Contribution of common polymorphisms in reduced folate carrier and γ-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis
Contribution of common polymorphisms in reduced folate carrier and γ-glutamylhydrolase to methotrexate polyglutamate levels in patients with rheumatoid arthritis
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DOI：
10.1097/00008571-200411000-00004
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发表时间：
2004-11-01
期刊：
影响因子：
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通讯作者：
Furst, DE
中科院分区：
文献类型：
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作者：
Dervieux, T;Kremer, J;Furst, DE
我们研究了在每周低剂量甲氨蝶呤（MTX）治疗的类风湿性关节炎患者中，还原叶酸载体（SLC 19 A1 G80 A）和γ-谷氨酰水解酶（GGH-401 C/T）的多态性是否可预测甲氨蝶呤聚谷氨酸（MTX PG）水平。接受MTX治疗的成人患者入组多中心研究。在访视时抽取血液，提取DNA，并通过高效液相色谱-荧光法测量红细胞（RBC）MTXPG水平（高达谷氨酸五阶）。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测SCL 19 A1基因G80 A多态性和GGH基因启动子-401C/T多态性。使用多变量线性和逻辑回归预测长链RBC MTXPG（3-5）。在226例接受MTX（中位数15 mg范围：5-25 mg）的成人患者中，RBC长链MTXPG（3-5）中位数为56 nmol/l（范围< 5-224 nmol/l）。共有35名患者携带SLC 19 A1 80 AA基因型，而36名患者携带GGH-401 TT基因型。MTX每周剂量、年龄、SLC 19 A1 80 AA和GGH-401 TT基因型的存在独立且显著地预测MTXPG（3-5）水平（总体r（2）= 0.38; P < 0.0001）。与GGH-401 CC或CT基因型携带者相比，GGH-401 TT基因型患者MTXPG（3-5）低于组中位数的可能性高4.8倍[比值比（OR）95%置信区间（CO 1.8-13.0; P= 0.002]。相反，与SLC 19 A1 80 GG或80 GA基因型相比，SLC 19 A1 80 AA基因型患者MTXPG（3-5）水平高于组中位数的可能性高3.4倍（OR CI 95% 1.4-8.4; P= 0.007）。这些数据表明，SLC 19 A1和GGH的多态性影响MTX的多聚谷氨酸化。(C)2004年利平科特威廉姆斯威尔金斯。
We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SCL19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG(3-5). In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG(3-5) was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG(3-5) levels (global r(2) = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CO 1.8-13.0; P= 0.002] more likely to have MTXPG(3-5) below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG(3-5) levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR Cl 95% 1.4-8.4; P= 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX. (C) 2004 Lippincott Williams Wilkins.