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 - 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.
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
SN - 0002-9297
VL - 96
SP - 565
EP - 580
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -