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%.

类风湿关节炎（RA）是一种影响美国成年人1％的慢性疾病。由于发病率高和 RA的死亡率，有效治疗的识别非常重要。甲氨蝶呤被认为 RA的金标准治疗；但是，对MTX的响应有很大的人之间的差异 在30-40％的治疗个体中，它无效。尽管没有进行广泛的研究，但早期报告 证明遗传变异导致MTX功效和毒性不一致。我们建议使用 全面的候选基因方法来表征确定MTX功效和毒性的基因座 用于治疗RA。我们将建立在一个大型调查员团队的专业知识的基础上 临床试验，早期侵略性RA（撕裂）的治疗，以研究RA中MTX的药物遗传学。撕 是IV期，研究人员发起的试验，招募了750名不接受治疗的RA患者。所有患者将接受治疗 MTX的剂量在研究条目的12周内上升至20 mg/wk。对于此建议，我们将重点放在 试验的前24周，因为那些在遗传上容易受到MTX疗效或毒性的人可能会 尽早表达这些与治疗相关的表型。已将DMA分离为95％的入学受试者；我们 将评估641名受试者。为了实现我们的第一个目标，我们将表征遗传之间的关联 使用以下步骤使用以下步骤的变异和MTX功效和毒性：（1）选择和基因型所有单倍型电视 据报道，SNP或遗传变异与26个候选者中MTX的功效或毒性有关 调节转运蛋白，谷化酶以及叶酸和嘌呤代谢的基因。 （2）分析单个 评估遗传变异与（a）功效之间关联的变体和单倍型（通过 临床指数的纵向变化是根据招标关节数量计算的CRP数量的函数 浓度以及患者沿10 cm的视觉量表对疾病的评估，在基线和 12周间隔）； （b）MTX聚谷氨酸浓度（这增强了MTX的细胞内保留率 并引起抗增殖作用以及抗炎，腺苷的释放）和（c）毒性 （在前24周期间，胃肠道，粘膜状，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 - 基因的相互作用 并控制其他药物混淆。我们将使用结构化关联测试来控制 祖先的历史混淆。为了实现我们的第二个目标，我们将评估非遗传的作用 因素（基线CRP，RF和抗CCP抗体状态），介导鉴定的遗传变异的影响 在AIM 1中。我们预计MTX功效和毒性的遗传预测因子的表征将改善 我们通过以60-70％的响应和减少试验的60-70％的目标来个性化治疗的能力 以及治疗100％的RA患者有害至少10％的药物的错误方法。