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: 7475994
• 负责人: Donna K Arnett
• 金额: $ 25.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475994
• 关键词: Address; Adenosine; Adult; Adverse effects; Affect; Anti-Inflammatory Agents; Anti-citrullinated peptide antibody; Anti-inflammatory; Arts; Autoantibodies; Biological Assay; Biological Markers; C-reactive protein; Candidate Disease Gene; Cartilage; Chronic Disease; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Collection; Condition; Count; DNA; Data; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Dose; Early treatment; Enrollment; Ensure; Enzymes; Erythrocytes; Folate; Funding; Genes; Genetic; Genetic Epistasis; 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; Numbers; Outcome; Outcome Measure; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phase; Phenotype; Population; Principal Investigator; Progressive Disease; Recording of previous events; Reporting; Research Infrastructure; Research Personnel; Rheumatoid Arthritis; Role; Score; Serum; Severity of illness; Standards of Weights and Measures; Structure; Swelling; Testing; Thymidylate Synthase; Toxic effect; Treatment Protocols; United States National Institutes of Health; Universities; Variant; Visual; Visual Analogue Pain Scale; Week; base; blood treatment; cohort; design; disorder control; dosage; experience; follow-up; gastrointestinal; gene interaction; genetic variant; improved; indexing; member; mortality; multidisciplinary; polyglutamate; polyglutamates; programs; purine metabolism; response; 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%.

类风湿性关节炎(RA)是一种慢性疾病，影响着1%的美国成年人。由于发病率高， RA病死率高，识别有效的治疗方法具有重要意义。甲氨蝶呤被认为是 类风湿关节炎的黄金标准治疗；然而，对MTX的反应在人与人之间有很大的差异，例如 它对30%-40%的接受治疗的人无效。虽然没有进行广泛的研究，但早期的报告 证明遗传变异导致MTX的疗效和毒性不一致。我们建议使用 确定甲氨蝶呤疗效和毒性基因座的综合候选基因方法 用于治疗类风湿性关节炎。我们将建立一个多学科调查团队的专业知识，在一个大的 临床试验，治疗早期侵袭性类风湿关节炎(TREE)，研究MTX在类风湿关节炎中的药物遗传学。撕裂 是一项由研究人员发起的第四阶段试验，招募了750名未接受治疗的RA患者。所有患者都将接受治疗 在进入研究的12周内，MTX的剂量上升到20毫克/周。对于这项提案，我们将重点关注 试验的前24周，因为那些对MTX疗效或毒性有遗传易感性的人很可能 早期表达这些与治疗相关的表型。95%的注册受试者已经隔离了DMA；我们 将对641名受试者进行评估。为了实现我们的第一个目标，我们将描述基因之间的联系 使用以下步骤进行变异和MTX的有效性和毒性：(1)选择所有单倍型标记并对其进行分型 26例候选甲氨蝶呤疗效或毒性相关的单核苷酸多态或基因变异 调节转运蛋白、谷氨酸酶、叶酸和嘌呤代谢的基因。(2)单项分析 变异和单倍型，以评估遗传变异和(A)疗效之间的关联(通过 根据压痛关节的数量计算的临床指数的纵向变化，CRP 浓度，以及患者对10厘米视觉范围内疾病的评估，在基线和 12周间隔)；(B)MTX聚谷氨酸浓度(其增强了MTX在细胞内的保留 并导致抗增殖作用和抗炎物质的释放)，以及(C)毒性 (前24周的胃肠道、皮肤粘膜、造血或肾脏不良反应)。我们会 使用线性回归模型评估遗传变异的主效应以及基因与基因的交互作用 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 被祖先的历史搞混了。为了实现我们的第二个目标，我们将评估非基因的作用 影响已识别基因变异影响的因素(基线CRP、RF和抗CCP抗体状态) 在目标1中，我们预计MTX疗效和毒性的遗传预测因子的特征将会改善 我们能够针对60%-70%对MTX有反应的患者进行个性化治疗，并减少试验 对100%的RA患者使用危害至少10%的药物治疗的错误做法。