人类DHODH 19C>A基因多态性对来氟米特治疗类风湿关节炎临床疗效影响
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摘要
目的来氟米特(LEF)是一种改善病情的抗风湿药物(DMARDs)。其代谢产物A771726具有抑制二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)的作用,本研究目的是观察DHODH(rs3213422)19C>A基因多态性对LEF治疗类风湿关节炎(RA)疗效的影响。方法本研究包括105例RA患者,口服来氟米特20mg/d治疗。3个月及6个月后,评价患者是否达到ACR20及ACR50缓解标准。并行DHODH(rs3213422)19C>A基因多态性检测,观察不同基因类型患者病情改善情况。结果 LEF治疗RA,3个月时ACR20总体缓解率:C等位基因为70.0%,A等位基因为51.7%,两者比较差异有统计学意义(P=0.012);ACR50总体缓解率:C等位基因为38.0%,A等位基因为28.3%,两者比较差异无统计学意义(P=0.185)。治疗6个月时,ACR20总体缓解率:C等位基因为84.7%,A等位基因为61.7%。两者比较差异有统计学意义(P=0.006);ACR50总体缓解率:C等位基因为60.7%,A等位基因率为38.3%,两者比较差异有统计学意义(P=0.039)。结论 LEF治疗RA患者ACR20及ACR50缓解率,随治疗时间的延长而增加。DHODH(19C>A)的基因多态性与LEF治疗RA的临床疗效有一定相关性。携带C等位基因的患者应用LEF治疗的效果优于携带A等位基因的患者,两者之间的差异随治疗时间的延长逐渐增加。
Objective Purpose leflunomide( LEF) is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis( RA). It is a prodrug that is rapidly converted in vivo to the active metabolite A77 1726. The mechanism of action of A77 1726 primarily involves inhibition of the enzyme DHODH. Related studies have found that DHOD gene has polymorphism. The aim of this study was to investigate whether genetic polymorphisms in DHODH( 19 C > A) influence leflunomide pharmacokinetics and treatment response.Methods We studied 105 patients diagnosed with RA and treated with LEF( 20 mg daily). Follow-up was 6 months. Clinical improvement was valuated according to the American College of Rheumatology 20% and 50% response criteria. The peripheral blood genomic DNA was extracted,and amplified by PCR,analyzed by direct sequencing. The gene detection was performed in our hospital 105 patients with DHODH polymorphism( 19 C > A). Results After 3 months of therapy,the ACR20 criteria was met by 70. 0% in C allele,51. 7%in A allele. Differences were statistically significant( P = 0. 012). The ACR50 criteria was met by 38. 0% in C allele,28. 3% in A allele.It did not reach statistically significant( P = 0. 185). After 6 months of therapy,the ACR20 criteria was met by 84. 7% in C allele,61. 7%in A allele. Differences were statistically significant( P = 0. 006). The ACR50 criteria was met by 60. 7% in C allele,38. 3% in A allele.Differences were statistically significant( P = 0. 039). Conclusion The remission rate of ACR20 and ACR50 in patients with rheumatoid arthritis was increased with the treatment time. The results of the study suggest that DHODH( 19 C > A) polymorphism may be associated with LEF treatment outcome in RA patients. Treatment response is better in the patients with the C allele than A allele. This trend is more obvious with the extension of time.
Objective Purpose leflunomide( LEF) is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis( RA). It is a prodrug that is rapidly converted in vivo to the active metabolite A77 1726. The mechanism of action of A77 1726 primarily involves inhibition of the enzyme DHODH. Related studies have found that DHOD gene has polymorphism. The aim of this study was to investigate whether genetic polymorphisms in DHODH( 19 C > A) influence leflunomide pharmacokinetics and treatment response.Methods We studied 105 patients diagnosed with RA and treated with LEF( 20 mg daily). Follow-up was 6 months. Clinical improvement was valuated according to the American College of Rheumatology 20% and 50% response criteria. The peripheral blood genomic DNA was extracted,and amplified by PCR,analyzed by direct sequencing. The gene detection was performed in our hospital 105 patients with DHODH polymorphism( 19 C > A). Results After 3 months of therapy,the ACR20 criteria was met by 70. 0% in C allele,51. 7%in A allele. Differences were statistically significant( P = 0. 012). The ACR50 criteria was met by 38. 0% in C allele,28. 3% in A allele.It did not reach statistically significant( P = 0. 185). After 6 months of therapy,the ACR20 criteria was met by 84. 7% in C allele,61. 7%in A allele. Differences were statistically significant( P = 0. 006). The ACR50 criteria was met by 60. 7% in C allele,38. 3% in A allele.Differences were statistically significant( P = 0. 039). Conclusion The remission rate of ACR20 and ACR50 in patients with rheumatoid arthritis was increased with the treatment time. The results of the study suggest that DHODH( 19 C > A) polymorphism may be associated with LEF treatment outcome in RA patients. Treatment response is better in the patients with the C allele than A allele. This trend is more obvious with the extension of time.
引文
1蒋明,Yu D,林孝义,等.中华风湿病学[M].北京:华夏出版社,2004:1714-1715
2 Proudman SM,Keen HI,Stamp LK,et al.Response-driven combination therapy with conventional disease-modifying antirheumatic drugs can achieve high response rates in early rheumatoid arthritis with minimal glucocorticoid and nonsteroidal anti-inflammatory drug use[J].Seminars Arthritis Rheum,2007,37(2):99-111
3 赵可新,石蕊,李岑,等,药物基因组学对个体化药物治疗的影响[J].中国医师2016,6(19):1162-1166
4 Ritchie MD,Motsinger AA.Multifactor dimensionality reduction for detecting gene-gene and gene-environment interactions in pharmacogenomics studies[J].Pharmacogenomics,2015,6(8):823-834
5 March IL.Pharmacogenetics:the genomics of drug response[J].Yeast,2000,17(1):16-21
6 Rahman P.Pharmacogenetics of rheumatoid arthritis:potential targets from susceptibility genes and present therapies.[J]Pharmacogenomics and Personalized Medicine,2010,3:15-31
7 陈雁飞,吴吉荣.药物基因组学在自身免疫性疾病治疗中的研究进展[J].临床荟萃,2017,32(4):357-359
8 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):1427-1434
9 Wiese MD,Schnabl M,O'Doherty C,et al.Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis.[J].Arthritis Res Therapy,2012,14(4):R163
10 Vega D,Petragalli A,Fernández D,et al.Polymorphism on leflunomide:stability and crystal structures[J].J Pharmaceut Sci,2006,95(5):1075-1083
11 Dziedziejko V,Kurzawski M,Safranow K,et al.The effect of ESR1and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide.[J].Pharmacogenomics,2011,12(1):41-47
12 Pawlik A,Herczynska M,Kurzawski M,et al.The effect of exon(19C>A)dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide.[J].Pharmacogenomics,2009,10(2):303
13 Hopkins AM,O'Doherty CE,Foster DJ,et al.The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity[J].Journal of Clinical Pharmacy&Therapeutics,2014,39(5):555
14 Listed N.Leflunomide for rheumatoid arthritis.[J].Drug Therapeuti Bulletin,2000,38(7):52-54
15 Lolli ML,Giorgis M,Tosco P,et al.New inhibitors of dihydroorotate dehydrogenase(DHODH)based on the 4-hydroxy-1,2,5-oxadiazol-3-yl(hydroxyfurazanyl)scaffold[J].Eur Journal of Medicinal Chemistry,2012,49(1):102-109
16 Baumann P,Mandlweber S,V9lkl A,et al.A771726,leflunomide,apoptosis,myeloma[J].Mol Cancer Therapeut,2004,23(8):307-310
17 Munier-Lehmann H,Vidalain PO,Tangy F,et al.On dihydroorotate dehydrogenases and their inhibitors and uses.[J].J Med Chem,2013,56(8):3148-3167
18 Davis JP,Cain GA,Pitts WJ,Magolda RL,et al.The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase[J]Biochemistry,1996,35(4),1270-1273
19 Barnes T,Parry P,Hart I,et al.Regional mapping of the gene encoding dihydroorotate dehydrogenase,an enzyme involved in UMP synthesis,electron transport,and superoxide generation,to human chromosome region 16q22.[J].Somatic Cell Mol Genet,1993,19(4):405-411
2 Proudman SM,Keen HI,Stamp LK,et al.Response-driven combination therapy with conventional disease-modifying antirheumatic drugs can achieve high response rates in early rheumatoid arthritis with minimal glucocorticoid and nonsteroidal anti-inflammatory drug use[J].Seminars Arthritis Rheum,2007,37(2):99-111
3 赵可新,石蕊,李岑,等,药物基因组学对个体化药物治疗的影响[J].中国医师2016,6(19):1162-1166
4 Ritchie MD,Motsinger AA.Multifactor dimensionality reduction for detecting gene-gene and gene-environment interactions in pharmacogenomics studies[J].Pharmacogenomics,2015,6(8):823-834
5 March IL.Pharmacogenetics:the genomics of drug response[J].Yeast,2000,17(1):16-21
6 Rahman P.Pharmacogenetics of rheumatoid arthritis:potential targets from susceptibility genes and present therapies.[J]Pharmacogenomics and Personalized Medicine,2010,3:15-31
7 陈雁飞,吴吉荣.药物基因组学在自身免疫性疾病治疗中的研究进展[J].临床荟萃,2017,32(4):357-359
8 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):1427-1434
9 Wiese MD,Schnabl M,O'Doherty C,et al.Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis.[J].Arthritis Res Therapy,2012,14(4):R163
10 Vega D,Petragalli A,Fernández D,et al.Polymorphism on leflunomide:stability and crystal structures[J].J Pharmaceut Sci,2006,95(5):1075-1083
11 Dziedziejko V,Kurzawski M,Safranow K,et al.The effect of ESR1and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide.[J].Pharmacogenomics,2011,12(1):41-47
12 Pawlik A,Herczynska M,Kurzawski M,et al.The effect of exon(19C>A)dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide.[J].Pharmacogenomics,2009,10(2):303
13 Hopkins AM,O'Doherty CE,Foster DJ,et al.The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity[J].Journal of Clinical Pharmacy&Therapeutics,2014,39(5):555
14 Listed N.Leflunomide for rheumatoid arthritis.[J].Drug Therapeuti Bulletin,2000,38(7):52-54
15 Lolli ML,Giorgis M,Tosco P,et al.New inhibitors of dihydroorotate dehydrogenase(DHODH)based on the 4-hydroxy-1,2,5-oxadiazol-3-yl(hydroxyfurazanyl)scaffold[J].Eur Journal of Medicinal Chemistry,2012,49(1):102-109
16 Baumann P,Mandlweber S,V9lkl A,et al.A771726,leflunomide,apoptosis,myeloma[J].Mol Cancer Therapeut,2004,23(8):307-310
17 Munier-Lehmann H,Vidalain PO,Tangy F,et al.On dihydroorotate dehydrogenases and their inhibitors and uses.[J].J Med Chem,2013,56(8):3148-3167
18 Davis JP,Cain GA,Pitts WJ,Magolda RL,et al.The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase[J]Biochemistry,1996,35(4),1270-1273
19 Barnes T,Parry P,Hart I,et al.Regional mapping of the gene encoding dihydroorotate dehydrogenase,an enzyme involved in UMP synthesis,electron transport,and superoxide generation,to human chromosome region 16q22.[J].Somatic Cell Mol Genet,1993,19(4):405-411