Inflammatory diseases, including arthritis, are often associated with reduced life expectancy, due in part to an excess of cardiovascular disease deaths. Low dose methotrexate (MTX) therapy is a mainstay for the long-term management of arthritis. Arthritis patients with cardiovascular disease who are treated with MTX have higher cardiovascular mortality rates than their peers treated with alternative disease-modifying anti-rheumatoid drugs (DMARDs). In addition, there is considerable inter-individual variation in the clinical efficacy of MTX, and about 30% of patents experience unacceptable toxicity. Objective methods to identify those for whom MTX therapy will be effective and minimally toxic, without greatly enhancing cardiovascular disease risk, would therefore contribute significantly to the clinical management of arthritis and other inflammatory conditions. ? ? MTX inhibits dihydrofolate reductase, an enzyme involved in purine synthesis and a component of the broader folate/Hcy metabolic axis. Methylenetetrahydrofolate reductase (MTHFR) is pivotal in controlling the distribution of folate derivatives between the two main constituent pathways that serve cellular methylation reactions and nucleic acid synthesis. In addition, methionine synthase (MTR), cystathionine Beta-synthase (CBS), and methionine synthase reductase (MTRR) are involved in reactions that control Hcy concentrations. Functional polymorphisms of MTHFR, MTR, CBS and MTRR significantly modify intracellular levels of folate derivatives and/or circulating Hcy levels, thereby increasing the risk of Hcy-associated pathologies. These polymorphisms, alone or in combination, may """"""""prime"""""""" the folate/Hcy metabolic axis to respond to MTX by adopting an extreme pathogenic phenotype, and may also be significant determinants of the efficacy and toxicity associated with the drug. We will access the above in a pharmacogenetic analysis of 300 arthritis patients who are about to embark on MTX therapy. Pre-treatment and in-treatment folate derivative, B vitamin and Hcy concentrations will be determined together with MTHFR, MTR, CBS, and MTRR genotypes to establish whether there are particular phenotypic and/or genotypic variables that can be used to predict MTX efficacy and toxicity, and the likelihood of MTX-mediated enhancement of Hcy-associated disease risk. ? ? This research may establish the genetic parameters that mandate the treatment of arthritic patients with either MTX or an alternative DMARD. It has the potential to facilitate individualized treatment protocols that are less empirical and therefore more effective, and to reduce the incidence of cardiovascular co-morbidity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047663-04
Application #
6944907
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Serrate-Sztein, Susana
Project Start
2002-09-15
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
4
Fiscal Year
2005
Total Cost
$592,603
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Summers, Carolyn M; Hammons, Andrea L; Arora, Jasbir et al. (2014) Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol 732:60-7
Summers, Carolyn M; Mitchell, Laura E; Stanislawska-Sachadyn, Anna et al. (2010) Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women. Birth Defects Res A Clin Mol Teratol 88:679-88
Stanislawska-Sachadyn, A; Woodside, J V; Sayers, C M et al. (2010) The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status. Eur J Clin Nutr 64:1338-43
Hammons, Andrea L; Summers, Carolyn M; Woodside, Jayne V et al. (2009) Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1. Clin Immunol 133:132-7
Stanis?awska-Sachadyn, Anna; Mitchell, Laura E; Woodside, Jayne V et al. (2009) The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women. Ann Hum Genet 73:484-91
Mitchell, Laura E; Morales, Megan; Khartulyari, Stefanie et al. (2009) Folate and homocysteine phenotypes: Comparative findings using research and clinical laboratory data. Clin Biochem 42:1275-81
Lu, Zhi-Yong; Jensen, Liselotte E; Huang, Yuehua et al. (2009) The up-regulation of monocyte chemoattractant protein-1 (MCP-1) in Ea.hy 926 endothelial cells under long-term low folate stress is mediated by the p38 MAPK pathway. Atherosclerosis 205:48-54
Lu, Zhi-Yong; Morales, Megan; Khartulyari, Stephanie et al. (2008) Genetic and biochemical determinants of serum concentrations of monocyte chemoattractant protein-1, a potential neural tube defect risk factor. Birth Defects Res A Clin Mol Teratol 82:736-41
Summers, Carolyn M; Cucchiara, Andrew J; Nackos, Eleni et al. (2008) Functional polymorphisms of folate-metabolizing enzymes in relation to homocysteine concentrations in systemic lupus erythematosus. J Rheumatol 35:2179-86
Summers, Carolyn M; Hammons, Andrea L; Mitchell, Laura E et al. (2008) Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations. Eur J Hum Genet 16:1010-3

Showing the most recent 10 out of 22 publications