Gene-Body Mass Index Interactions Are Associated With Methotrexate Toxicity in Rheumatoid Arthritis

Stella Aslibekyan¹, Jin Sha¹, David T. Redden², Larry W. Moreland³, James R. O'Dell⁴, Jeffrey R. Curtis⁵, Ted R. Mikuls⁶, S. Louis Bridges Jr.⁷ and Donna K. Arnett¹, ¹University of Alabama at Birmingham, Birmingham, AL, ²Biostatistics, University of Alabama at Birmingham, Birmingham, AL, ³Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, ⁴Dept of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, ⁵Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ⁶Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ⁷Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Genetic architecture, methotrexate (MTX) and rheumatoid arthritis (RA)

Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Response to methotrexate (MTX) therapy in rheumatoid arthritis (RA) is highly heterogeneous, with both genetic and environmental factors contributing to the efficacy and toxicity of the drug. However, known predictors account for a small proportion of observed variability, and interactions between genetic and environmental factors, in particularly the body mass index (BMI) have not been extensively studied.

Methods: Using data from the Treatment of Aggressive Rheumatoid Arthritis (TEAR) trial (n=755), we fit logistic regressions to test for associations between 3,127 genetic markers selected based on their biological significance and the odds of MTX toxicity, adjusting for age, sex, race, active smoking, BMI, and interactions between genetic variants and BMI. The cohort was randomly split into discovery and replication sets. Genetic variants that reached nominal statistical significance in the discovery phase were subsequently tested in the replication subset.

Results: We observed statistically significant, replicated interactions between BMI and a variant in CMYA5 (cardiomyopathy 5), a known RA susceptibility gene (P=0.005 for discovery, 0.04 for replication), as well as with a variant located near the chemokine (CCL2 and others) gene cluster (P= 0.005 for discovery, 0.05 for replication). Among carriers of at least one copy of the minor allele at either locus, the estimate of BMI effect on MTX toxicity was fourfold higher compared to wild type individuals. Both genetic variants also had significant, replicated main effects on toxicity.

Conclusion: We have identified and replicated interactions between two biologically plausible genetic variants and BMI in models of methotrexate toxicity. Our findings lay the groundwork for developing more accurate and complete algorithms of MTX response prediction in RA.

Disclosure:

S. Aslibekyan,
None;

J. Sha,
None;

D. T. Redden,
None;

L. W. Moreland,
None;

J. R. O’Dell,
None;

J. R. Curtis,

Roche/Genentech, UCB, Janssen, CORRONA, Amgen, Pfizer, BMS, Crescendo, AbbVie,

T. R. Mikuls,

Roche/Genentech and Biogen IDEC Inc.,

S. L. Bridges Jr.,
None;

D. K. Arnett,
None.

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