Susceptibility to childhood-onset rheumatoid arthritis

Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci

Sampath Prahalad, Karen N. Conneely, Yunxuan Jiang, Marc Sudman, Carol A. Wallace, Milton R. Brown, Lori A. Ponder, Mina Rohani-Pichavant, Michael E. Zwick, David J. Cutler, Sheila T. Angeles-Han, Larry B. Vogler, Christine Kennedy, Kelly Rouster-Stevens, Carol A. Wise, Marilynn Punaro, Ann M. Reed, Elizabeth D. Mellins, John F. Bohnsack, David N. Glass & 1 others Susan D. Thompson

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1663-1667
Number of pages5
JournalArthritis and Rheumatism
Volume65
Issue number6
DOIs
StatePublished - Jun 2013

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Genetic Loci
Rheumatoid Arthritis
Odds Ratio
Confidence Intervals
TNF Receptor-Associated Factor 1
Logistic Models
HLA-DRB1 Chains
Juvenile Arthritis
Rheumatoid Factor

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Susceptibility to childhood-onset rheumatoid arthritis : Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci. / Prahalad, Sampath; Conneely, Karen N.; Jiang, Yunxuan; Sudman, Marc; Wallace, Carol A.; Brown, Milton R.; Ponder, Lori A.; Rohani-Pichavant, Mina; Zwick, Michael E.; Cutler, David J.; Angeles-Han, Sheila T.; Vogler, Larry B.; Kennedy, Christine; Rouster-Stevens, Kelly; Wise, Carol A.; Punaro, Marilynn; Reed, Ann M.; Mellins, Elizabeth D.; Bohnsack, John F.; Glass, David N.; Thompson, Susan D.

In: Arthritis and Rheumatism, Vol. 65, No. 6, 06.2013, p. 1663-1667.

Research output: Contribution to journalArticle

Prahalad, S, Conneely, KN, Jiang, Y, Sudman, M, Wallace, CA, Brown, MR, Ponder, LA, Rohani-Pichavant, M, Zwick, ME, Cutler, DJ, Angeles-Han, ST, Vogler, LB, Kennedy, C, Rouster-Stevens, K, Wise, CA, Punaro, M, Reed, AM, Mellins, ED, Bohnsack, JF, Glass, DN & Thompson, SD 2013, 'Susceptibility to childhood-onset rheumatoid arthritis: Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci', Arthritis and Rheumatism, vol. 65, no. 6, pp. 1663-1667. https://doi.org/10.1002/art.37913
Prahalad, Sampath ; Conneely, Karen N. ; Jiang, Yunxuan ; Sudman, Marc ; Wallace, Carol A. ; Brown, Milton R. ; Ponder, Lori A. ; Rohani-Pichavant, Mina ; Zwick, Michael E. ; Cutler, David J. ; Angeles-Han, Sheila T. ; Vogler, Larry B. ; Kennedy, Christine ; Rouster-Stevens, Kelly ; Wise, Carol A. ; Punaro, Marilynn ; Reed, Ann M. ; Mellins, Elizabeth D. ; Bohnsack, John F. ; Glass, David N. ; Thompson, Susan D. / Susceptibility to childhood-onset rheumatoid arthritis : Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 6. pp. 1663-1667.
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abstract = "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.",
author = "Sampath Prahalad and Conneely, {Karen N.} and Yunxuan Jiang and Marc Sudman and Wallace, {Carol A.} and Brown, {Milton R.} and Ponder, {Lori A.} and Mina Rohani-Pichavant and Zwick, {Michael E.} and Cutler, {David J.} and Angeles-Han, {Sheila T.} and Vogler, {Larry B.} and Christine Kennedy and Kelly Rouster-Stevens and Wise, {Carol A.} and Marilynn Punaro and Reed, {Ann M.} and Mellins, {Elizabeth D.} and Bohnsack, {John F.} and Glass, {David N.} and Thompson, {Susan D.}",
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TY - JOUR

T1 - Susceptibility to childhood-onset rheumatoid arthritis

T2 - Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci

AU - Prahalad, Sampath

AU - Conneely, Karen N.

AU - Jiang, Yunxuan

AU - Sudman, Marc

AU - Wallace, Carol A.

AU - Brown, Milton R.

AU - Ponder, Lori A.

AU - Rohani-Pichavant, Mina

AU - Zwick, Michael E.

AU - Cutler, David J.

AU - Angeles-Han, Sheila T.

AU - Vogler, Larry B.

AU - Kennedy, Christine

AU - Rouster-Stevens, Kelly

AU - Wise, Carol A.

AU - Punaro, Marilynn

AU - Reed, Ann M.

AU - Mellins, Elizabeth D.

AU - Bohnsack, John F.

AU - Glass, David N.

AU - Thompson, Susan D.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

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