Pharmacogenetics of Methotrexate Therapy in Arthritis

描述(申请人提供)：炎症性疾病，包括关节炎，通常与预期寿命缩短有关，部分原因是心血管疾病死亡人数过多。小剂量甲氨蝶呤(MTX)治疗是长期治疗关节炎的主要手段。接受MTX治疗的患有心血管疾病的关节炎患者的心血管死亡率比使用替代疾病修饰抗类风湿药物(DMARDS)治疗的同龄人更高。此外，MTX的临床疗效存在相当大的个体差异，约30%的患者经历了不可接受的毒性。目的确定那些MTX治疗有效且毒性最小，且不会显著增加心血管疾病风险的患者，这将对关节炎和其他炎症性疾病的临床治疗做出重大贡献。 MTX抑制二氢叶酸还原酶，二氢叶酸还原酶是一种参与嘌呤合成的酶，也是更广泛的叶酸/同型半胱氨酸代谢轴的组成部分。亚甲基四氢叶酸还原酶(MTHFR)在控制叶酸衍生物在细胞甲基化反应和核酸合成两条主要组成途径之间的分布中起着关键作用。此外，蛋氨酸合成酶(MTR)、胱硫氨酸β-合成酶(CBS)和蛋氨酸合成酶还原酶(MTRR)也参与控制Hcy浓度的反应。MTHFR、MTR、CBS和MTRR的功能多态性显著改变了细胞内叶酸衍生物水平和/或循环Hcy水平，从而增加了Hcy相关疾病的风险。这些基因多态，单独或结合在一起，可能使叶酸/同型半胱氨酸代谢轴通过采用极端致病表型来对MTX做出反应，也可能是与药物相关的疗效和毒性的重要决定因素。我们将在对300名即将开始MTX治疗的关节炎患者的药物遗传学分析中获得上述信息。治疗前和治疗中的叶酸衍生物、维生素B和同型半胱氨酸浓度将与MTHFR、MTR、CBS和MTR型一起测定，以确定是否有特定的表型和/或基因变量可用于预测MTX的疗效和毒性，以及MTX介导的Hcy相关疾病风险增加的可能性。 这项研究可能会建立强制使用MTX或替代DMARD治疗关节炎患者的遗传参数。它具有促进个体化治疗方案的潜力，这些方案经验性较少，因此更有效，并可减少心血管并发症的发生率。

DESCRIPTION (provided by applicant): Inflammatory diseases, including arthritis, are often associated with reduced life expectancy, due in part to an excess of cardiovascular disease deaths. Low dose methotrexate (MTX) therapy is a mainstay for the long-term management of arthritis. Arthritis patients with cardiovascular disease who are treated with MTX have higher cardiovascular mortality rates than their peers treated with alternative disease-modifying anti-rheumatoid drugs (DMARDs). In addition, there is considerable inter-individual variation in the clinical efficacy of MTX, and about 30% of patents experience unacceptable toxicity. Objective methods to identify those for whom MTX therapy will be effective and minimally toxic, without greatly enhancing cardiovascular disease risk, would therefore contribute significantly to the clinical management of arthritis and other inflammatory conditions. MTX inhibits dihydrofolate reductase, an enzyme involved in purine synthesis and a component of the broader folate/Hcy metabolic axis. Methylenetetrahydrofolate reductase (MTHFR) is pivotal in controlling the distribution of folate derivatives between the two main constituent pathways that serve cellular methylation reactions and nucleic acid synthesis. In addition, methionine synthase (MTR), cystathionine Beta-synthase (CBS), and methionine synthase reductase (MTRR) are involved in reactions that control Hcy concentrations. Functional polymorphisms of MTHFR, MTR, CBS and MTRR significantly modify intracellular levels of folate derivatives and/or circulating Hcy levels, thereby increasing the risk of Hcy-associated pathologies. These polymorphisms, alone or in combination, may "prime" the folate/Hcy metabolic axis to respond to MTX by adopting an extreme pathogenic phenotype, and may also be significant determinants of the efficacy and toxicity associated with the drug. We will access the above in a pharmacogenetic analysis of 300 arthritis patients who are about to embark on MTX therapy. Pre-treatment and in-treatment folate derivative, B vitamin and Hcy concentrations will be determined together with MTHFR, MTR, CBS, and MTRR genotypes to establish whether there are particular phenotypic and/or genotypic variables that can be used to predict MTX efficacy and toxicity, and the likelihood of MTX-mediated enhancement of Hcy-associated disease risk. This research may establish the genetic parameters that mandate the treatment of arthritic patients with either MTX or an alternative DMARD. It has the potential to facilitate individualized treatment protocols that are less empirical and therefore more effective, and to reduce the incidence of cardiovascular co-morbidity.