A Large-Scale Genetic Analysis Reveals a Strong Contribution of the HLA Class II Region to Giant Cell Arteritis Susceptibility

被引：131

作者：

David Carmona, F. ^{[1
]}

Mackie, Sarah L. ^{[2
,3
]}

Martin, Jose-Ezequiel ^{[1
]}

Taylor, John C. ^{[4
,5
]}

Vaglio, Augusto ^{[6
]}

Eyre, Stephen ^{[7
,8
]}

Bossini-Castillo, Lara ^{[1
]}

Castaneda, Santos ^{[9
]}

Cid, Maria C. ^{[10
]}

Hernandez-Rodriguez, Jose ^{[10
]}

Prieto-Gonzalez, Sergio ^{[10
]}

Solans, Roser ^{[11
]}

Ramentol-Sintas, Marc ^{[11
]}

Francisca Gonzalez-Escribano, M. ^{[12
]}

Ortiz-Fernandez, Lourdes ^{[12
]}

Morado, Inmaculada C. ^{[13
]}

Narvaez, Javier ^{[14
]}

Miranda-Filloy, Jose A. ^{[15
]}

Beretta, Lorenzo ^{[16
]}

Lunardi, Claudio ^{[17
]}

Cimmino, Marco A. ^{[18
]}

Gianfreda, Davide ^{[19
]}

Santilli, Daniele ^{[20
]}

Ramirez, Giuseppe A. ^{[21
,22
]}

Soriano, Alessandra ^{[23
]}

Muratore, Francesco ^{[24
]}

Pazzola, Giulia ^{[24
]}

Addimanda, Olga ^{[24
]}

Wijmenga, Cisca ^{[25
]}

Witte, Torsten ^{[26
]}

Schirmer, Jan H. ^{[27
,28
]}

Moosig, Frank ^{[27
,28
]}

Schoenau, Verena ^{[29
]}

Franke, Andre ^{[30
]}

Palm, Oyvind ^{[31
]}

Molberg, Oyvind ^{[31
]}

Diamantopoulos, Andreas P. ^{[32
]}

Carette, Simon ^{[33
]}

Cuthbertson, David ^{[34
]}

Forbess, Lindsy J. ^{[35
]}

Hoffman, Gary S. ^{[36
]}

Khalidi, Nader A. ^{[37
]}

Koening, Curry L. ^{[38
]}

Langford, Carol A. ^{[36
]}

McAlear, Carol A. ^{[39
]}

Moreland, Larry ^{[40
]}

Monach, Paul A. ^{[41
]}

Pagnoux, Christian ^{[33
]}

Seo, Philip ^{[42
]}

Spiera, Robert ^{[43
]}

机构：

[1] PTS Granada, CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18016, Spain

[2] Univ Leeds, Leeds Inst Rheumat & Musculoskeletal Med, Leeds LS7 4SA, W Yorkshire, England

[3] Univ Leeds, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds LS7 4SA, W Yorkshire, England

[4] Univ Leeds, Sch Med, Leeds LS9 7TF, W Yorkshire, England

[5] Univ Leeds, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds LS9 7TF, W Yorkshire, England

[6] Univ Hosp Parma, Nephrol Unit, I-43126 Parma, Italy

[7] Manchester Acad Hlth Sci, NIHR Manchester Musculoskeletal Biomed Res Unit, Manchester, Lancs, England

[8] Univ Manchester, Arthrit Res UK Epidemiol Unit, Manchester M13 9NT, Lancs, England

[9] Hosp Princesa, IIS Princesa, Dept Rheumatol, Madrid 28006, Spain

[10] Univ Barcelona, Hosp Clin, Dept Autoimmune Dis, Vasculitis Res Unit,IDIBAPS, E-08036 Barcelona, Spain

[11] Autonomous Univ Barcelona, Dept Internal Med, Hosp Vall Hebron, Autoimmune Syst Dis Unit, E-08035 Barcelona, Spain

[12] US, CSIC, Hosp Univ Virgen Rocio, Dept Immunol,IBiS, Seville 41013, Spain

[13] Hosp Clin San Carlos, Dept Rheumatol, Madrid 28040, Spain

[14] Hosp Univ Bellvitge IDIBELL, Dept Rheumatol, Barcelona 08907, Spain

[15] Hosp Xeral Calde, Dept Rheumatol, Lugo 27004, Spain

[16] Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Referral Ctr Syst Autoimmune Dis, I-20122 Milan, Italy

[17] Univ Verona, Dept Med, I-37134 Verona, Italy

[18] Univ Genoa, Dept Internal Med, Div Clin Rheumatol, Res Lab & Acad Div Clin Rheumatol, I-16132 Genoa, Italy

[19] Univ Parma, Sch Med, Dept Clin & Expt Med, I-43126 Parma, Italy

[20] Univ Hosp Parma, Unit Internal Med & Rheumatol, I-43126 Parma, Italy

[21] IRCCS Osped San Raffaele, Unit Internal Med & Immunol, I-20132 Milan, Italy

[22] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[23] Campus Biomedico Univ, Dept Clin Med & Rheumatol, I-00128 Rome, Italy

[24] Azienda Osped Arcispedale Santa Maria Nuova, Ist Ricovero & Cura Carattere Sci, Dept Internal Med, Rheumatol Unit, I-42123 Reggio Emilia, Italy

[25] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 Groningen, Netherlands

[26] Hannover Med Sch, D-30625 Hannover, Germany

[27] Klinikum Bad Bramstedt, Vasculitis Clin, D-24576 Bad Bramstedt, Germany

[28] Univ Hosp Schleswig Holstein, D-24576 Bad Bramstedt, Germany

[29] Univ Klinikum Erlangen, Dept Rheumatol & Immunol, D-91054 Erlangen, Germany

[30] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[31] Oslo Univ Hosp, Dept Rheumatol, N-0424 Oslo, Norway

[32] Hosp Southern Norway Trust, Dept Rheumatol, N-4604 Kristiansand, Norway

[33] Mt Sinai Hosp, Div Rheumatol, Toronto, ON M5T 3L9, Canada

[34] Univ S Florida, Dept Biostat, Tampa, FL 33612 USA

[35] Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA

[36] Cleveland Clin Fdn, Ctr Vasculitis Care & Res, Cleveland, OH 44195 USA

[37] McMaster Univ, St Josephs Healthcare, Div Rheumatol, Hamilton, ON L8N 1Y2, Canada

[38] Univ Utah, Div Rheumatol, Salt Lake City, UT 84132 USA

[39] Univ Penn, Div Rheumatol, Penn Vasculitis Ctr, Philadelphia, PA 19104 USA

[40] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA 15261 USA

[41] Boston Univ, Sch Med, Rheumatol Sect, Boston, MA 02118 USA

[42] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD 21224 USA

[43] Hosp Special Surg, Dept Rheumatol, New York, NY 10021 USA

[44] Mayo Clin, Coll Med, Div Rheumatol, Rochester, MN 55905 USA

[45] North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY 11030 USA

[46] Leeds Teaching Hosp NHS Trust, Dept Rheumatol, Leeds LS7 4SA, W Yorkshire, England

[47] Harrogate & Dist NHS Fdn Trust, Dept Rheumatol, Harrogate HG2 7SX, England

[48] York Teaching Hosp NHS Fdn Trust, Dept Rheumatol, York YO31 8HE, N Yorkshire, England

[49] Mid Yorkshire Hosp NHS Trust, Dewsbury & Dist Hosp, Dept Rheumatol, Dewsbury WF13 4HS, England

[50] Mid Yorkshire Hosp NHS Trust, Pinderfields Hosp, Dept Rheumatol, Wakefield WF1 4DG, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 96卷 / 04期

基金：

英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; TYROSINE-PHOSPHATASE PTPN22; PRIMARY BILIARY-CIRRHOSIS; EXTENDED HUMAN MHC; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; POLYMYALGIA-RHEUMATICA; RISK LOCI; ATOPIC-DERMATITIS; FOXP3; EXPRESSION;

D O I：

10.1016/j.ajhg.2015.02.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DR beta 1 and HLA-DQ alpha 1 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 DR beta 1 13 (p = 4.08 x 10(-43)) and HLA-DQ alpha 1 47 (p = 4.02 x 10(-46)), 56, and 76 (both p = 1.84 x 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 x 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 x 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 x 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.

引用

页码：565 / 580

页数：16

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