Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope

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

Research output: Contribution to journalArticle

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Abstract

Objective Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. Methods High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S 2, S 3P, or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. Results We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10 -7). We also observed associations between individual SE alleles (HLA-DRB1*0101,*0401,*0404,*0405,*0408, and*1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S 2/S 3P (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). Conclusion We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S 2 and S 3P risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.

Original languageEnglish (US)
Pages (from-to)925-930
Number of pages6
JournalArthritis and Rheumatism
Volume64
Issue number3
DOIs
StatePublished - Mar 2012

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HLA-DRB1 Chains
Epitopes
Rheumatoid Arthritis
Alleles
Odds Ratio
Genotype
Confidence Intervals
Amino Acid Sequence
Juvenile Arthritis
Rheumatoid Factor
Healthy Volunteers

ASJC Scopus subject areas

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

Cite this

Prahalad, S., Thompson, S. D., Conneely, K. N., Jiang, Y., Leong, T., Prozonic, J., ... Glass, D. N. (2012). Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. Arthritis and Rheumatism, 64(3), 925-930. https://doi.org/10.1002/art.33376

Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. / Prahalad, Sampath; Thompson, Susan D.; Conneely, Karen N.; Jiang, Yunxuan; Leong, Traci; Prozonic, Jennifer; Brown, Milton R.; Ponder, Lori A.; Angeles-Han, Sheila T.; Vogler, Larry B.; Kennedy, Christine; Wallace, Carol A.; Wise, Carol A.; Punaro, Marilynn; Reed, Ann; Park, Jane L.; Mellins, Elizabeth D.; Zeft, Andrew S.; Bohnsack, John F.; Glass, David N.

In: Arthritis and Rheumatism, Vol. 64, No. 3, 03.2012, p. 925-930.

Research output: Contribution to journalArticle

Prahalad, S, Thompson, SD, Conneely, KN, Jiang, Y, Leong, T, Prozonic, J, Brown, MR, Ponder, LA, Angeles-Han, ST, Vogler, LB, Kennedy, C, Wallace, CA, Wise, CA, Punaro, M, Reed, A, Park, JL, Mellins, ED, Zeft, AS, Bohnsack, JF & Glass, DN 2012, 'Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope', Arthritis and Rheumatism, vol. 64, no. 3, pp. 925-930. https://doi.org/10.1002/art.33376
Prahalad, Sampath ; Thompson, Susan D. ; Conneely, Karen N. ; Jiang, Yunxuan ; Leong, Traci ; Prozonic, Jennifer ; Brown, Milton R. ; Ponder, Lori A. ; Angeles-Han, Sheila T. ; Vogler, Larry B. ; Kennedy, Christine ; Wallace, Carol A. ; Wise, Carol A. ; Punaro, Marilynn ; Reed, Ann ; Park, Jane L. ; Mellins, Elizabeth D. ; Zeft, Andrew S. ; Bohnsack, John F. ; Glass, David N. / Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 3. pp. 925-930.
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abstract = "Objective Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. Methods High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95{\%} confidence intervals (95{\%} CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S 2, S 3P, or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. Results We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76{\%} of patients carried 1 or 2 SE alleles compared with 46{\%} of control subjects; OR 3.81, 95{\%} CI 2.4-6.0, P < 1 × 10 -7). We also observed associations between individual SE alleles (HLA-DRB1*0101,*0401,*0404,*0405,*0408, and*1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S 2/S 3P (OR 22.3, 95{\%} CI 9.9-50.5, P < 0.0001). Conclusion We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S 2 and S 3P risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.",
author = "Sampath Prahalad and Thompson, {Susan D.} and Conneely, {Karen N.} and Yunxuan Jiang and Traci Leong and Jennifer Prozonic and Brown, {Milton R.} and Ponder, {Lori A.} and Angeles-Han, {Sheila T.} and Vogler, {Larry B.} and Christine Kennedy and Wallace, {Carol A.} and Wise, {Carol A.} and Marilynn Punaro and Ann Reed and Park, {Jane L.} and Mellins, {Elizabeth D.} and Zeft, {Andrew S.} and Bohnsack, {John F.} and Glass, {David N.}",
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T1 - Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope

AU - Prahalad, Sampath

AU - Thompson, Susan D.

AU - Conneely, Karen N.

AU - Jiang, Yunxuan

AU - Leong, Traci

AU - Prozonic, Jennifer

AU - Brown, Milton R.

AU - Ponder, Lori A.

AU - Angeles-Han, Sheila T.

AU - Vogler, Larry B.

AU - Kennedy, Christine

AU - Wallace, Carol A.

AU - Wise, Carol A.

AU - Punaro, Marilynn

AU - Reed, Ann

AU - Park, Jane L.

AU - Mellins, Elizabeth D.

AU - Zeft, Andrew S.

AU - Bohnsack, John F.

AU - Glass, David N.

PY - 2012/3

Y1 - 2012/3

N2 - Objective Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. Methods High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S 2, S 3P, or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. Results We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10 -7). We also observed associations between individual SE alleles (HLA-DRB1*0101,*0401,*0404,*0405,*0408, and*1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S 2/S 3P (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). Conclusion We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S 2 and S 3P risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.

AB - Objective Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. Methods High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S 2, S 3P, or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. Results We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10 -7). We also observed associations between individual SE alleles (HLA-DRB1*0101,*0401,*0404,*0405,*0408, and*1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S 2/S 3P (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). Conclusion We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S 2 and S 3P risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.

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