HLA-DRB1∗11 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 Rosenberg; Lucy 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 Estivill; Ahmet Gül; Paul I.W. De Bakker; Soumya Raychaudhuri; Carl D. Langefeld; Susan Thompson; Eleftheria Zeggini; Wendy Thomson; Daniel L. Kastner; Patricia Woo

doi:10.1073/pnas.1520779112

HLA-DRB1^∗11 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 Estivill, Ahmet Gül, Paul I.W. De Bakker, Soumya Raychaudhuri, Carl D. Langefeld, Susan Thompson, Eleftheria Zeggini, Wendy Thomson, Daniel L. Kastner, Patricia Woo

Pediatrics

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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.

Original language	English (US)
Pages (from-to)	15970-15975
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	52
DOIs	https://doi.org/10.1073/pnas.1520779112
State	Published - Dec 29 2015

Keywords

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

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1073/pnas.1520779112

Cite this

Ombrello, M. J., Remmers, E. F., Tachmazidou, I., Grom, A., Foell, D., Haas, J. P., Martini, A., Gattorno, M., Özen, S., Prahalad, S., Zeft, A. S., Bohnsack, J. F., Mellins, E. D., Ilowite, N. T., Russo, R., Len, C., Hilario, M. O. E., Oliveira, S., Yeung, R. S. M., ... Woo, P. (2015). HLA-DRB1^∗11 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, 112(52), 15970-15975. https://doi.org/10.1073/pnas.1520779112

HLA-DRB1^∗11 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 et al.
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 journal › Article › peer-review

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, X, Gül, A, De Bakker, PIW, Raychaudhuri, S, Langefeld, CD, Thompson, S, Zeggini, E, Thomson, W, Kastner, DL & Woo, P 2015, 'HLA-DRB1^∗11 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

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title = "HLA-DRB1∗11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis",

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.",

keywords = "Autoinflammation, Human leukocyte antigen, Still's disease, Systemic juvenile idiopathic arthritis",

author = "Ombrello, {Michael J.} and Remmers, {Elaine F.} and Ioanna Tachmazidou and Alexei Grom and Dirk Foell and Haas, {Johannes Peter} and Alberto Martini and Marco Gattorno and Seza {\"O}zen and Sampath Prahalad and Zeft, {Andrew S.} and Bohnsack, {John F.} and Mellins, {Elizabeth D.} and Ilowite, {Norman T.} and Ricardo Russo and Claudio Len and Hilario, {Maria Odete E.} and Sheila Oliveira and Yeung, {Rae S.M.} and Alan Rosenberg and Wedderburn, {Lucy R.} and Jordi Anton and Tobias Schwarza and Anne Hinksb and Yelda Bilginer and Jane Park and Joanna Cobb and Satorius, {Colleen L.} and Buhm Han and Elizabeth Baskin and Sara Signa and Duerr, {Richard H.} and Achkar, {J. P.} and Kamboh, {M. Ilyas} and Kaufman, {Kenneth M.} and Kottyan, {Leah C.} and Dalila Pinto and Scherer, {Stephen W.} and Alarc{\'o}n-Riquelme, {Marta E.} and Elisa Docampo and Xavier Estivill and Ahmet G{\"u}l and {De Bakker}, {Paul I.W.} and Soumya Raychaudhuri and Langefeld, {Carl D.} and Susan Thompson and Eleftheria Zeggini and Wendy Thomson and Kastner, {Daniel L.} and Patricia Woo",

note = "Funding Information: This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198, to M.J.O.) and the National Human Genome Research Institute (Z01-HG200370, to D.L.K.) of the NIH. Additional funding was provided by NIH Grants R01-AR059049 (to A. Grom), R01-AR060893 (to S.P.), N1R01-AR062886 (to P.I.W.d.B.), AG030653, AG041718, and AG005133 (to M.I.K.), and U01-DK062420 and R01-DK076025 (to R.H.D.); Arthritis Research UK Grant 20385 (to W.T.); the Netherlands Organization for Scientific Research Project No. 016.126.354 (to P.I.W.d.B.); the Marcus Foundation (S.P.); the Wellcome Trust Grant 098051 (to E.Z.); the Val A. Browning Charitable Foundation (J.F.B.); and a Crohn''s & Colitis Foundation of America Senior Research Award (to R.H.D.). UK patient cohorts were supported by Arthritis Research UK (Grants 20542 and 20386). Sparks-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08), the Medical Research Council (MR/M004600/1), and the UK National Institute for Health Research Medicines for Children Research Network. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of data is available at www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. This study utilized the computational resources of the NIH high-performance computing Biowulf cluster (https://hpc.nih.gov).",

year = "2015",

month = dec,

day = "29",

doi = "10.1073/pnas.1520779112",

language = "English (US)",

volume = "112",

pages = "15970--15975",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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publisher = "National Academy of Sciences",

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TY - JOUR

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

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

N1 - Funding Information: This work was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Z01-AR041198, to M.J.O.) and the National Human Genome Research Institute (Z01-HG200370, to D.L.K.) of the NIH. Additional funding was provided by NIH Grants R01-AR059049 (to A. Grom), R01-AR060893 (to S.P.), N1R01-AR062886 (to P.I.W.d.B.), AG030653, AG041718, and AG005133 (to M.I.K.), and U01-DK062420 and R01-DK076025 (to R.H.D.); Arthritis Research UK Grant 20385 (to W.T.); the Netherlands Organization for Scientific Research Project No. 016.126.354 (to P.I.W.d.B.); the Marcus Foundation (S.P.); the Wellcome Trust Grant 098051 (to E.Z.); the Val A. Browning Charitable Foundation (J.F.B.); and a Crohn''s & Colitis Foundation of America Senior Research Award (to R.H.D.). UK patient cohorts were supported by Arthritis Research UK (Grants 20542 and 20386). Sparks-CHARMS was funded by grants from SPARKS UK (08ICH09 and 12ICH08), the Medical Research Council (MR/M004600/1), and the UK National Institute for Health Research Medicines for Children Research Network. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of data is available at www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. This study utilized the computational resources of the NIH high-performance computing Biowulf cluster (https://hpc.nih.gov).

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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