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

• Type of Material: Article
• Authors: Sampath Prahalad, Emory University; Karen N Conneely, Emory University; Yunxuan Jiang, Emory University; Marc Sudman, Cincinnati Children’s Medical Center; Carol A. Wallace, University of Washington; Milton R Brown, Emory University; Lori A. Ponder, Children’s Healthcare of Atlanta; Mina Rohani-Pichavant, Emory University; Michael Zwick, Emory University; David J Cutler, Emory University; Sheila Angeles-Han, Emory University; Larry B Vogler, Emory University; Christine Kennedy, Emory University; Kelly A. Rouster Stevens, Emory University; Carol A. Wise, Texas Scottish Rite Hospital for Children; Marilynn Punaro, Texas Scottish Rite Hospital for Children; Ann M. Reed, Mayo Clinic; Elizabeth D. Mellins, Stanford University Medical Center; John F. Bohnsack, University of Utah School of Medicine; David N. Glass, Cincinnati Children’s Medical Center; Susan D. Thompson, Cincinnati Children’s Medical Center
• Language: English
• Date: 2013-06
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 by the American College of Rheumatology
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/art.37913/abstract;jsessionid=CBF9A1114DCBD7A762D0BC6571E7312E.f01t04
• Title of Journal or Parent Work: Arthritis and Rheumatism
• ISSN: 0004-3591
• Volume: 65
• Issue: 6
• Start Page: 1663
• End Page: 1667
• Grant/Funding Information: 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; genetics; rheumatoid arthritis; association
• Research Categories: Health Sciences, General; Biology, Genetics; Health Sciences, Human Development

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.