HLA-DRB111 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Michael J. Ombrello, Elaine F. Remmers, Ioanna Tachmazidou, Alexei Grom, Dirk Foell, Johannes Peter Haas, Alberto Martini, Marco Gattorno, Seza Özen, Sampath Prahalad, Andrew S. Zeft, John F. Bohnsack, Elizabeth D. Mellins, Norman T. Ilowite, Ricardo Russo, Claudio Len, Maria Odete E Hilario, Sheila Oliveira, Rae S M Yeung, Alan RosenbergLucy R. Wedderburn, Jordi Anton, Tobias Schwarza, Anne Hinksb, Yelda Bilginer, Jane Park, Joanna Cobb, Colleen L. Satorius, Buhm Han, Elizabeth Baskin, Sara Signa, Richard H. Duerr, J. P. Achkar, M. Ilyas Kamboh, Kenneth M. Kaufman, Leah C. Kottyan, Dalila Pinto, Stephen W. Scherer, Marta E. Alarcón-Riquelme, Elisa Docampo, Xavier P. Estivill, Ahmet Gül, Paul I W De Bakker, Soumya Raychaudhuri, Carl D. Langefeld, Susan Thompson, Eleftheria Zeggini, Wendy Thomson, Daniel L. Kastner, Patricia Woo

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10-17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10-5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB111 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10-16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB111-HLADQA1 05-HLA-DQB103 haplotype [6.4 × 10-17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

Original languageEnglish
Pages (from-to)15970-15975
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number52
DOIs
Publication statusPublished - 29 Dec 2015
Externally publishedYes

Fingerprint

Juvenile Arthritis
Odds Ratio
Single Nucleotide Polymorphism
Meta-Analysis
Chromosomes, Human, Pair 6
Haplotypes
Glutamic Acid
Healthy Volunteers
Genotype
Amino Acids

Keywords

  • Autoinflammation
  • Human leukocyte antigen
  • Still's disease
  • Systemic juvenile idiopathic arthritis

ASJC Scopus subject areas

  • General

Cite this

HLA-DRB111 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. / Ombrello, Michael J.; Remmers, Elaine F.; Tachmazidou, Ioanna; Grom, Alexei; Foell, Dirk; Haas, Johannes Peter; Martini, Alberto; Gattorno, Marco; Özen, Seza; Prahalad, Sampath; Zeft, Andrew S.; Bohnsack, John F.; Mellins, Elizabeth D.; Ilowite, Norman T.; Russo, Ricardo; Len, Claudio; Hilario, Maria Odete E; Oliveira, Sheila; Yeung, Rae S M; Rosenberg, Alan; Wedderburn, Lucy R.; Anton, Jordi; Schwarza, Tobias; Hinksb, Anne; Bilginer, Yelda; Park, Jane; Cobb, Joanna; Satorius, Colleen L.; Han, Buhm; Baskin, Elizabeth; Signa, Sara; Duerr, Richard H.; Achkar, J. P.; Kamboh, M. Ilyas; Kaufman, Kenneth M.; Kottyan, Leah C.; Pinto, Dalila; Scherer, Stephen W.; Alarcón-Riquelme, Marta E.; Docampo, Elisa; Estivill, Xavier P.; Gül, Ahmet; De Bakker, Paul I W; Raychaudhuri, Soumya; Langefeld, Carl D.; Thompson, Susan; Zeggini, Eleftheria; Thomson, Wendy; Kastner, Daniel L.; Woo, Patricia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 52, 29.12.2015, p. 15970-15975.

Research output: Contribution to journalArticle

Ombrello, MJ, Remmers, EF, Tachmazidou, I, Grom, A, Foell, D, Haas, JP, Martini, A, Gattorno, M, Özen, S, Prahalad, S, Zeft, AS, Bohnsack, JF, Mellins, ED, Ilowite, NT, Russo, R, Len, C, Hilario, MOE, Oliveira, S, Yeung, RSM, Rosenberg, A, Wedderburn, LR, Anton, J, Schwarza, T, Hinksb, A, Bilginer, Y, Park, J, Cobb, J, Satorius, CL, Han, B, Baskin, E, Signa, S, Duerr, RH, Achkar, JP, Kamboh, MI, Kaufman, KM, Kottyan, LC, Pinto, D, Scherer, SW, Alarcón-Riquelme, ME, Docampo, E, Estivill, XP, Gül, A, De Bakker, PIW, Raychaudhuri, S, Langefeld, CD, Thompson, S, Zeggini, E, Thomson, W, Kastner, DL & Woo, P 2015, 'HLA-DRB111 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 52, pp. 15970-15975. https://doi.org/10.1073/pnas.1520779112
Ombrello, Michael J. ; Remmers, Elaine F. ; Tachmazidou, Ioanna ; Grom, Alexei ; Foell, Dirk ; Haas, Johannes Peter ; Martini, Alberto ; Gattorno, Marco ; Özen, Seza ; Prahalad, Sampath ; Zeft, Andrew S. ; Bohnsack, John F. ; Mellins, Elizabeth D. ; Ilowite, Norman T. ; Russo, Ricardo ; Len, Claudio ; Hilario, Maria Odete E ; Oliveira, Sheila ; Yeung, Rae S M ; Rosenberg, Alan ; Wedderburn, Lucy R. ; Anton, Jordi ; Schwarza, Tobias ; Hinksb, Anne ; Bilginer, Yelda ; Park, Jane ; Cobb, Joanna ; Satorius, Colleen L. ; Han, Buhm ; Baskin, Elizabeth ; Signa, Sara ; Duerr, Richard H. ; Achkar, J. P. ; Kamboh, M. Ilyas ; Kaufman, Kenneth M. ; Kottyan, Leah C. ; Pinto, Dalila ; Scherer, Stephen W. ; Alarcón-Riquelme, Marta E. ; Docampo, Elisa ; Estivill, Xavier P. ; Gül, Ahmet ; De Bakker, Paul I W ; Raychaudhuri, Soumya ; Langefeld, Carl D. ; Thompson, Susan ; Zeggini, Eleftheria ; Thomson, Wendy ; Kastner, Daniel L. ; Woo, Patricia. / HLA-DRB111 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 52. pp. 15970-15975.
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abstract = "Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10-17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10-5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1∗11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10-16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1∗11-HLADQA1∗ 05-HLA-DQB1∗03 haplotype [6.4 × 10-17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.",
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T1 - HLA-DRB1∗11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

AU - Ombrello, Michael J.

AU - Remmers, Elaine F.

AU - Tachmazidou, Ioanna

AU - Grom, Alexei

AU - Foell, Dirk

AU - Haas, Johannes Peter

AU - Martini, Alberto

AU - Gattorno, Marco

AU - Özen, Seza

AU - Prahalad, Sampath

AU - Zeft, Andrew S.

AU - Bohnsack, John F.

AU - Mellins, Elizabeth D.

AU - Ilowite, Norman T.

AU - Russo, Ricardo

AU - Len, Claudio

AU - Hilario, Maria Odete E

AU - Oliveira, Sheila

AU - Yeung, Rae S M

AU - Rosenberg, Alan

AU - Wedderburn, Lucy R.

AU - Anton, Jordi

AU - Schwarza, Tobias

AU - Hinksb, Anne

AU - Bilginer, Yelda

AU - Park, Jane

AU - Cobb, Joanna

AU - Satorius, Colleen L.

AU - Han, Buhm

AU - Baskin, Elizabeth

AU - Signa, Sara

AU - Duerr, Richard H.

AU - Achkar, J. P.

AU - Kamboh, M. Ilyas

AU - Kaufman, Kenneth M.

AU - Kottyan, Leah C.

AU - Pinto, Dalila

AU - Scherer, Stephen W.

AU - Alarcón-Riquelme, Marta E.

AU - Docampo, Elisa

AU - Estivill, Xavier P.

AU - Gül, Ahmet

AU - De Bakker, Paul I W

AU - Raychaudhuri, Soumya

AU - Langefeld, Carl D.

AU - Thompson, Susan

AU - Zeggini, Eleftheria

AU - Thomson, Wendy

AU - Kastner, Daniel L.

AU - Woo, Patricia

PY - 2015/12/29

Y1 - 2015/12/29

N2 - Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10-17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10-5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1∗11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10-16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1∗11-HLADQA1∗ 05-HLA-DQB1∗03 haplotype [6.4 × 10-17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

AB - Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10-17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10-5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1∗11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10-16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1∗11-HLADQA1∗ 05-HLA-DQB1∗03 haplotype [6.4 × 10-17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

KW - Autoinflammation

KW - Human leukocyte antigen

KW - Still's disease

KW - Systemic juvenile idiopathic arthritis

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