂志2007年第27卷第1期5-7
23 U Hindorf,M Lindqvist,C Peterson,P S(o|¨)derkvist,M Str(o|¨)m,H Hjortswang,A Pousette and S Almer Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease Gut 2006;55;1423-1431
24 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Huang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
25 陶利萍,曹倩,姒健敏.药物代谢遗传学检测在硫唑嘌呤治疗炎症性肠病中的应用.中华内科杂志 2006年6月第45卷第6期 517-519;
26 郑家驹 化学免疫调节剂在溃疡性结肠炎中的应用 医学与哲学(临床决策讨论版)2008年5月第29卷第5期 24-24;
27 Present DH,Korelitz BI,Wisch N,et al.Treatment of Crohn's disease with 6-mercaptopurine:a long-term randomised double blind study.N Engl J Med 1980;302:981-7.
28 Lowry P,Franklin CL,Weaver AL,et al.Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine,sulphasalazine,or balsalazide.Gut 2001;49:656-64.
28 张建萍 黄民 关永源 徐安龙 吴珏珩 广西京族硫嘌呤甲基转移酶突变基因研究 中华医学遗传学杂志2003年8月第20卷第4期 303-306
29 张建萍 黄民 关永源 白丽 魏红 吴珏珩 中国新疆维吾尔族硫嘌呤甲基转移酶基因突变研究 中国临床药理杂志 2003年10月No 5 Vol19 345-347
30 魏红 黄民 李智毅 张祯 张建萍 吴珏珩 中国哈萨克族硫嘌呤甲基转移酶基因突变研究 中国临床药理杂志 2005年11月No 6 Vol21 423-426
1 郑家驹.炎症性肠病药物治疗进展 胃肠病学和肝病学杂志 2006年8月第15卷第4期 347-349;
2 陶利萍,曹倩,姒健敏.药物代谢遗传学检测在硫唑嘌呤治疗炎症性肠病中的应用.中华内科杂志 2006年6月第45卷第6期 517-519;
3 A.F.Y.Al Hadithya,N.K.H.de Boerb,L.J.J.Derijksc,d,J.C.Eschere,C.J.J.Mulderb,J.R.B.J.Brouwersa,Thiopurines in inflammatory bowel disease:pharmacogenetics,therapeutic drug monitoring and clinical recommendations Digestive and Liver Disease 37(2005) 282-297
4 刘继喜,李冰,孙钢。炎性肠病患者服用硫哩嘿岭的不良反应及处理 临床消化杂志 2006年第18卷第5期 268-269;
5 张波,徐小薇,李大魁 巯嘌呤甲基转移酶遗传多态性对硫唑嘌呤药动学和药效学影响的研究概况 中国药学杂志2006年6月第41卷第11期 801-803;
6 Escousse A,Guedon F,Mounie J,Rifle G,Mousson C,D'Athis P.6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.J Pharm Pharmacol.1998Nov;50(11):1261-6;
7 RICHARD M.WEINSHILBOUM1 AND SUSAN L.SLADEK Mercaptopurine Pharmacogenetics:Monogenic Inheritance of Erythrocyte Thiopurine Methyltransferase Activity Am JHum Genet 1980 32:651-662;
8 LENNARD L,REES C A,LILLEYMAN J S,et al.Childhood leukemia:a relationship between intracellular 6-mercaptopurine metabolites and neutropenia[J].Br J Clin Pharmacol,1983,16:359-363.
9 LENNARD L,VAN LOON J A,LILLEYMAN J S,et al.Thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations [J].Clin Pharmacol Ther,1989,46:149-154.
10 EUGENE Y.RRYNETSRI,JOHN D.SCHUETZ,AMY J.GALPIN,CHING-HON PUI,MARY V.RELLING,AND WILLIAM E.EvANs A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase Proc.Natl.Acad.Sci.USA Vol.92,pp.,February 1995,949-953;
11 Szumlanski,C.;Otterness,D.;Her,C.;Lee,D.;Brandriff,B.;Relsell,D.;Spurr,R.;Lennard,L.;Wieben,E.;Weinshilboum,R.Thiopurine methyltransferase pharmacogenetics:human gene cloning and characterization of a common polymorphism.DNA Cell Biol.1996 15:17-30;
12 Tai,H.-L.;Krynetski,E.Y.;Yates,C.R.;Loennechen,T.;Fessing,M.Y.;Krynetskaia,N.F.;Evans,W.E.:Thiopurine S-methyltransferase deficiency:two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.Am.J.Hum.Genet.58:1996.694-702;
13 Sofie Haglund,Malin Lindqvist,Sven Almer,Curt Peterson,and Jan Taipalensuul Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease Clinical Chemistry 50:2 288-295(2004)
14 Hon,Y.Y.;Fessing,M.Y.;Pui,C.-H.;Relling,M.V.;Krynetski,E.Y.;Evans,W.E.:Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.Hum.Molec.Genet.8:371-376,1999.
15 Margaret-Mary Ameyaw,Wlaina S R.Collie-duguid,Robert H.Powrie,David Ofori-Adjei and Howard L.McLeod Thiopurine methyltransferase alleles in British and Ghanaian populations Human Molecular Genetics,1999,VoL 8,No.2;
16 Collie-Duguid ES,Pritchard SC,Powrie RH,Sludden J,Collier DA,Li T,McLeod HL The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.Pharmacogenetics.1999Feb;9(1):37-42;
17 张建萍,关永源,吴珏珩.等.健康汉族人硫嘌呤甲基转移酶遗传多态性研究.癌症,2003,22(4):385-388;
18 张建萍 黄民 关永源 徐安龙 吴珏珩 广西京族硫嘌呤甲基转移酶突变基因研究 中华医学遗传学杂志2003年8月第20卷第4期 303-306
19 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Buang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
20 Li-Rong Zhang a,Dong-Kui Song,Wei Zhang,Jun Zhao,Lin-jing Jia,Dong-Liang Xing Efficient screening method of the thiopurine methyltransferase po]ymorphisms for patients considering taking thiopurine drugs in a Chinese Han population in Henan Province(central China) Clinica Chimica Acta 376(2007) 45-51;
21 Pousette and S Almer U Hindorf,M Lindqvist,C Peterson,P S(o|¨)derkvist,M Str(o|¨)m,H Hjortswang,thiopurine treatment in inflammatory bowel Pharmacogenetics during standardised initiation Gut 2006;55;1423-1431;
22 NAUGHTON MA,BATTAGLIA E.Identification of thiopurine methyltransferase polymorphism can not predict myllosuppression in system lupus erythematosus patients taking azathioprine[J].Rheumatology,1999,38:640-644.
23 COLOMBEL J F,FERRARI N,DEBUYSERE H,et al.Genotypic analysis of thiopurine S-methyltransferase in patients with Chohn's disease and severe myelosuppression during azathioprine therapy[J].Gastroenterology,2000,118:1025-1030.
24 G.Stocco,S.Martelossi,A.Barabino,M.Fontana,P.Lionetti,G.Decorti N.Malus,F.Bartoli,M.Fezzi,T.Giraldi,A.Ventura TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease Digestive and Liver Disease 37(2005) 940-945;
25 Alison J.Black,MB,ChB;Howard L.McLeod,PharmD;Hillary A.Capell,MB,ChB,MD,FRCP;Robert H.Powrie,BSc;Lloyd K.Matowe,MSc;Stuart C.Pritchard,MSc;Elaina S.R.Collie-Duguid,PhD;and David M.Reid,MB,ChB,MD,FRCP Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine.Ann Intern Med.1998Nov 1;129(9):716-8
26 杨程德,郭强,李挺,鲍春德,顾越英,陈顺乐 硫唑嘌呤致SLE骨髓抑制者的TPMT酶基因多态性 上海第二医科大学学报 VoL24 Suppl 2004 76-79
28 詹钟平 梁柳琴 杨岫岩 王一西 黄民 李昊 风湿病人群硫唑嘌呤代谢酶基因型与药物耐受性的关系 中华医学杂志.2007,87(25).-1734-1737
28 B A Kaskas,E Louis,U Hindorf,E Schaeffeler,J Deftandre,F Graepler,K Schmiegelow,M Gregor,U M Zanger,M Eichelbaum,M Schwab.Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine.Gut 2003;52:140-142;
29 Marie Pierik,Paul Rutgeerts,Robert Vlietinck,Severine Vermeire.Pharmacogenetics in inflammatory bowel disease.World J Gastroenterol 2006 June 21;12(23):3657-3667
30 辛华雯,Christine Fischerl,Matthias Schwabl,Ulrich Klotzl 速尿、苯氧 比酸、硫唑嘌呤对慢性炎症性肠病患者红细胞TPMT活性的影响 中国临床药理学与治疗学2005 Jun;10(6)655-657
31 L Lennard TPMT in the treatment of Crohn's disease with azathioprine Gut 2002;51;143-146
2 刘继喜,李冰,孙钢。炎性肠病患者服用硫唑嘌呤的不良反应及处理 临床消化杂志 2006年第18卷第5期 268-269;
3 A.F.Y.Al Hadithya,N.K.H.de Boerb,L.J.J.Derijksc,d,J.C.Eschere,C.J.J.Mulderb,J.R.B.J.Brouwersa,Thiopurines in inflammatory bowel disease:pharmacogenetics,therapeutic drug monitoring and clinical recommendations Digestive and Liver Disease 37(2005) 282-297
4 张波,徐小薇,李大魁 巯嘌呤甲基转移酶遗传多态性对硫唑嘌呤药动学和药效学影响的研究概况 中国药学杂志2006年6月第41卷第11期 801-803;
5 Escousse A,Guedon F,Mounie J,Rifle G,Mousson C,D'Athis P.6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.J Pharm Pharmacol.
6 LENNARD L,REES C A,LILLEYMAN J S,et al.Childhood leukemia:a relationship between intracellular 6-mercaptopurine metabolites and neutropenia[J].Br J Olin Pharmacol,1983,16:359-363.
7 LENNARD L,VAN LOON J A,LILLEYMAN J S,et al.Thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations [J].Olin Pharmacol Ther,1989,46:149-154.
8 RICHARD M.WEINSHILBOUM1 AND SUSAN L.SLADEK Mercaptopurine Pharmacogenetics:Monogenic Inheritance of Erythrocyte Thiopurine Methyltransferase Activity Am JHum Genet 1980 32:651-662;
9 Tai,H.-L.;Krynetski,E.Y.;Yates,C.R.;Loennechen,T.;Fessing,M.Y.;Krynetskaia,N.F.;Evans,W.E.:Thiopurine S-methyltransferase deficiency:two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.Am.J.Hum.Genet.58:1996.694-702;
10 Sofie Haglund,Malin Lindqvist,Sven Almer,Curt Peterson,and Jan Taipalensuul Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease Clinical Chemistry 50:2 288-295(2004)
11 Diane M.Otterness,Carol L.Szumlanski,Thomas C.Wood,and Richard M.Weinshilboum Human Thiopurine Methyltransferase Pharmacogenetics Kindred with a Terminal Exon Splice Junction Mutation That Results in Loss of Activity J.Clin.Invest.Volume 101,Number 5,March 1998,1036-1044
12 Takamitsu Sasaki,Emi Goto,Yumiko konno,Masahiro Hiratsuka and Michinao Mizugaki Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals Drug Metab.Pharacokinet.21(4):SNP25(332)-SNP29(336)(2006)
13 Hon,Y.Y.;Fessing,M.Y.;Pui,C.-H.;Relling,M.V.;Krynetski,E.Y.;Evans,W.E.:Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.Hum.Molec.Genet.8:371-376,1999.
14Collie-Duguid ES,Pritchard SC,Powrie RH,Sludden J,Collier DA,Li T,McLeod HL The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.Pharmacogenetics.1999Feb;9(1):37-42:
15 张建萍,关永源,吴珏珩.等.健康汉族人硫嘌呤甲基转移酶遗传多态性研究.癌症,2003,22(4):385-388;
16 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Huang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
17 Li-Rong Zhang a,Dong-Kui Song,Wei Zhang,Jun Zhao,Lin-jing Jia,Dong-Liang Xing Efficient screening method of the thiopurine methyltransferase polymorphisms for patients considering taking thiopurine drugs in a Chinese Han population in Henan Province(central China) Clinica Chimica Acta 376(2007) 45-51;
18 Alison J.Black,MB,ChB;Howard L.McLeod,PharmD;Hillary A.Capell,MB,ChB,MD,FRCP;Robert H.Powrie,BSc;Lloyd K.Matowe,MSc;Stuart C.Pritchard,MSc;Elaina S.R.Collie-Duguid,PhD;and David M.Reid,MB,ChB,MD,FRCP Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine.Ann Intern Med.1998Nov 1;129(9):716-8
19 COLOMBEL J F,FERRARI N,DEBUYSERE H,et al.Genotypic analysis of thiopurine S-methyltransferase in patients with Chohn's disease and severe myelosuppression during azathioprine therapy[J].Gastroenterology,2000,118:1025-1030.
20 杨程德,郭强,李挺,鲍春德,顾越英,陈顺乐 硫唑嘌呤致SLE骨髓抑制者的TPMT酶基因多态性 上海第二医科大学学报 VoL24 Suppl 2004 76-79
21 詹钟平 梁柳琴 杨岫岩 王一西 黄民 李昊 风湿病人群硫唑嘌呤代谢酶基因型与药物耐受性的关系 中华医学杂志.2007,87(25).-1734-1737
22 魏红,李成荣,李智毅,刘芳,黄民,王国兵,吴珏珩,张建萍,硫嘌呤甲基转移酶遗传多态性检测在6-MP个体化治疗中的意义 中国医院药学杂志2007年第27卷第1期5-7
23 U Hindorf,M Lindqvist,C Peterson,P S(o|¨)derkvist,M Str(o|¨)m,H Hjortswang,A Pousette and S Almer Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease Gut 2006;55;1423-1431
24 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Huang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
25 陶利萍,曹倩,姒健敏.药物代谢遗传学检测在硫唑嘌呤治疗炎症性肠病中的应用.中华内科杂志 2006年6月第45卷第6期 517-519;
26 郑家驹 化学免疫调节剂在溃疡性结肠炎中的应用 医学与哲学(临床决策讨论版)2008年5月第29卷第5期 24-24;
27 Present DH,Korelitz BI,Wisch N,et al.Treatment of Crohn's disease with 6-mercaptopurine:a long-term randomised double blind study.N Engl J Med 1980;302:981-7.
28 Lowry P,Franklin CL,Weaver AL,et al.Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine,sulphasalazine,or balsalazide.Gut 2001;49:656-64.
28 张建萍 黄民 关永源 徐安龙 吴珏珩 广西京族硫嘌呤甲基转移酶突变基因研究 中华医学遗传学杂志2003年8月第20卷第4期 303-306
29 张建萍 黄民 关永源 白丽 魏红 吴珏珩 中国新疆维吾尔族硫嘌呤甲基转移酶基因突变研究 中国临床药理杂志 2003年10月No 5 Vol19 345-347
30 魏红 黄民 李智毅 张祯 张建萍 吴珏珩 中国哈萨克族硫嘌呤甲基转移酶基因突变研究 中国临床药理杂志 2005年11月No 6 Vol21 423-426
1 郑家驹.炎症性肠病药物治疗进展 胃肠病学和肝病学杂志 2006年8月第15卷第4期 347-349;
2 陶利萍,曹倩,姒健敏.药物代谢遗传学检测在硫唑嘌呤治疗炎症性肠病中的应用.中华内科杂志 2006年6月第45卷第6期 517-519;
3 A.F.Y.Al Hadithya,N.K.H.de Boerb,L.J.J.Derijksc,d,J.C.Eschere,C.J.J.Mulderb,J.R.B.J.Brouwersa,Thiopurines in inflammatory bowel disease:pharmacogenetics,therapeutic drug monitoring and clinical recommendations Digestive and Liver Disease 37(2005) 282-297
4 刘继喜,李冰,孙钢。炎性肠病患者服用硫哩嘿岭的不良反应及处理 临床消化杂志 2006年第18卷第5期 268-269;
5 张波,徐小薇,李大魁 巯嘌呤甲基转移酶遗传多态性对硫唑嘌呤药动学和药效学影响的研究概况 中国药学杂志2006年6月第41卷第11期 801-803;
6 Escousse A,Guedon F,Mounie J,Rifle G,Mousson C,D'Athis P.6-Mercaptopurine pharmacokinetics after use of azathioprine in renal transplant recipients with intermediate or high thiopurine methyl transferase activity phenotype.J Pharm Pharmacol.1998Nov;50(11):1261-6;
7 RICHARD M.WEINSHILBOUM1 AND SUSAN L.SLADEK Mercaptopurine Pharmacogenetics:Monogenic Inheritance of Erythrocyte Thiopurine Methyltransferase Activity Am JHum Genet 1980 32:651-662;
8 LENNARD L,REES C A,LILLEYMAN J S,et al.Childhood leukemia:a relationship between intracellular 6-mercaptopurine metabolites and neutropenia[J].Br J Clin Pharmacol,1983,16:359-363.
9 LENNARD L,VAN LOON J A,LILLEYMAN J S,et al.Thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations [J].Clin Pharmacol Ther,1989,46:149-154.
10 EUGENE Y.RRYNETSRI,JOHN D.SCHUETZ,AMY J.GALPIN,CHING-HON PUI,MARY V.RELLING,AND WILLIAM E.EvANs A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase Proc.Natl.Acad.Sci.USA Vol.92,pp.,February 1995,949-953;
11 Szumlanski,C.;Otterness,D.;Her,C.;Lee,D.;Brandriff,B.;Relsell,D.;Spurr,R.;Lennard,L.;Wieben,E.;Weinshilboum,R.Thiopurine methyltransferase pharmacogenetics:human gene cloning and characterization of a common polymorphism.DNA Cell Biol.1996 15:17-30;
12 Tai,H.-L.;Krynetski,E.Y.;Yates,C.R.;Loennechen,T.;Fessing,M.Y.;Krynetskaia,N.F.;Evans,W.E.:Thiopurine S-methyltransferase deficiency:two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.Am.J.Hum.Genet.58:1996.694-702;
13 Sofie Haglund,Malin Lindqvist,Sven Almer,Curt Peterson,and Jan Taipalensuul Pyrosequencing of TPMT Alleles in a General Swedish Population and in Patients with Inflammatory Bowel Disease Clinical Chemistry 50:2 288-295(2004)
14 Hon,Y.Y.;Fessing,M.Y.;Pui,C.-H.;Relling,M.V.;Krynetski,E.Y.;Evans,W.E.:Polymorphism of the thiopurine S-methyltransferase gene in African-Americans.Hum.Molec.Genet.8:371-376,1999.
15 Margaret-Mary Ameyaw,Wlaina S R.Collie-duguid,Robert H.Powrie,David Ofori-Adjei and Howard L.McLeod Thiopurine methyltransferase alleles in British and Ghanaian populations Human Molecular Genetics,1999,VoL 8,No.2;
16 Collie-Duguid ES,Pritchard SC,Powrie RH,Sludden J,Collier DA,Li T,McLeod HL The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations.Pharmacogenetics.1999Feb;9(1):37-42;
17 张建萍,关永源,吴珏珩.等.健康汉族人硫嘌呤甲基转移酶遗传多态性研究.癌症,2003,22(4):385-388;
18 张建萍 黄民 关永源 徐安龙 吴珏珩 广西京族硫嘌呤甲基转移酶突变基因研究 中华医学遗传学杂志2003年8月第20卷第4期 303-306
19 Jian-ping Zhang,Yong-yuan Guan,Jue-heng Wu,An-Long Xu,Shufeng Zhou & Min Buang,Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children:A comparison of Han and Yao ethnic groups Br J Clin Pharmacol 58:2 163-168
20 Li-Rong Zhang a,Dong-Kui Song,Wei Zhang,Jun Zhao,Lin-jing Jia,Dong-Liang Xing Efficient screening method of the thiopurine methyltransferase po]ymorphisms for patients considering taking thiopurine drugs in a Chinese Han population in Henan Province(central China) Clinica Chimica Acta 376(2007) 45-51;
21 Pousette and S Almer U Hindorf,M Lindqvist,C Peterson,P S(o|¨)derkvist,M Str(o|¨)m,H Hjortswang,thiopurine treatment in inflammatory bowel Pharmacogenetics during standardised initiation Gut 2006;55;1423-1431;
22 NAUGHTON MA,BATTAGLIA E.Identification of thiopurine methyltransferase polymorphism can not predict myllosuppression in system lupus erythematosus patients taking azathioprine[J].Rheumatology,1999,38:640-644.
23 COLOMBEL J F,FERRARI N,DEBUYSERE H,et al.Genotypic analysis of thiopurine S-methyltransferase in patients with Chohn's disease and severe myelosuppression during azathioprine therapy[J].Gastroenterology,2000,118:1025-1030.
24 G.Stocco,S.Martelossi,A.Barabino,M.Fontana,P.Lionetti,G.Decorti N.Malus,F.Bartoli,M.Fezzi,T.Giraldi,A.Ventura TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease Digestive and Liver Disease 37(2005) 940-945;
25 Alison J.Black,MB,ChB;Howard L.McLeod,PharmD;Hillary A.Capell,MB,ChB,MD,FRCP;Robert H.Powrie,BSc;Lloyd K.Matowe,MSc;Stuart C.Pritchard,MSc;Elaina S.R.Collie-Duguid,PhD;and David M.Reid,MB,ChB,MD,FRCP Thiopurine Methyltransferase Genotype Predicts Therapy-Limiting Severe Toxicity from Azathioprine.Ann Intern Med.1998Nov 1;129(9):716-8
26 杨程德,郭强,李挺,鲍春德,顾越英,陈顺乐 硫唑嘌呤致SLE骨髓抑制者的TPMT酶基因多态性 上海第二医科大学学报 VoL24 Suppl 2004 76-79
28 詹钟平 梁柳琴 杨岫岩 王一西 黄民 李昊 风湿病人群硫唑嘌呤代谢酶基因型与药物耐受性的关系 中华医学杂志.2007,87(25).-1734-1737
28 B A Kaskas,E Louis,U Hindorf,E Schaeffeler,J Deftandre,F Graepler,K Schmiegelow,M Gregor,U M Zanger,M Eichelbaum,M Schwab.Safe treatment of thiopurine S-methyltransferase deficient Crohn's disease patients with azathioprine.Gut 2003;52:140-142;
29 Marie Pierik,Paul Rutgeerts,Robert Vlietinck,Severine Vermeire.Pharmacogenetics in inflammatory bowel disease.World J Gastroenterol 2006 June 21;12(23):3657-3667
30 辛华雯,Christine Fischerl,Matthias Schwabl,Ulrich Klotzl 速尿、苯氧 比酸、硫唑嘌呤对慢性炎症性肠病患者红细胞TPMT活性的影响 中国临床药理学与治疗学2005 Jun;10(6)655-657
31 L Lennard TPMT in the treatment of Crohn's disease with azathioprine Gut 2002;51;143-146
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