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

Research output: Contribution to journalArticle

69 Citations (Scopus)

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<sup>-40</sup>, 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<sup>∗</sup>04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10<sup>-43</sup>) and HLA-DQα1 47 (p = 4.02 × 10<sup>-46</sup>), 56, and 76 (both p = 1.84 × 10<sup>-45</sup>) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10<sup>-6</sup>, OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10<sup>-6</sup>, OR = 1.20), and REL (rs115674477, p = 1.10 × 10<sup>-5</sup>, 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 languageEnglish (US)
Pages (from-to)565-580
Number of pages16
JournalAmerican Journal of Human Genetics
Volume96
Issue number4
DOIs
StatePublished - Apr 2 2015

Fingerprint

Giant Cell Arteritis
Amino Acids
HLA-DR1 Antigen
Th17 Cells
Th1 Cells
HLA-B Antigens
Disease Susceptibility
Regulatory T-Lymphocytes
Vasculitis
Alleles

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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

In: American Journal of Human Genetics, Vol. 96, No. 4, 02.04.2015, p. 565-580.

Research output: Contribution to journalArticle

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
Carmona, F. David ; Mackie, Sarah L. ; Martín, Jose Ezequiel ; Taylor, John C. ; Vaglio, Augusto ; Eyre, Stephen ; Bossini-Castillo, Lara ; Castañeda, Santos ; Cid, Maria C. ; Hernández-Rodríguez, José ; Prieto-González, Sergio ; Solans, Roser ; Ramentol-Sintas, Marc ; González-Escribano, M. Francisca ; Ortiz-Fernández, Lourdes ; Morado, Inmaculada C. ; Narváez, Javier ; Miranda-Filloy, José A. ; Beretta, Lorenzo ; Lunardi, Claudio ; Cimmino, Marco A. ; Gianfreda, Davide ; Santilli, Daniele ; Ramirez, Giuseppe A. ; Soriano, Alessandra ; Muratore, Francesco ; Pazzola, Giulia ; Addimanda, Olga ; Wijmenga, Cisca ; Witte, Torsten ; Schirmer, Jan H. ; Moosig, Frank ; Schönau, Verena ; Franke, Andre ; Palm, Oyvind ; Molberg, Oyvind ; Diamantopoulos, Andreas P. ; Carette, Simon ; Cuthbertson, David ; Forbess, Lindsy J. ; Hoffman, Gary S. ; Khalidi, Nader A. ; Koening, Curry L. ; Langford, Carol A. ; McAlear, Carol A. ; Moreland, Larry ; Monach, Paul A. ; Pagnoux, Christian ; Seo, Philip ; Spiera, Robert ; Sreih, Antoine G. ; Warrington, Kenneth J ; Ytterberg, Steven R ; Gregersen, Peter K. ; Pease, Colin T. ; Gough, Andrew ; Green, Michael ; Hordon, Lesley ; Jarrett, Stephen ; Watts, Richard ; Levy, Sarah ; Patel, Yusuf ; Kamath, Sanjeet ; Dasgupta, Bhaskar ; Worthington, Jane ; Koeleman, Bobby P C ; De Bakker, Paul I W ; Barrett, Jennifer H. ; Salvarani, Carlo ; Merkel, Peter A. ; González-Gay, Miguel A. ; Morgan, Ann W. ; Martín, Javier. / A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 4. pp. 565-580.
@article{ca079a1df3be4dbb91a0a47fdb1fda79,
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",
year = "2015",
month = "4",
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

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.

UR - http://www.scopus.com/inward/record.url?scp=84926262586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926262586&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.02.009

DO - 10.1016/j.ajhg.2015.02.009

M3 - Article

C2 - 25817017

AN - SCOPUS:84926262586

VL - 96

SP - 565

EP - 580

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -