Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Gene-Interactions Influence Methotrexate Efficacy in Rheumatoid Arthritis: Analysis of 62 SNPs Panel in a Monocentric Cohort of Rheumatoid Arthritis Affected Patients.

Barnetche1,  Thomas, Rooryck-Thambo4,  Caroline, Hubert3,  Christophe, Richez2,  Christophe, Arveiler4,  Benoit, Schaeverbeke2,  Thierry

Bordeaux University Hospital, Rheumatology Department, Bordeaux, France
Bordeaux University Hospital, Rheumatology Department
Genomics-Transcriptomics Facility, Bordeaux
Human Genetics Laboratory EA4137, University Victor Segalen Bordeaux 2

Purpose:

Methotrexate (MTX) is one of the most widely used disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis. No single genetic marker allows predicting response to the treatment. Here, we aimed to establish gene-gene epistatic interactions to predict MTX response therapy. SNPs were selected in proteins and enzymes that step in folate, purine and adenosine pathways, and also in several transporters that participate to MTX cellular absorption and elimination.

Method:

A sample of 222 RA affected patients treated with low dose of MTX (7,5mg to 25mg with oral, intra-muscular or subcutaneous administration) was included in a monocentric study. Efficacy to MTX was assessed using EULAR response criteria and/or physician's assessment. A panel of 62 SNPs was analyzed for each patient. Univariate analysis in genotypes and allele frequencies was performed. Then gene-gene interactions were studied using Multifactor Dimensionality Reduction (MDR). MDR is considered as a non-parametric approach to detect non-linear interactions between binary variables that influence a binary outcome. This method reduces the dimensionality of genotypes predictors from N-dimensions to one dimension in pooling multilocus genotypes into high-risk and low risks MTX response groups. The robustness and significance of the model were tested through cross validation consistency (CVC, 10-fold).

Results:

The MDR method highlights that MTX response (about 67% in this sample) is related with epistatic interactions among variants in ABCC3 (ATP-binding cassette, sub-family C) efflux transporter (rs739921 [C/G], rs4148412[C/T]), ABCC5 efflux transporter (rs4148575 [C/T]) and adenosine monophosphate deaminase 1 (rs2268699 [A/C]). Testing accuracy was 0.635 and CVC was 10/10. Carriers of a predisposing genotype combination were 22.14-fold more likely to respond to MTX than those without (CI95%: 9.76–50.21; p<0.0001). Sensitivity was 73%, specificity was 89% and accuracy was 78%. Univariate analysis revealed independent association for only two of these four SNPs: rs4148412[C/T] (ABCC3) and rs2268699 [A/C] (AMPD1) (p<0.05).

Conclusion:

These data indicate that epistatic interactions in MTX pharmacology pathway influence the treatment response. Further studies are needed to confirm the role of genetic variants in ABCC transporters in MTX response, and to determine the exact functional impact of this genetic model.

To cite this abstract, please use the following information:
Barnetche, Thomas, Rooryck-Thambo, Caroline, Hubert, Christophe, Richez, Christophe, Arveiler, Benoit, Schaeverbeke, Thierry; Gene-Interactions Influence Methotrexate Efficacy in Rheumatoid Arthritis: Analysis of 62 SNPs Panel in a Monocentric Cohort of Rheumatoid Arthritis Affected Patients. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1596
DOI: 10.1002/art.29362

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