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Author Notes:

Correspondence: Sampath Prahalad, MD, MSc, Associate Professor of Pediatrics and Human Genetics, Emory University School of Medicine, 2015 Uppergate Drive NE, Atlanta, GA 30322. Phone: 404-727 8949. Fax 404-727-3757. Email: sprahal@emory.edu

Authors' Contributions: All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.

Dr. Prahalad had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design: Prahalad, Cutler.

Acquisition of data: Prahalad, Sudman, Wallace, Brown, Ponder, Angeles-Han, Vogler, Kennedy, Rouster-Stevens, Wise, Punaro, Reed, Mellins, Bohnsack, Glass, Thompson.

Analysis and interpretation of data: Prahalad, Conneely, Jiang, Rohani-Pichavant, Zwick, Cutler, Vogler, Thompson.

Acknowledgments: We thank the subjects who participated and the TREAT investigators who enrolled subjects in the TREAT study.

Disclosures: Dr. Mellins has received consulting fees, speaking fees, and/or honoraria from Novartis (less than $10,000).

Subjects:

Research Funding:

Supported by grants from the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants R01-AR- 060893 to Dr. Prahalad, R01-AR-049762 to Dr. Wallace, R21-AI- 075254 to Dr. Mellins, P01-AR-048929 and N01-AR-42272 to Dr. Glass, and RC1-AR-058587 and P30-AR-047363 to Dr. Thompson), the Marcus Foundation, Inc. (to Dr. Prahalad), the Arthritis Foundation (to Dr. Prahalad), the Val A. Browning Charitable Foundation (to Drs. Prahalad and Bohnsack), the Primary Children’s Medical Center Foundation (to Dr. Prahalad), the Texas Scottish Rite Hospital Foundation (to Drs. Wallace and Punaro), and the Dana Foundation (to Dr. Mellins).

Keywords:

  • juvenile idiopathic arthritis
  • rheumatoid arthritis
  • genetics
  • association

Susceptibility to childhood onset rheumatoid arthritis: Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci

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Journal Title:

Arthritis and Rheumatism

Volume:

Volume 65, Number 6

Publisher:

, Pages 1663-1667

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Objectives Children with rheumatoid-factor or anti-citrullinated peptide antibody positive juvenile idiopathic arthritis represent the childhood onset of RA (CORA). To test the hypothesis that adult-onset RA-associated variants are also associated with CORA, we investigated RA-associated variants at five loci in our CORA cohort. We also assessed the cumulative association of these variants in the susceptibility to CORA using a weighted genetic risk score (wGRS). Methods 155 children with CORA and 684 healthy controls were genotyped for five variants in PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with CORA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios for the alleles investigated, and used logistic regression to test the wGRS for association with CORA. Results CORA was associated with TNFAIP3-rs10499194 [OR 0.60 (95%CI 0.44–0.83)], PTPN22-rs2476601 [OR 1.61 (1.11–2.31)], and STAT4-rs7574865 [OR 1.41 (1.06–1.87)] variants. The wGRS was significantly different between cases and controls (P<2×10−16). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to the baseline. Higher wGRS associated with increased risk of CORA, especially among males. Conclusions TNFAIP3, STAT4 and PTPN22 variants are associated with CORA in a similar magnitude and direction as in RA, suggesting that adult-onset RA and CORA share common genetic risk factors. Utilizing a wGRS, we have demonstrated the cumulative association of RA-associated variants in the susceptibility to CORA.

Copyright information:

© 2013 by the American College of Rheumatology

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