Rheumatoid arthritis (RA) is a chronic disease affecting 1% of US adults. Because of high morbidity andmortality of RA, identification of effective treatment is of great importance. Methotrexate is considered thegold-standard treatment for RA; however, there is large between-person variation in response to MTX, suchthat it is ineffective in 30-40% of treated individuals. Although not extensively studied, early reportsdemonstrate that genetic variation contributes to inconsistent MTX efficacy and toxicity. We propose to use acomprehensive candidate gene approach to characterize loci that determine efficacy and toxicity of MTXused to treat RA. We will build on the expertise of a multidisciplinary team of investigators within a largeclinical trial, Treatment of Early Aggressive RA (TEAR), to study the pharmacogenetics of MTX in RA. TEARis a Phase IV, investigator-initiated trial enrolling 750 treatment-naive RA patients. All patients will be treatedwith MTX with doses uptitrated to 20 mg/wk within 12 wks of study entry. For this proposal, we will focus onthe first 24 wk of the trial since those who are genetically susceptible to MTX efficacy or toxicity will likelyexpress these treatment-related phenotypes early. DMA has been isolated for 95% of enrolled subjects; wewill evaluate 641 subjects. To accomplish our first aim we will characterize the association between geneticvariation and MTX efficacy and toxicity using the following steps: (1) Select and genotype all haplotypetaggingSNPs or genetic variants reported to be related to the efficacy or toxicity of MTX in 26 candidategenes regulating transporters, glutamination enzymes, and folate and purine metabolism. (2) Analyze singlevariants and haplotypes to assess associations between genetic variation and (a) efficacy (via thelongitudinal change in a clinical index calculated as a function of the number of tender joints, CRPconcentration, and patients' assessment of disease along a 10 cm visual scale, measured at baseline and12-wk intervals); (b) MTX polyglutamate concentrations (which enhances intracellular retention of MTXand 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 willuse linear regression models to evaluate main effects of genetic variants as well as gene-gene interactionand to control for confounding by other drugs. We will use structured association testing to control forconfounding by ancestral history. To accomplish our second aim, we will evaluate the role of non-geneticfactors (baseline CRP, RF, and anti-CCP antibody status) that mediate effects of genetic variants identifiedin Aim 1. We anticipate that characterization of genetic predictors of efficacy and toxicity of MTX will improveour ability to personalize treatment by targeting the 60-70% who are MTX responsive and reducing the trialand error approach of treating 100% of RA patients with a drug that is harmful to at least 10%.
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