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.
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 TNFAIP3rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4rs7574865 (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.
Authors: Sampath Prahalad; Susan D Thompson; Karen N Conneely; Yunxuan Jiang; Traci Leong; Jennifer Prozonic; Milton R Brown; Lori A Ponder; Sheila T Angeles-Han; Larry B Vogler; Christine Kennedy; Carol A Wallace; Carol A Wise; Marilynn Punaro; Ann Reed; Jane L Park; Elizabeth D Mellins; Andrew S Zeft; John F Bohnsack; David N Glass Journal: Arthritis Rheum Date: 2012-03
Authors: Robert M Plenge; Chris Cotsapas; Leela Davies; Alkes L Price; Paul I W de Bakker; Julian Maller; Itsik Pe'er; Noel P Burtt; Brendan Blumenstiel; Matt DeFelice; Melissa Parkin; Rachel Barry; Wendy Winslow; Claire Healy; Robert R Graham; Benjamin M Neale; Elena Izmailova; Ronenn Roubenoff; Alexander N Parker; Roberta Glass; Elizabeth W Karlson; Nancy Maher; David A Hafler; David M Lee; Michael F Seldin; Elaine F Remmers; Annette T Lee; Leonid Padyukov; Lars Alfredsson; Jonathan Coblyn; Michael E Weinblatt; Stacey B Gabriel; Shaun Purcell; Lars Klareskog; Peter K Gregersen; Nancy A Shadick; Mark J Daly; David Altshuler Journal: Nat Genet Date: 2007-11-04 Impact factor: 38.330
Authors: Elaine F Remmers; Robert M Plenge; Annette T Lee; Robert R Graham; Geoffrey Hom; Timothy W Behrens; Paul I W de Bakker; Julie M Le; Hye-Soon Lee; Franak Batliwalla; Wentian Li; Seth L Masters; Matthew G Booty; John P Carulli; Leonid Padyukov; Lars Alfredsson; Lars Klareskog; Wei V Chen; Christopher I Amos; Lindsey A Criswell; Michael F Seldin; Daniel L Kastner; Peter K Gregersen Journal: N Engl J Med Date: 2007-09-06 Impact factor: 91.245
Authors: Robert R Graham; Chris Cotsapas; Leela Davies; Rachel Hackett; Christopher J Lessard; Joanlise M Leon; Noel P Burtt; Candace Guiducci; Melissa Parkin; Casey Gates; Robert M Plenge; Timothy W Behrens; Joan E Wither; John D Rioux; Paul R Fortin; Deborah Cunninghame Graham; Andrew K Wong; Timothy J Vyse; Mark J Daly; David Altshuler; Kathy L Moser; Patrick M Gaffney Journal: Nat Genet Date: 2008-09 Impact factor: 38.330
Authors: Michelle M A Fernando; Christine R Stevens; Emily C Walsh; Philip L De Jager; Philippe Goyette; Robert M Plenge; Timothy J Vyse; John D Rioux Journal: PLoS Genet Date: 2008-04-25 Impact factor: 5.917
Authors: Sheila T Angeles-Han; Courtney McCracken; Steven Yeh; Se Ryeong Jang; Kirsten Jenkins; Spencer Cope; John Bohnsack; Aimee Hersh; Susan D Thompson; Sampath Prahalad Journal: Invest Ophthalmol Vis Sci Date: 2015-09 Impact factor: 4.799
Authors: Lauren Lange; Geoffrey M Thiele; Courtney McCracken; Gabriel Wang; Lori A Ponder; Sheila T Angeles-Han; Kelly A Rouster-Stevens; Aimee O Hersh; Larry B Vogler; John F Bohnsack; Shelly Abramowicz; Ted R Mikuls; Sampath Prahalad Journal: Pediatr Rheumatol Online J Date: 2016-02-09 Impact factor: 3.054