Associate Professor of Medicine
Division of Rheumatology
Dr. Ranganathan acquired impressive research skills in epidemiology and research design, statistical genetics, and pharmacogenetic assays and analyses through mentoring and participation in didactic courses as part of her BIRCWH training. She has become an expert on the effects of pharmacogenetics on the occurrence of adverse events in rheumatoid arthritis and has published numerous papers and book chapters. The ultimate goal of her research in pharmacogenetics is to help individualize treatment for patients with rheumatoid arthritis by defining genetic profiles that would predict therapeutic outcomes and avoid toxicities. She is involved in outcomes research in rheumatoid arthritis as a co-investigator in a large pharmacovigilance effort using the national Veterans Affairs (VA) administrative databases to identify adverse outcomes in veterans with RA treated with disease-modifying agents. This work has the potential to revolutionize the care of women with this disease. She has been successful at obtaining grant support and, in 2011 she was promoted to Associate Professor of Medicine at Washington University.
BIRCWH Scholar from 01/01/2003 until 06/30/2006
Pharmacogenetics Of Methotrexate Toxicity And Efficacy In Rheumatoid Arthritis
Methotrexate (MTX) is one of the most widely used disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). However, factors limiting its use in RA are 1) variability in efficacy in patients with RA and 2) toxicity. The influence of pharmacogenetics on MTX metabolism has not been extensively studied so far. In this proposal, we hypothesize that genetic polymorphisms in specific enzymes involved in MTX metabolism will predict both the efficacy and toxicity of MTX in patients with RA. We will address this hypothesis in a 3 step approach. First, we will determine the frequency of genetic polymorphisms in 5 specific enzymes involved in MTX metabolism in 200 patients with RA and compare this to the frequency in 300 healthy controls. Second, using a case-control approach, we will determine if specific polymorphisms in these enzymes correlate with toxicity from MTX in these 200 patients. Third, in a prospective design, we will determine if genetic polymorphisms in these 5 enzymes are associated with efficacy and/or toxicity of MTX in RA, assessing efficacy using standardized criteria such as the ACR (American College of Rheumatology) 20, 50 and 70 response rates.
Statement Of Hypothesis and Specific Aims:
In this proposal, we hypothesize that genotype analysis of specific enzymes involved in MTX metabolism in patients with RA will identify patients who will respond to MTX or are at risk for toxicity from MTX.
Specific Aim 1- To determine the frequency of genetic polymorphisms in five specific enzymes involved in MTX metabolism in patients with RA.
Specific Aim 2- To correlate the presence of specific polymorphisms in these enzymes with toxicity from MTX in patients with RA.
Aim 2a. Correlate the presence of specific polymorphisms in these enzymes with toxicity retrospectively.
Aim 2b. Correlate the presence of specific polymorphisms in these enzymes with toxicity prospectively.
Specific Aim 3- To correlate the presence of specific polymorphisms in these enzymes with efficacy of MTX in patients with RA.