Genetic and Molecular Markers of Methotrexate Efficacy and Toxicity in Early...

早期甲氨蝶呤功效和毒性的遗传和分子标记...

• 批准号: 8304146
• 负责人: Donna K Arnett
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304146
• 关键词: Address; Adenosine; Adult; Adverse effects; Affect; Anti-Inflammatory Agents; Anti-citrullinated peptide antibody; Anti-inflammatory; Autoantibodies; Biological Assay; C-reactive protein; Candidate Disease Gene; Cartilage; Chronic Disease; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Collaborations; Collection; DNA; Data; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Dose; Early treatment; Enrollment; Ensure; Enzymes; Erythrocytes; Funding; Genes; Genetic; Genetic Epistasis; Genetic Markers; Genetic Variation; Genotype; Glutamic Acid; Gold; Grant; Haplotypes; Hematopoietic; High Pressure Liquid Chromatography; Individual; Joints; Kidney; Laboratories; Life; Linear Regressions; Measurement; Measures; Mediating; Mediation; Methodology; Methods; Methotrexate; Methylenetetrahydrofolate reductase (NADPH); Modeling; Molecular; Morbidity - disease rate; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Outcome; Outcome Measure; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phase; Phenotype; Population; Principal Investigator; Progressive Disease; Recording of previous events; Regimen; Reporting; Research Infrastructure; Research Personnel; Rheumatoid Arthritis; Role; Serum; Severity of illness; Structure; Swelling; Testing; Thymidylate Synthase; Toxic effect; United States National Institutes of Health; Universities; Variant; Visual; analog; base; blood treatment; cohort; design; disorder control; dosage; effective therapy; efficacy testing; experience; folic acid metabolism; follow-up; gastrointestinal; gene interaction; genetic variant; improved; indexing; member; molecular marker; mortality; multidisciplinary; non-genetic; polyglutamate; polyglutamates; programs; purine metabolism; response; standard care; treatment duration; treatment trial; week trial

Rheumatoid arthritis (RA) is a chronic disease affecting 1% of US adults. Because of high morbidity and mortality of RA, identification of effective treatment is of great importance. Methotrexate is considered the gold-standard treatment for RA; however, there is large between-person variation in response to MTX, such that it is ineffective in 30-40% of treated individuals. Although not extensively studied, early reports demonstrate that genetic variation contributes to inconsistent MTX efficacy and toxicity. We propose to use a comprehensive candidate gene approach to characterize loci that determine efficacy and toxicity of MTX used to treat RA. We will build on the expertise of a multidisciplinary team of investigators within a large clinical trial, Treatment of Early Aggressive RA (TEAR), to study the pharmacogenetics of MTX in RA. TEAR is a Phase IV, investigator-initiated trial enrolling 750 treatment-naive RA patients. All patients will be treated with MTX with doses uptitrated to 20 mg/wk within 12 wks of study entry. For this proposal, we will focus on the first 24 wk of the trial since those who are genetically susceptible to MTX efficacy or toxicity will likely express these treatment-related phenotypes early. DMA has been isolated for 95% of enrolled subjects; we will evaluate 641 subjects. To accomplish our first aim we will characterize the association between genetic variation and MTX efficacy and toxicity using the following steps: (1) Select and genotype all haplotypetagging SNPs or genetic variants reported to be related to the efficacy or toxicity of MTX in 26 candidate genes regulating transporters, glutamination enzymes, and folate and purine metabolism. (2) Analyze single variants and haplotypes to assess associations between genetic variation and (a) efficacy (via the longitudinal change in a clinical index calculated as a function of the number of tender joints, CRP concentration, and patients' assessment of disease along a 10 cm visual scale, measured at baseline and 12-wk intervals); (b) MTX polyglutamate concentrations (which enhances intracellular retention of MTX and causes an anti-proliferative effect and the release of the anti-inflammatory, adenosine), and (c) toxicity (gastrointestinal, mucocutaneous, hematopoietic, or renal adverse effects during the first 24 wks). We will use linear regression models to evaluate main effects of genetic variants as well as gene-gene interaction and to control for confounding by other drugs. We will use structured association testing to control for confounding by ancestral history. To accomplish our second aim, we will evaluate the role of non-genetic factors (baseline CRP, RF, and anti-CCP antibody status) that mediate effects of genetic variants identified in Aim 1. We anticipate that characterization of genetic predictors of efficacy and toxicity of MTX will improve our ability to personalize treatment by targeting the 60-70% who are MTX responsive and reducing the trial and error approach of treating 100% of RA patients with a drug that is harmful to at least 10%.

风湿性关节炎（RA）是一种慢性疾病，影响1%的美国成年人。由于发病率高， RA的死亡率，确定有效的治疗是非常重要的。甲氨蝶呤被认为是 RA的金标准治疗;然而，对MTX的反应存在很大的人与人之间的差异， 它在30-40%的治疗个体中无效。虽然没有被广泛研究，但早期的报告 表明遗传变异导致MTX疗效和毒性不一致。我们建议使用 综合候选基因方法表征决定MTX疗效和毒性的基因座 用于治疗RA。我们将在一个大的调查范围内建立一个多学科调查小组的专业知识。 临床试验，早期侵袭性RA（TEAR）的治疗，以研究MTX在RA中的药物遗传学。撕裂 是一项IV期、促发剂启动的试验，招募了750名未经治疗的RA患者。所有患者都将接受治疗 MTX剂量在研究开始后12周内上调至20 mg/wk。对于这一建议，我们将重点放在 试验的前24周，因为那些遗传上对MTX疗效或毒性敏感的人可能 早期表达这些治疗相关的表型。95%的入组受试者已分离出DMA;我们 将评估641名受试者。为了实现我们的第一个目标，我们将描述基因之间的关联， 变异和MTX疗效和毒性使用以下步骤：（1）选择和基因型所有单倍型标记 据报道，26名候选人的SNP或遗传变异与MTX的疗效或毒性相关 调节转运蛋白、谷氨酰胺化酶、叶酸和嘌呤代谢的基因。(2)分析单个 变异和单倍型，以评估遗传变异与（a）疗效之间的关联（通过 根据压痛关节数计算的临床指数的纵向变化，CRP 浓度，以及患者对疾病的沿着10 cm视觉量表评估，在基线和 12周间隔）;（B）MTX聚谷氨酸浓度（其增强MTX的细胞内滞留 并引起抗增殖作用和抗炎剂腺苷的释放），和（c）毒性 （前24周期间的胃肠道、粘膜皮肤、造血或肾脏不良反应）。我们将 使用线性回归模型评估遗传变异的主要影响以及基因-基因相互作用 并控制其他药物的混杂。我们将使用结构化关联测试来控制 被祖先的历史所迷惑为了实现我们的第二个目标，我们将评估非遗传因素的作用。 介导确定的遗传变异影响的因素（基线CRP、RF和抗CCP抗体状态） 目标1。我们预计，MTX疗效和毒性的遗传预测因子的特征将得到改善 我们有能力通过针对60-70%的MTX应答者进行个性化治疗， 和错误的方法治疗100%的RA患者的药物是有害的至少10%。