基因多态性对类风湿关节炎药物疗效和不良反应影响的研究进展
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摘要
治疗类风湿关节炎(rheumatoid arthritis,RA)的药物主要包括疾病调修抗风湿药物(disease-modifying antirheumatic drugs,DMARDs)、非甾体抗炎药物(nonsteroidal anti-inflammatory drugs,NSAIDs)、生物制剂等。这些药物对于阻止RA病程和预防并发症起着重要作用,但是药物疗效和不良反应在RA患者中存在个体差异。编码药物代谢酶(二氢叶酸还原酶、细胞色素P450酶、N-乙酰转移酶等)、药物转运蛋白(ATP结合盒转运蛋白等)和药物靶点(肿瘤坏死因子-α受体等)的基因存在多态性。药物转运蛋白基因多态性可改变药物的分布、排泄,药物靶标的多态性明显影响药物的敏感性。这些基因多态性会影响药物代谢动力学和药效学,也可能是导致个体间药物疗效和不良反应差异的重要机制。该文系统综述了基因多态性对RA药物疗效和不良反应的影响。
Drugs for the treatment of rheumatoid arthritis (RA) include disease-modifying antirheumatic drugs (DMARDs),nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents,etc. These drugs are critical in preventing the process and complications of RA. However,the outcome of treatment and adverse drug reactions with these drugs in RA patients are different individually. Drug-metabolizing enzymes (dihydrofolate reductase,cytochrome P450enzymes,N-acetyltransferases,and so on.),drug transporters (ATP-binding cassette transporters) and drug targets (tumor necrosis factor-α receptors) are coded for by variant alleles. The gene polymorphism of drug transporters can change the distribution and excretion of drugs. The polymorphisms of drug target affect significantly drug sensitivity.These gene polymorphisms may influence the pharmacokinetics,pharmacodynamics and side effects of medicine. In this article,we review the genetic polymorphisms that affect the efficacy of drug or the occurrence of adverse drug reactions in RA.
Drugs for the treatment of rheumatoid arthritis (RA) include disease-modifying antirheumatic drugs (DMARDs),nonsteroidal anti-inflammatory drugs (NSAIDs) and biological agents,etc. These drugs are critical in preventing the process and complications of RA. However,the outcome of treatment and adverse drug reactions with these drugs in RA patients are different individually. Drug-metabolizing enzymes (dihydrofolate reductase,cytochrome P450enzymes,N-acetyltransferases,and so on.),drug transporters (ATP-binding cassette transporters) and drug targets (tumor necrosis factor-α receptors) are coded for by variant alleles. The gene polymorphism of drug transporters can change the distribution and excretion of drugs. The polymorphisms of drug target affect significantly drug sensitivity.These gene polymorphisms may influence the pharmacokinetics,pharmacodynamics and side effects of medicine. In this article,we review the genetic polymorphisms that affect the efficacy of drug or the occurrence of adverse drug reactions in RA.
引文
[1]魏伟.炎症免疫反应软调节[J].中国药理学通报,2016,32(3):297-303.[1]Wei W.Soft regulation of inflammatory immune responses[J].Chin Pharmacol Bull,2016,32(3):297-303.
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[3]Hughes L B,Beasley T M,Patel H,et al.Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis[J].Ann Rheum Dis,2006,65(9):1213-8.
[4]Stamp L K,Roberts R L.Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases[J].Pharmacogenomics,2011,12(10):1449-63.
[5]Jekic B,Vejnovic D,Milic V,et al.Association of 63/91 length polymorphism in the DHFR gene major promoter with toxicity of methotrexate in patients with rheumatoid arthritis[J].Pharmacogenomics,2016,17(15):1687-91.
[6]Tasbas O,Borman P,Gurhan K H,et al.The frequency of A1298C and C677T polymorphisms of the methylentetrahydrofolate gene in Turkish patients with rheumatoid arthritis:relationship with methotrexate toxicity[J].Open Rheumatol J,2011,5:30-5.
[7]Caliz R,Del A J,Balsa A,et al.The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population[J].Scand J Rheumatol,2012,41(1):10-4.
[8]Shao W,Yuan Y,Li Y.Association between MTHFR C677T polymorphism and methotrexate treatment outcome in rheumatoid arthritis patients:a systematic review and meta-analysis[J].Genet Test Mol Biomarkers,2017,21(5):275-85.
[9]Hayashi H,Tazoe Y,Tsuboi S et al.A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis[J].Drug Metab Pharmacokinet,2013,28(2):164-8.
[10]Kravljaca M,Perovic V,Pravica V,et al.The importance of MDR1 gene polymorphisms for tacrolimus dosage[J].Eur J Pharm Sci,2016,83:109-13.
[11]Jekic B,Lukovic L,Bunjevacki V,et al.Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients[J].Eur J Clin Pharmacol,2013,69(3):377-83.
[12]Wiese M D,Alotaibi N,O'Doherty C,et al.Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis[J].Pharmacogenomics J,2014,14(4):350-5.
[13]Kuhn U D,Anschutz M,Schmucker K,et al.Phenotyping with sulfasalazine-time dependence and relation to NAT2 pharmacogenetics[J].Int J Clin Pharmacol Ther,2010,48(1):1-10.
[14]Soukup T,Dosedel M,Nekvindova J,et al.Genetic polymorphisms in metabolic pathways of leflunomide in the treatment of rheumatoid arthritis[J].Clin Exp Rheumatol,2015,33(3):426-32.
[15]Colleoni L,Kapetis D,Maggi L,et al.A new thiopurine s-methyltransferase haplotype associated with intolerance to azathioprine[J].J Clin Pharmacol,2013,53(1):67-74.
[16]Seinen M L,van Bodegraven A A,van Kuilenburg A B,et al.High TPMT activity as a risk factor for severe myelosuppression during thiopurine therapy[J].Neth J Med,2013,71(4):222.
[17]O'Doherty C,Schnabl M,Spargo L,et al.Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis[J].Pharmacogenomics,2012,13(12):1427-34.
[18]Bohanec G P,Rozman B,Tomsic M,et al.Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients[J].Eur J Clin Pharmacol,2008,64(9):871-6.
[19]Sevilla-Mantilla C,Ortega L,Agúndez J A,et al.Leflunomide-induced acute hepatitis[J].Dig Liver Dis,2004,36(1):82-4.
[20]Garcia DLPM,Mendez C R,Garrido G E,et al.Polymorphism rs2275913 of interleukin-17A is related to more intensive therapy with disease-modifying anti rheumatic drugs in Mexican patients with rheumatoid arthritis[J].Acta Reumatol Port,2017,42(2):155-61.
[21]Ruiz-Padilla A J,Gamez-Nava J I,Saldana-Cruz A M,et al.The-174G/C interleukin-6 gene promoter polymorphism as a genetic marker of differences in therapeutic response to methotrexate and leflunomide in rheumatoid arthritis[J].Biomed Res Int,2016,2016:4193538.
[22]Krasniqi V,Dimovski A,Domjanovic I K,et al.How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity[J].Arh Hig Rada Toksikol,2016,67(1):1-8.
[23]Lee H I,Bae J W,Choi C I,et al.Strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals[J].Pharmacogenet Genomics,2014,24(2):113-7.
[24]Kim S H,Kim D H,Byeon J Y,et al.Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite[J].Arch Pharm res,2017,40(3):382-90.
[25]Fisher M D,Watson C,Fox K M,et al.Dosing patterns of three tumor necrosis factor-blockers among patients with rheumatoid arthritis in a large United States managed care population[J].Curr Med Res Opin,2013,29(5):561-8.
[26]Lee Y H,Bae S C.Associations between PTPRC rs10919563 A/G and FCGR2A R131H polymorphisms and responsiveness to TNF blockers in rheumatoid arthritis:a meta-analysis[J].Rheumatol Int,2016,36(6):837-44.
[27]Tsukamoto M,Kameda H,Ohshige T,et al.Fcgamma receptor3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis[J].Mod Rheumatol,2017,27(5):778-81.
[28]Jancic I,Arsenovic-Ranin N,Sefik-Bukilica M,et al.-174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis[J].Rheumatol Int,2013,33(6):1481-6.
[29]Ruyssen-Witrand A,Rouanet S,Combe B,et al.Association between-871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients[J].Rheumatology(Oxford),2013,52(4):636-41.
[30]Ruyssenwitrand A,Rouanet S,Combe B,et al.Fcγreceptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab[J].Ann Rheum Dis,2012,71(6):875.
[2]Castaneda S,Lopez-Mejias R,Gonzalez-Gay M A.Gene polymorphisms and therapy in rheumatoid arthritis[J].Expert Opin Drug Metab Toxicol,2016,12(3):225-9.
[3]Hughes L B,Beasley T M,Patel H,et al.Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis[J].Ann Rheum Dis,2006,65(9):1213-8.
[4]Stamp L K,Roberts R L.Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases[J].Pharmacogenomics,2011,12(10):1449-63.
[5]Jekic B,Vejnovic D,Milic V,et al.Association of 63/91 length polymorphism in the DHFR gene major promoter with toxicity of methotrexate in patients with rheumatoid arthritis[J].Pharmacogenomics,2016,17(15):1687-91.
[6]Tasbas O,Borman P,Gurhan K H,et al.The frequency of A1298C and C677T polymorphisms of the methylentetrahydrofolate gene in Turkish patients with rheumatoid arthritis:relationship with methotrexate toxicity[J].Open Rheumatol J,2011,5:30-5.
[7]Caliz R,Del A J,Balsa A,et al.The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population[J].Scand J Rheumatol,2012,41(1):10-4.
[8]Shao W,Yuan Y,Li Y.Association between MTHFR C677T polymorphism and methotrexate treatment outcome in rheumatoid arthritis patients:a systematic review and meta-analysis[J].Genet Test Mol Biomarkers,2017,21(5):275-85.
[9]Hayashi H,Tazoe Y,Tsuboi S et al.A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis[J].Drug Metab Pharmacokinet,2013,28(2):164-8.
[10]Kravljaca M,Perovic V,Pravica V,et al.The importance of MDR1 gene polymorphisms for tacrolimus dosage[J].Eur J Pharm Sci,2016,83:109-13.
[11]Jekic B,Lukovic L,Bunjevacki V,et al.Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients[J].Eur J Clin Pharmacol,2013,69(3):377-83.
[12]Wiese M D,Alotaibi N,O'Doherty C,et al.Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis[J].Pharmacogenomics J,2014,14(4):350-5.
[13]Kuhn U D,Anschutz M,Schmucker K,et al.Phenotyping with sulfasalazine-time dependence and relation to NAT2 pharmacogenetics[J].Int J Clin Pharmacol Ther,2010,48(1):1-10.
[14]Soukup T,Dosedel M,Nekvindova J,et al.Genetic polymorphisms in metabolic pathways of leflunomide in the treatment of rheumatoid arthritis[J].Clin Exp Rheumatol,2015,33(3):426-32.
[15]Colleoni L,Kapetis D,Maggi L,et al.A new thiopurine s-methyltransferase haplotype associated with intolerance to azathioprine[J].J Clin Pharmacol,2013,53(1):67-74.
[16]Seinen M L,van Bodegraven A A,van Kuilenburg A B,et al.High TPMT activity as a risk factor for severe myelosuppression during thiopurine therapy[J].Neth J Med,2013,71(4):222.
[17]O'Doherty C,Schnabl M,Spargo L,et al.Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis[J].Pharmacogenomics,2012,13(12):1427-34.
[18]Bohanec G P,Rozman B,Tomsic M,et al.Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients[J].Eur J Clin Pharmacol,2008,64(9):871-6.
[19]Sevilla-Mantilla C,Ortega L,Agúndez J A,et al.Leflunomide-induced acute hepatitis[J].Dig Liver Dis,2004,36(1):82-4.
[20]Garcia DLPM,Mendez C R,Garrido G E,et al.Polymorphism rs2275913 of interleukin-17A is related to more intensive therapy with disease-modifying anti rheumatic drugs in Mexican patients with rheumatoid arthritis[J].Acta Reumatol Port,2017,42(2):155-61.
[21]Ruiz-Padilla A J,Gamez-Nava J I,Saldana-Cruz A M,et al.The-174G/C interleukin-6 gene promoter polymorphism as a genetic marker of differences in therapeutic response to methotrexate and leflunomide in rheumatoid arthritis[J].Biomed Res Int,2016,2016:4193538.
[22]Krasniqi V,Dimovski A,Domjanovic I K,et al.How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity[J].Arh Hig Rada Toksikol,2016,67(1):1-8.
[23]Lee H I,Bae J W,Choi C I,et al.Strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals[J].Pharmacogenet Genomics,2014,24(2):113-7.
[24]Kim S H,Kim D H,Byeon J Y,et al.Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite[J].Arch Pharm res,2017,40(3):382-90.
[25]Fisher M D,Watson C,Fox K M,et al.Dosing patterns of three tumor necrosis factor-blockers among patients with rheumatoid arthritis in a large United States managed care population[J].Curr Med Res Opin,2013,29(5):561-8.
[26]Lee Y H,Bae S C.Associations between PTPRC rs10919563 A/G and FCGR2A R131H polymorphisms and responsiveness to TNF blockers in rheumatoid arthritis:a meta-analysis[J].Rheumatol Int,2016,36(6):837-44.
[27]Tsukamoto M,Kameda H,Ohshige T,et al.Fcgamma receptor3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis[J].Mod Rheumatol,2017,27(5):778-81.
[28]Jancic I,Arsenovic-Ranin N,Sefik-Bukilica M,et al.-174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis[J].Rheumatol Int,2013,33(6):1481-6.
[29]Ruyssen-Witrand A,Rouanet S,Combe B,et al.Association between-871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients[J].Rheumatology(Oxford),2013,52(4):636-41.
[30]Ruyssenwitrand A,Rouanet S,Combe B,et al.Fcγreceptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab[J].Ann Rheum Dis,2012,71(6):875.