Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases.
Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.
Department of Biochemistry, University of Otago, Dunedin 9054, New Zealand. lisa.stamp@cdhb.govt.nz
Lisa K
LK
Stamp
Rebecca L
RL
Roberts
D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008727:Methotrexate / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein / Q000235:genetics / Q000378:metabolism; D012216:Rheumatic Diseases / Q000188:drug therapy*
D018501:Antirheumatic Agents; D054316:Biomarkers, Pharmacological; D058978:Reduced Folate Carrier Protein; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D005492:Folic Acid; D008727:Methotrexate