Pharmacogenetics of Methotrexate Therapy in Arthritis

Summary

Principal Investigator: ALEXANDER WHITEHEAD
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable] 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. [unreadable] [unreadable] 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.
Funding Period: 2002-09-15 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells
    Carolyn M Summers
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
    Eur J Pharmacol 732:60-7. 2014
  2. ncbi The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status
    A Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Eur J Clin Nutr 64:1338-43. 2010
  3. pmc Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women
    Carolyn M Summers
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Birth Defects Res A Clin Mol Teratol 88:679-88. 2010
  4. pmc Genetic and biochemical determinants of serum concentrations of monocyte chemoattractant protein-1, a potential neural tube defect risk factor
    Zhi Yong Lu
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Birth Defects Res A Clin Mol Teratol 82:736-41. 2008
  5. pmc 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
    Zhi Yong Lu
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
    Atherosclerosis 205:48-54. 2009
  6. ncbi Thiol and cardiovascular risk factor status in a male northern Irish population
    Kevin S Edgar
    Centre for Clinical and Population Science, School of Medicine and Dentistry, Queen s University Belfast, Belfast, Nothern Ireland
    Int J Vitam Nutr Res 78:208-16. 2008
  7. pmc Folate and homocysteine phenotypes: Comparative findings using research and clinical laboratory data
    Laura E Mitchell
    Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, USA
    Clin Biochem 42:1275-81. 2009
  8. ncbi Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1
    Andrea L Hammons
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Clin Immunol 133:132-7. 2009
  9. pmc The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women
    Anna Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Ann Hum Genet 73:484-91. 2009
  10. pmc Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study
    A Gibson
    Centre for Clinical and Population Science, Queen s University Belfast, Belfast, UK
    QJM 101:881-7. 2008

Scientific Experts

  • Joan M Von Feldt
  • Alexander S Whitehead
  • Carolyn M Summers
  • Laura E Mitchell
  • Ian A Blair
  • Anna Stanisławska-Sachadyn
  • Yuehua Huang
  • Jayne V Woodside
  • Karen S Brown
  • Ian S Young
  • Zhi Yong Lu
  • Helene McNulty
  • Colin A Boreham
  • John M Scott
  • J J Strain
  • Liam Murray
  • Andrea L Hammons
  • Carmel Kealey
  • Anna Stanislawska-Sachadyn
  • Liselotte E Jensen
  • A Stanisławska-Sachadyn
  • A S Whitehead
  • J V Woodside
  • I S Young
  • Minghua Mei
  • Stefanie Khartulyari
  • Megan Morales
  • Alun Evans
  • A Gibson
  • Kevin S Edgar
  • John W G Yarnell
  • Eleni Nackos
  • Jasbir Arora
  • Jeanine Jochems
  • Suhong Zhang
  • L E Mitchell
  • A E Evans
  • Shirley F Baido
  • J W Yarnell
  • C M Sayers
  • Peter T Buckley
  • Kristen Murphy
  • P C Sharpe
  • A Evans
  • C C Patterson
  • Megan E Morales
  • Andrew J Cucchiara
  • K Fred Gey
  • Kathryn Farelll
  • C Mercer
  • Elisabeth Mohr
  • Michelle C McKinley
  • Kristen M Murphy
  • Christopher Cardwell
  • L A J Kluijtmans
  • M C McKinley
  • Stephanie Khartulyari
  • Paula Skidmore
  • Suneetha Morthala
  • Wenying Jian
  • Joseph McPartlin
  • Ian Young

Detail Information

Publications21

  1. ncbi Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells
    Carolyn M Summers
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
    Eur J Pharmacol 732:60-7. 2014
    ..hy 926 cells such that its therapeutic properties may, at least under some conditions, be accompanied by the induction of a subset of gene products that promote and/or maintain comorbid pathologies. ..
  2. ncbi The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status
    A Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Eur J Clin Nutr 64:1338-43. 2010
    ..This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C>G) polymorphism and both serum vitamin B(12) and total Hcy (tHcy) levels...
  3. pmc Genetic and lifestyle variables associated with homocysteine concentrations and the distribution of folate derivatives in healthy premenopausal women
    Carolyn M Summers
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Birth Defects Res A Clin Mol Teratol 88:679-88. 2010
    ..Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype...
  4. pmc Genetic and biochemical determinants of serum concentrations of monocyte chemoattractant protein-1, a potential neural tube defect risk factor
    Zhi Yong Lu
    Centers for Cancer Pharmacology, Pharmacogenetics, and Excellence in Environmental Toxicology, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Birth Defects Res A Clin Mol Teratol 82:736-41. 2008
    ..The present study was undertaken to identify potential determinants of MCP-1 levels in women of reproductive age...
  5. pmc 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
    Zhi Yong Lu
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
    Atherosclerosis 205:48-54. 2009
    ..We investigated the mechanisms underlying the modulation of MCP-1 expression by long-term "folate stress"...
  6. ncbi Thiol and cardiovascular risk factor status in a male northern Irish population
    Kevin S Edgar
    Centre for Clinical and Population Science, School of Medicine and Dentistry, Queen s University Belfast, Belfast, Nothern Ireland
    Int J Vitam Nutr Res 78:208-16. 2008
    ..Cysteine has also been associated with CVD risk. In this study, we investigated the association between known CVD risk factors, dietary factors, and total plasma cysteine, cysteinyl-glycine, and homocysteine...
  7. pmc Folate and homocysteine phenotypes: Comparative findings using research and clinical laboratory data
    Laura E Mitchell
    Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, USA
    Clin Biochem 42:1275-81. 2009
    ..This study was designed to evaluate a method based on stable isotope dilution liquid chromatography-multiple reaction monitoring/mass spectrometry (LC-MRM/MS)...
  8. ncbi Folate/homocysteine phenotypes and MTHFR 677C>T genotypes are associated with serum levels of monocyte chemoattractant protein-1
    Andrea L Hammons
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6084, USA
    Clin Immunol 133:132-7. 2009
    ..Similar relationships were not seen in males. These findings may have implications for understanding the female predominance observed for a range of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis...
  9. pmc The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women
    Anna Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Ann Hum Genet 73:484-91. 2009
    ....
  10. pmc Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study
    A Gibson
    Centre for Clinical and Population Science, Queen s University Belfast, Belfast, UK
    QJM 101:881-7. 2008
    ..Few studies have examined the effect of alcohol consumption on total homocysteine (tHcy) concentrations...
  11. pmc Functional polymorphisms of folate-metabolizing enzymes in relation to homocysteine concentrations in systemic lupus erythematosus
    Carolyn M Summers
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Rheumatol 35:2179-86. 2008
    ....
  12. ncbi Quantification of key red blood cell folates from subjects with defined MTHFR 677C>T genotypes using stable isotope dilution liquid chromatography/mass spectrometry
    Yuehua Huang
    Center for Cancer Pharmacology, University of Pennsylvania School of Medicine, 854 BRB II III, 421 Curie Boulevard, Philadelphia, PA 19104 6160, USA
    Rapid Commun Mass Spectrom 22:2403-12. 2008
    ....
  13. ncbi Mild folate deficiency induces a proatherosclerotic phenotype in endothelial cells
    Karen S Brown
    Department of Pharmacology, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Atherosclerosis 189:133-41. 2006
    ..LO cell monolayers were more permeable than HI cell monolayers at confluence, and MCP-1 mRNA and protein expression was higher in LO than HI cells. Our results suggest that mild folate deficiency is proatherosclerotic...
  14. ncbi Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus
    Joan M Von Feldt
    University of Pennsylvania, 5 Maloney, Suite 504, 3600 Spruce Street, Philadelphia, PA 19104, USA
    Arthritis Rheum 54:2220-7. 2006
    ....
  15. ncbi Association between the NAT1 1095C > A polymorphism and homocysteine concentration
    Anna Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6084, USA
    Am J Med Genet A 140:2374-7. 2006
  16. ncbi Quantification of intracellular homocysteine by stable isotope dilution liquid chromatography/tandem mass spectrometry
    Yuehua Huang
    Centers for Cancer Pharmacology and Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 6160, USA
    Biomed Chromatogr 21:107-12. 2007
    ..The limit of detection was 2 ng/10(6) EA.hy 926 cells. Using this method, the intracellular homocysteine concentration in EA.hy 926 cells ranged from 10 to 36 ng/10(6) cells...
  17. ncbi Monocyte chemoattractant protein-1: plasma concentrations and A(-2518)G promoter polymorphism of its gene in systemic lupus erythematosus
    Karen S Brown
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Rheumatol 34:740-6. 2007
    ....
  18. ncbi Evidence for sex differences in the determinants of homocysteine concentrations
    Anna Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Mol Genet Metab 93:355-62. 2008
    ..Among females, smokers (regardless of MTHFR genotype) appear to be at the highest risk, and to be the most vulnerable to a single factor (i.e. RBC folate) that is associated with homocysteine raising effects...
  19. ncbi An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women
    Anna Stanisławska-Sachadyn
    Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA, 19104 6084, USA
    Hum Genet 123:289-95. 2008
    ....
  20. pmc Influence of the cystathionine beta-synthase 844ins68 and methylenetetrahydrofolate reductase 677C>T polymorphisms on folate and homocysteine concentrations
    Carolyn M Summers
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Eur J Hum Genet 16:1010-3. 2008
    ..66 vs 8.77 micromol/l, P=0.045), and serum folate levels were 27.7% higher (11.16 vs 8.74 nmol/l, P=0.034). These findings suggest that the CBS 844ins68 allele 'normalizes' homocysteine and folate levels in MTHFR 677TT individuals...
  21. ncbi A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations
    Carmel Kealey
    Department of Pharmacology, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104 6084, USA
    Hum Genet 116:347-53. 2005
    ....