Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial
Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with...
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2013
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701736/ |
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pubmed-37017362014-08-01 Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial Aslibekyan, Stella Brown, Elizabeth E. Reynolds, Richard J. Redden, David T. Morgan, Sarah Baggott, Joseph Sha, Jin Moreland, Larry W. O’Dell, James R. Curtis, Jeffrey R. Mikuls, Ted R. Bridges, S. Louis Arnett, Donna K. Article Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches. 2013-04-02 2014-02 /pmc/articles/PMC3701736/ /pubmed/23545897 http://dx.doi.org/10.1038/tpj.2013.11 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
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Foreign Institution |
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US National Center for Biotechnology Information |
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NCBI PubMed |
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Online Access |
| language |
English |
| format |
Online |
| author |
Aslibekyan, Stella Brown, Elizabeth E. Reynolds, Richard J. Redden, David T. Morgan, Sarah Baggott, Joseph Sha, Jin Moreland, Larry W. O’Dell, James R. Curtis, Jeffrey R. Mikuls, Ted R. Bridges, S. Louis Arnett, Donna K. |
| spellingShingle |
Aslibekyan, Stella Brown, Elizabeth E. Reynolds, Richard J. Redden, David T. Morgan, Sarah Baggott, Joseph Sha, Jin Moreland, Larry W. O’Dell, James R. Curtis, Jeffrey R. Mikuls, Ted R. Bridges, S. Louis Arnett, Donna K. Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| author_facet |
Aslibekyan, Stella Brown, Elizabeth E. Reynolds, Richard J. Redden, David T. Morgan, Sarah Baggott, Joseph Sha, Jin Moreland, Larry W. O’Dell, James R. Curtis, Jeffrey R. Mikuls, Ted R. Bridges, S. Louis Arnett, Donna K. |
| author_sort |
Aslibekyan, Stella |
| title |
Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| title_short |
Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| title_full |
Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| title_fullStr |
Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| title_full_unstemmed |
Genetic Variants Associated with Methotrexate Efficacy and Toxicity in Early Rheumatoid Arthritis: Results from the Treatment of Early Aggressive Rheumatoid Arthritis Trial |
| title_sort |
genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial |
| description |
Methotrexate (MTX) has emerged as first-line therapy for early moderate to severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 TEAR Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P <0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches. |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701736/ |
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1611991955204472832 |