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 Martin; J C Taylor; Augusto Vaglio; Steve Eyre; L. Bossini-Castillo; s Castenada; Maria C. Cid; José Hernández-Rodríguez; Sergio Prieto-González; Roser Solans; Marc Ramentol-Sintas; María F. González-Escribano; Lourdes Ortiz-Fernández; Inmaculada C. Morado; Javier Narváez; José A. Miranda-Filloy; Luciano Beretta; Claudio Lunardi; Marco A. Cimmino; Davide Gianfreda; Daniele Santilli; Giuseppe A. Ramirez; Alessandra Soriano; F. Muratore; Giulia Pazzola; Olga Addimanda; Cisca Wijmenga; t witte; Jan H. Schirmer; Frank Moosig; Verena Schönau; a franke; Øyvind Palm; Øyvind Molberg; A.P. Diamantopulos; Simon Carette; David Cuthbertson; Lindsy J. Forbess; Gary S. Hoffman; NA Khalidi; Curry L. Koening; Carol A. Langford; Carol A. McAlear; Larry Moreland; Paul A. Monach; C. 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; B Dasqupta; Jane Worthington; Bobby P C Koeleman; PI De Bakker; Jennifer H. Barrett; Carlo Salvarani; Peter A. Merkel; Miguelángel González-Gay; Ann W. Morgan; J Martin

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 Martin, J C Taylor, Augusto Vaglio, Steve Eyre, L. Bossini-Castillo, s Castenada, Maria C. Cid, José Hernández-Rodríguez, Sergio Prieto-González, Roser Solans, Marc Ramentol-Sintas, María F. González-Escribano, Lourdes Ortiz-Fernández, Inmaculada C. Morado, Javier Narváez, José A. Miranda-Filloy, Luciano Beretta, Claudio LunardiMarco A. Cimmino, Davide Gianfreda, Daniele Santilli, Giuseppe A. Ramirez, Alessandra Soriano, F. Muratore, Giulia Pazzola, Olga Addimanda, Cisca Wijmenga, t witte, Jan H. Schirmer, Frank Moosig, Verena Schönau, a franke, Øyvind Palm, Øyvind Molberg, A.P. Diamantopulos, Simon Carette, David Cuthbertson, Lindsy J. Forbess, Gary S. Hoffman, NA Khalidi, Curry L. Koening, Carol A. Langford, Carol A. McAlear, Larry Moreland, Paul A. Monach, C. 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, B Dasqupta, Jane Worthington, Bobby P C Koeleman, PI De Bakker, Jennifer H. Barrett, Carlo Salvarani, Peter A. Merkel, Miguelángel González-Gay, Ann W. Morgan, J Martin

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

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
Pages (from-to)	565-580
Number of pages	15
Journal	American Journal of Human Genetics
Volume	96
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2015.02.009
Publication status	Published - 2015

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David Carmona, F., Mackie, S. L., Martin, J. E., Taylor, J. C., Vaglio, A., Eyre, S., Bossini-Castillo, L., Castenada, 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., ... Martin, 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

David Carmona, F, Mackie, SL, Martin, JE, Taylor, JC, Vaglio, A, Eyre, S, Bossini-Castillo, L, Castenada, 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, Ø, Molberg, Ø, Diamantopulos, 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, Dasqupta, B, Worthington, J, Koeleman, BPC, De Bakker, PI, Barrett, JH, Salvarani, C, Merkel, PA, González-Gay, M, Morgan, AW & Martin, 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{a3c333b3745c4209a29baa8e2878c388,

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 = "{David Carmona}, F. and Mackie, {Sarah L.} and Martin, {Jose Ezequiel} and Taylor, {J C} and Augusto Vaglio and Steve Eyre and L. Bossini-Castillo and s Castenada 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, {Mar{\'i}a F.} and Lourdes Ortiz-Fern{\'a}ndez and Morado, {Inmaculada C.} and Javier Narv{\'a}ez and Miranda-Filloy, {Jos{\'e} A.} and Luciano Beretta and Claudio Lunardi and Cimmino, {Marco A.} and Davide Gianfreda and Daniele Santilli and Ramirez, {Giuseppe A.} and Alessandra Soriano and F. Muratore and Giulia Pazzola and Olga Addimanda and Cisca Wijmenga and t witte and Schirmer, {Jan H.} and Frank Moosig and Verena Sch{\"o}nau and a franke and {\O}yvind Palm and {\O}yvind Molberg and A.P. Diamantopulos and Simon Carette and David Cuthbertson and Forbess, {Lindsy J.} and Hoffman, {Gary S.} and NA Khalidi and Koening, {Curry L.} and Langford, {Carol A.} and McAlear, {Carol A.} and Larry Moreland and Monach, {Paul A.} and C. 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 B Dasqupta and Jane Worthington and Koeleman, {Bobby P C} and {De Bakker}, PI and Barrett, {Jennifer H.} and Carlo Salvarani and Merkel, {Peter A.} and Miguel{\'a}ngel Gonz{\'a}lez-Gay and Morgan, {Ann W.} and J Martin",

year = "2015",

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

language = "English",

volume = "96",

pages = "565--580",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

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TY - JOUR

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

AU - David Carmona, F.

AU - Mackie, Sarah L.

AU - Martin, Jose Ezequiel

AU - Taylor, J C

AU - Vaglio, Augusto

AU - Eyre, Steve

AU - Bossini-Castillo, L.

AU - Castenada, s

AU - Cid, Maria C.

AU - Hernández-Rodríguez, José

AU - Prieto-González, Sergio

AU - Solans, Roser

AU - Ramentol-Sintas, Marc

AU - González-Escribano, María F.

AU - Ortiz-Fernández, Lourdes

AU - Morado, Inmaculada C.

AU - Narváez, Javier

AU - Miranda-Filloy, José A.

AU - Beretta, Luciano

AU - Lunardi, Claudio

AU - Cimmino, Marco A.

AU - Gianfreda, Davide

AU - Santilli, Daniele

AU - Ramirez, Giuseppe A.

AU - Soriano, Alessandra

AU - Muratore, F.

AU - Pazzola, Giulia

AU - Addimanda, Olga

AU - Wijmenga, Cisca

AU - witte, t

AU - Schirmer, Jan H.

AU - Moosig, Frank

AU - Schönau, Verena

AU - franke, a

AU - Palm, Øyvind

AU - Molberg, Øyvind

AU - Diamantopulos, A.P.

AU - Carette, Simon

AU - Cuthbertson, David

AU - Forbess, Lindsy J.

AU - Hoffman, Gary S.

AU - Khalidi, NA

AU - Koening, Curry L.

AU - Langford, Carol A.

AU - McAlear, Carol A.

AU - Moreland, Larry

AU - Monach, Paul A.

AU - Pagnoux, C.

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 - Dasqupta, B

AU - Worthington, Jane

AU - Koeleman, Bobby P C

AU - De Bakker, PI

AU - Barrett, Jennifer H.

AU - Salvarani, Carlo

AU - Merkel, Peter A.

AU - González-Gay, Miguelángel

AU - Morgan, Ann W.

AU - Martin, J

PY - 2015

Y1 - 2015

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.

U2 - 10.1016/j.ajhg.2015.02.009

DO - 10.1016/j.ajhg.2015.02.009

M3 - Article

VL - 96

SP - 565

EP - 580

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

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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