ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 997

Evidence of Novel Genetic Predictors of Methotrexate Efficacy in Rheumatoid Arthritis

Stella Aslibekyan1, Maria I. Danila2, Jin Sha1, David T. Redden3, Richard J. Reynolds4, Elizabeth Brown5, Laura B. Hughes6, Molly S. Bray1, Sarah L. Morgan7, Larry W. Moreland8, James R. O'Dell9, Jeffrey R. Curtis10, Robert P. Kimberly11, Lindsey A. Criswell12, Robert M. Plenge13, S. Louis Bridges Jr.14 and Donna K. Arnett1, 1University of Alabama at Birmingham, Birmingham, AL, 2Med/Clinical Immun & Rheum, Univ of Alabama-Birmingham, Birmingham, AL, 3Biostatistics, University of Alabama at Birmingham, Birmingham, AL, 4Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 5Univ of Alabama at Birmingham, Birmingham, AL, Birmingham, AL, 6Med Div of Clin Imm & Rheum, University of Alabama at Birmingham, Birmingham, AL, 7University of Alabama Birmingham, Birmingham, AL, 8Division of Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 9Dept of Internal Medicine, Univ of Nebraska Med Ctr, Omaha, NE, 10Rheumatology & Immunology, Univ of Alabama-Birmingham, Birmingham, AL, 11Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 12Department of Medicine, University of California, San Francisco, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, 13Division of Rheumatology, Immunology and Allergy and Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 14Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: Methotrexate (MTX), a disease-modifying anti-rheumatic drug used as first-line therapy in rheumatoid arthritis (RA), is characterized by considerable heterogeneity in individual treatment response. We tested the hypothesis that polymorphisms in RA susceptibility genes and MTX metabolism pathways are associated with MTX efficacy and toxicity.

Methods: Data from a combined population of three MTX trials (Treatment of Early Aggressive RA Trial; Immunex Early RA Trial; UAB Folic Acid Supplementation Trial, total subjects = 633) were analyzed for 3,127 genetic markers previously linked to RA risk or MTX metabolism pathways, with MTX efficacy (defined as the change joint count scores over 24 weeks of MTX therapy) and toxicity (defined as self-report of any adverse events) as outcomes. Gene-based tests were conducted to complement single marker analyses. All statistical models were adjusted for age, sex, race, and treatment as fixed effects, and for study as a random effect; the efficacy models were additionally adjusted for baseline disease activity.

Results: In the MTX efficacy models, the strongest signals were observed with variation in genes encoding efflux transporters (ABCC1; gene-based P= 1.4×10-4), B cell surface antigen (CD40, gene-based P=3.8×10-4), and immunoglobulin receptors (FCGR2A, FCGR3A; gene-based P= 1.5×10-5 and P= 1.6×10-5 respectively). Although no genetic variants reached statistical significance in the models of adverse effects associated with MTX therapy, the top hits included markers near GFRA2 (rs12549890, P= 2.8×10-3), the ABCA12 transporter (rs4673907, P= 4.6×10-3), and multiple SNPs in ADK included in the adenosine pathway.

Conclusion: This study provides preliminary identification of several novel targets relevant to MTX metabolism in RA. These findings will inform future studies aimed at developing pharmacogenetic tools to predict response to MTX therapy.

Disclosure:

S. Aslibekyan,
None;

M. I. Danila,
None;

J. Sha,
None;

D. T. Redden,
None;

R. J. Reynolds,
None;

E. Brown,
None;

L. B. Hughes,
None;

M. S. Bray,
None;

S. L. Morgan,
None;

L. W. Moreland,
None;

J. R. O’Dell,
None;

J. R. Curtis,

Roche/Genetech, UCB, Centocor, CORRONA, Amgen Pfizer, BMS, Crescendo, Abbott,

5,

Roche/Genetech, UCB, Centocor, CORRONA, Amgen Pfizer, BMS, Crescendo, Abbott,

2;

R. P. Kimberly,
None;

L. A. Criswell,
None;

R. M. Plenge,
None;

S. L. Bridges Jr.,
None;

D. K. Arnett,
None.

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