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 Schwarz; Anne Hinks; 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 Schwarz, Anne Hinks, 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,

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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-HLA-DQA1*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
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
Publication status	Published - 29 Dec 2015

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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. (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

@article{05f0b8afc3464ef185c29752c46e3d54,

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-HLA-DQA1*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.",

author = "Ombrello, {Michael J} and Remmers, {Elaine F} and Ioanna Tachmazidou and Alexei Grom and Dirk Foell and Johannes-Peter Haas 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 Schwarz and Anne Hinks 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",

year = "2015",

month = dec,

day = "29",

doi = "10.1073/pnas.1520779112",

language = "English",

volume = "112",

pages = "15970--15975",

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

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Ombrello, MJ, Remmers, EF, Tachmazidou, I, Grom, A, Foell, D, Haas, J-P, 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, Schwarz, T, Hinks, 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

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 › Academic › peer-review

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 - Schwarz, Tobias

AU - Hinks, 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

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-HLA-DQA1*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-HLA-DQA1*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.

U2 - 10.1073/pnas.1520779112

DO - 10.1073/pnas.1520779112

M3 - Article

C2 - 26598658

SN - 0027-8424

VL - 112

SP - 15970

EP - 15975

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 52

ER -

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

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