A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

F. David Carmona; Sarah L. Mackie; Jose Ezequiel Martín; John C. Taylor; Augusto Vaglio; Stephen Eyre; Lara Bossini-Castillo; Santos Castañeda; Maria C. Cid; José Hernández-Rodríguez; Sergio Prieto-González; Roser Solans; Marc Ramentol-Sintas; M. Francisca González-Escribano; Lourdes Ortiz-Fernández; Inmaculada C. Morado; Javier Narváez; José A. Miranda-Filloy; Lorenzo Beretta; Claudio Lunardi; Marco A. Cimmino; Davide Gianfreda; Daniele Santilli; Giuseppe A. Ramirez; Alessandra Soriano; Francesco Muratore; Giulia Pazzola; Olga Addimanda; Cisca Wijmenga; Torsten Witte; Jan H. Schirmer; Frank Moosig; Verena Schönau; Andre Franke; Oyvind Palm; Oyvind Molberg; Andreas P. Diamantopoulos; Simon Carette; David Cuthbertson; Lindsy J. Forbess; Gary S. Hoffman; Nader A. Khalidi; Curry L. Koening; Carol A. Langford; Carol A. McAlear; Larry Moreland; Paul A. Monach; Christian Pagnoux; Philip Seo; Robert Spiera; Antoine G. Sreih; Kenneth J. Warrington; Steven R. Ytterberg; Peter K. Gregersen; Colin T. Pease; Andrew Gough; Michael Green; Lesley Hordon; Stephen Jarrett; Richard Watts; Sarah Levy; Yusuf Patel; Sanjeet Kamath; Bhaskar Dasgupta; Jane Worthington; Bobby P.C. Koeleman; Paul I.W. De Bakker; Jennifer H. Barrett; Carlo Salvarani; Peter A. Merkel; Miguel A. González-Gay; Ann W. Morgan; Javier Martín

doi:10.1016/j.ajhg.2015.02.009

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

F. David Carmona, Sarah L. Mackie, Jose Ezequiel Martín, John C. Taylor, Augusto Vaglio, Stephen Eyre, Lara Bossini-Castillo, Santos Castañeda, Maria C. Cid, José Hernández-Rodríguez, Sergio Prieto-González, Roser Solans, Marc Ramentol-Sintas, M. Francisca González-Escribano, Lourdes Ortiz-Fernández, Inmaculada C. Morado, Javier Narváez, José A. Miranda-Filloy, Lorenzo Beretta, Claudio LunardiMarco A. Cimmino, Davide Gianfreda, Daniele Santilli, Giuseppe A. Ramirez, Alessandra Soriano, Francesco Muratore, Giulia Pazzola, Olga Addimanda, Cisca Wijmenga, Torsten Witte, Jan H. Schirmer, Frank Moosig, Verena Schönau, Andre Franke, Oyvind Palm, Oyvind Molberg, Andreas P. Diamantopoulos, Simon Carette, David Cuthbertson, Lindsy J. Forbess, Gary S. Hoffman, Nader A. Khalidi, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Larry Moreland, Paul A. Monach, Christian Pagnoux, Philip Seo, Robert Spiera, Antoine G. Sreih, Kenneth J. Warrington, Steven R. Ytterberg, Peter K. Gregersen, Colin T. Pease, Andrew Gough, Michael Green, Lesley Hordon, Stephen Jarrett, Richard Watts, Sarah Levy, Yusuf Patel, Sanjeet Kamath, Bhaskar Dasgupta, Jane Worthington, Bobby P.C. Koeleman, Paul I.W. De Bakker, Jennifer H. Barrett, Carlo Salvarani, Peter A. Merkel, Miguel A. González-Gay, Ann W. Morgan, Javier Martín

School of Medicine

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

93 Scopus citations

Abstract

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10^-40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1^∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10^-43) and HLA-DQα1 47 (p = 4.02 × 10^-46), 56, and 76 (both p = 1.84 × 10^-45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10^-6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10^-6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10^-5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

Original language	English (US)
Pages (from-to)	565-580
Number of pages	16
Journal	American journal of human genetics
Volume	96
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2015.02.009
State	Published - Apr 2 2015

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2015.02.009

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Carmona, F. D., Mackie, S. L., Martín, J. E., Taylor, J. C., Vaglio, A., Eyre, S., Bossini-Castillo, L., Castañeda, S., Cid, M. C., Hernández-Rodríguez, J., Prieto-González, S., Solans, R., Ramentol-Sintas, M., González-Escribano, M. F., Ortiz-Fernández, L., Morado, I. C., Narváez, J., Miranda-Filloy, J. A., Beretta, L., ... Martín, J. (2015). A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. American journal of human genetics, 96(4), 565-580. https://doi.org/10.1016/j.ajhg.2015.02.009

Carmona, FD, Mackie, SL, Martín, JE, Taylor, JC, Vaglio, A, Eyre, S, Bossini-Castillo, L, Castañeda, S, Cid, MC, Hernández-Rodríguez, J, Prieto-González, S, Solans, R, Ramentol-Sintas, M, González-Escribano, MF, Ortiz-Fernández, L, Morado, IC, Narváez, J, Miranda-Filloy, JA, Beretta, L, Lunardi, C, Cimmino, MA, Gianfreda, D, Santilli, D, Ramirez, GA, Soriano, A, Muratore, F, Pazzola, G, Addimanda, O, Wijmenga, C, Witte, T, Schirmer, JH, Moosig, F, Schönau, V, Franke, A, Palm, O, Molberg, O, Diamantopoulos, AP, Carette, S, Cuthbertson, D, Forbess, LJ, Hoffman, GS, Khalidi, NA, Koening, CL, Langford, CA, McAlear, CA, Moreland, L, Monach, PA, Pagnoux, C, Seo, P, Spiera, R, Sreih, AG, Warrington, KJ, Ytterberg, SR, Gregersen, PK, Pease, CT, Gough, A, Green, M, Hordon, L, Jarrett, S, Watts, R, Levy, S, Patel, Y, Kamath, S, Dasgupta, B, Worthington, J, Koeleman, BPC, De Bakker, PIW, Barrett, JH, Salvarani, C, Merkel, PA, González-Gay, MA, Morgan, AW & Martín, J 2015, 'A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility', American journal of human genetics, vol. 96, no. 4, pp. 565-580. https://doi.org/10.1016/j.ajhg.2015.02.009

@article{20155022bfdf4130901fdc96a4b18f9b,

title = "A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility",

abstract = "We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10-40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10-43) and HLA-DQα1 47 (p = 4.02 × 10-46), 56, and 76 (both p = 1.84 × 10-45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10-6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10-6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10-5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.",

author = "Carmona, {F. David} and Mackie, {Sarah L.} and Mart{\'i}n, {Jose Ezequiel} and Taylor, {John C.} and Augusto Vaglio and Stephen Eyre and Lara Bossini-Castillo and Santos Casta{\~n}eda and Cid, {Maria C.} and Jos{\'e} Hern{\'a}ndez-Rodr{\'i}guez and Sergio Prieto-Gonz{\'a}lez and Roser Solans and Marc Ramentol-Sintas and Gonz{\'a}lez-Escribano, {M. Francisca} and Lourdes Ortiz-Fern{\'a}ndez and Morado, {Inmaculada C.} and Javier Narv{\'a}ez and Miranda-Filloy, {Jos{\'e} A.} and Lorenzo Beretta and Claudio Lunardi and Cimmino, {Marco A.} and Davide Gianfreda and Daniele Santilli and Ramirez, {Giuseppe A.} and Alessandra Soriano and Francesco Muratore and Giulia Pazzola and Olga Addimanda and Cisca Wijmenga and Torsten Witte and Schirmer, {Jan H.} and Frank Moosig and Verena Sch{\"o}nau and Andre Franke and Oyvind Palm and Oyvind Molberg and Diamantopoulos, {Andreas P.} and Simon Carette and David Cuthbertson and Forbess, {Lindsy J.} and Hoffman, {Gary S.} and Khalidi, {Nader A.} and Koening, {Curry L.} and Langford, {Carol A.} and McAlear, {Carol A.} and Larry Moreland and Monach, {Paul A.} and Christian Pagnoux and Philip Seo and Robert Spiera and Sreih, {Antoine G.} and Warrington, {Kenneth J.} and Ytterberg, {Steven R.} and Gregersen, {Peter K.} and Pease, {Colin T.} and Andrew Gough and Michael Green and Lesley Hordon and Stephen Jarrett and Richard Watts and Sarah Levy and Yusuf Patel and Sanjeet Kamath and Bhaskar Dasgupta and Jane Worthington and Koeleman, {Bobby P.C.} and {De Bakker}, {Paul I.W.} and Barrett, {Jennifer H.} and Carlo Salvarani and Merkel, {Peter A.} and Gonz{\'a}lez-Gay, {Miguel A.} and Morgan, {Ann W.} and Javier Mart{\'i}n",

note = "Funding Information: The authors thank Sof{\'i}a Vargas, Sonia Garc{\'i}a, Gema Robledo, Steve Martin, Lubna-Haroon Raashid, and Edward Flynn for their excellent technical assistance and the participants for kindly accepting their collaboration. Steve Rich, Stephen Suna Onengut-Gumuscu, and Wei-Min Chen are thanked for genotyping and quality control. Marta Conde-Jald{\'o}n is thanked for assisting in HLA typing. The Norwegian Systemic Vasculitis and Connective Tissue Disease Registry (NOSVAR) at Oslo University Hospital is acknowledged for providing data on the Norwegian cases. F.D.C., J.M., and M.A.G.-G. were supported by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Program RD12/0009/0004 (RIER). M.C.C., J.H.-R., and S.P.-G. were supported by Ministerio de Econom{\'i}a y Competitividad, Spain (SAF 11/30073). S.L.M. received grant funding from Research into Ageing, a Wellcome Trust/AMS Starter Grant for Clinical Lecturers, the Leeds Teaching Hospitals Charitable Trustees, and the Mason Medical Research Foundation and is funded by a NIH Research Clinician Scientist Award. A.W.M., J.H.B., and J.C.T. were supported by the NIHR-Leeds Musculoskeletal Biomedical Research Unit and the Ann Wilks Memorial Fund. The Vasculitis Clinical Research Consortium (VCRC) received support from the United States National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319), the National Center for Research Resources (U54 RR019497), the Office of Rare Diseases Research, and the National Center for Advancing Translational Science. The VCRC is part of the Rare Diseases Clinical Research Network (RDCRN). A.P.D. was funded by Agder Medforsk (non-profit research organization stationed in Southern Norway). T.W. was funded by the grant DFG KFO TP03. Publisher Copyright: {\textcopyright} 2015 The American Society of Human Genetics.",

year = "2015",

month = apr,

day = "2",

doi = "10.1016/j.ajhg.2015.02.009",

language = "English (US)",

volume = "96",

pages = "565--580",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

AU - Carmona, F. David

AU - Mackie, Sarah L.

AU - Martín, Jose Ezequiel

AU - Taylor, John C.

AU - Vaglio, Augusto

AU - Eyre, Stephen

AU - Bossini-Castillo, Lara

AU - Castañeda, Santos

AU - Cid, Maria C.

AU - Hernández-Rodríguez, José

AU - Prieto-González, Sergio

AU - Solans, Roser

AU - Ramentol-Sintas, Marc

AU - González-Escribano, M. Francisca

AU - Ortiz-Fernández, Lourdes

AU - Morado, Inmaculada C.

AU - Narváez, Javier

AU - Miranda-Filloy, José A.

AU - Beretta, Lorenzo

AU - Lunardi, Claudio

AU - Cimmino, Marco A.

AU - Gianfreda, Davide

AU - Santilli, Daniele

AU - Ramirez, Giuseppe A.

AU - Soriano, Alessandra

AU - Muratore, Francesco

AU - Pazzola, Giulia

AU - Addimanda, Olga

AU - Wijmenga, Cisca

AU - Witte, Torsten

AU - Schirmer, Jan H.

AU - Moosig, Frank

AU - Schönau, Verena

AU - Franke, Andre

AU - Palm, Oyvind

AU - Molberg, Oyvind

AU - Diamantopoulos, Andreas P.

AU - Carette, Simon

AU - Cuthbertson, David

AU - Forbess, Lindsy J.

AU - Hoffman, Gary S.

AU - Khalidi, Nader A.

AU - Koening, Curry L.

AU - Langford, Carol A.

AU - McAlear, Carol A.

AU - Moreland, Larry

AU - Monach, Paul A.

AU - Pagnoux, Christian

AU - Seo, Philip

AU - Spiera, Robert

AU - Sreih, Antoine G.

AU - Warrington, Kenneth J.

AU - Ytterberg, Steven R.

AU - Gregersen, Peter K.

AU - Pease, Colin T.

AU - Gough, Andrew

AU - Green, Michael

AU - Hordon, Lesley

AU - Jarrett, Stephen

AU - Watts, Richard

AU - Levy, Sarah

AU - Patel, Yusuf

AU - Kamath, Sanjeet

AU - Dasgupta, Bhaskar

AU - Worthington, Jane

AU - Koeleman, Bobby P.C.

AU - De Bakker, Paul I.W.

AU - Barrett, Jennifer H.

AU - Salvarani, Carlo

AU - Merkel, Peter A.

AU - González-Gay, Miguel A.

AU - Morgan, Ann W.

AU - Martín, Javier

N1 - Funding Information: The authors thank Sofía Vargas, Sonia García, Gema Robledo, Steve Martin, Lubna-Haroon Raashid, and Edward Flynn for their excellent technical assistance and the participants for kindly accepting their collaboration. Steve Rich, Stephen Suna Onengut-Gumuscu, and Wei-Min Chen are thanked for genotyping and quality control. Marta Conde-Jaldón is thanked for assisting in HLA typing. The Norwegian Systemic Vasculitis and Connective Tissue Disease Registry (NOSVAR) at Oslo University Hospital is acknowledged for providing data on the Norwegian cases. F.D.C., J.M., and M.A.G.-G. were supported by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Program RD12/0009/0004 (RIER). M.C.C., J.H.-R., and S.P.-G. were supported by Ministerio de Economía y Competitividad, Spain (SAF 11/30073). S.L.M. received grant funding from Research into Ageing, a Wellcome Trust/AMS Starter Grant for Clinical Lecturers, the Leeds Teaching Hospitals Charitable Trustees, and the Mason Medical Research Foundation and is funded by a NIH Research Clinician Scientist Award. A.W.M., J.H.B., and J.C.T. were supported by the NIHR-Leeds Musculoskeletal Biomedical Research Unit and the Ann Wilks Memorial Fund. The Vasculitis Clinical Research Consortium (VCRC) received support from the United States National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR057319), the National Center for Research Resources (U54 RR019497), the Office of Rare Diseases Research, and the National Center for Advancing Translational Science. The VCRC is part of the Rare Diseases Clinical Research Network (RDCRN). A.P.D. was funded by Agder Medforsk (non-profit research organization stationed in Southern Norway). T.W. was funded by the grant DFG KFO TP03. Publisher Copyright: © 2015 The American Society of Human Genetics.

PY - 2015/4/2

Y1 - 2015/4/2

N2 - We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10-40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10-43) and HLA-DQα1 47 (p = 4.02 × 10-46), 56, and 76 (both p = 1.84 × 10-45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10-6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10-6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10-5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

AB - We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10-40, OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1∗04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10-43) and HLA-DQα1 47 (p = 4.02 × 10-46), 56, and 76 (both p = 1.84 × 10-45) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10-6, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10-6, OR = 1.20), and REL (rs115674477, p = 1.10 × 10-5, OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

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U2 - 10.1016/j.ajhg.2015.02.009

DO - 10.1016/j.ajhg.2015.02.009

M3 - Article

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AN - SCOPUS:84926262586

SN - 0002-9297

VL - 96

SP - 565

EP - 580

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

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