Open AccessBrief Report: Susceptibility to Childhood‐Onset Rheumatoid Arthritis: Investigation of a Weighted Genetic Risk Score That Integrates Cumulative Effects of Variants at Five Genetic Loci
Author(s) -
Prahalad Sampath,
Conneely Karen N.,
Jiang Yunxuan,
Sudman Marc,
Wallace Carol A.,
Brown Milton R.,
Ponder Lori A.,
RohaniPichavant Mina,
Zwick Michael E.,
Cutler David J.,
AngelesHan Sheila T.,
Vogler Larry B.,
Kennedy Christine,
RousterStevens Kelly,
Wise Carol A.,
Punaro Marilynn,
Reed Ann M.,
Mellins Elizabeth D.,
Bohnsack John F.,
Glass David N.,
Thompson Susan D.
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.37913
Subject(s) - medicine , ptpn22 , odds ratio , confidence interval , cohort , rheumatoid arthritis , oncology , genotype , single nucleotide polymorphism , genetics , biology , gene
Objective Children with childhood‐onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti–citrullinated protein antibody–positive juvenile idiopathic arthritis. To test the hypothesis that adult‐onset RA–associated variants are also associated with childhood‐onset RA, we investigated RA‐associated variants at 5 loci in a cohort of patients with childhood‐onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood‐onset RA using a weighted genetic risk score (wGRS). Methods A total of 155 children with childhood‐onset RA and 684 healthy controls were genotyped for 5 variants in the 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 childhood‐onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood‐onset RA. Results Childhood‐onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44–0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11–2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 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 baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood‐onset RA, especially among males. Conclusion The magnitude and direction of the association between TNFAIP3 , STAT4 , and PTPN22 variants and childhood‐onset RA are similar to those observed in RA, suggesting that adult‐onset RA and childhood‐onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA‐associated variants with susceptibility to childhood‐onset RA.