A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis

被引：76

作者：

David Carmona, F. ^{[1
,2
,3
]}

Vaglio, Augusto ^{[4
]}

Mackie, Sarah L. ^{[5
,6
]}

Hernandez-Rodriguez, Jose ^{[7
]}

Monach, Paul A. ^{[8
]}

Castaneda, Santos ^{[9
]}

Solans, Roser ^{[10
]}

Morado, Inmaculada C. ^{[11
]}

Narvaez, Javier ^{[12
]}

Ramentol-Sintas, Marc ^{[10
]}

Pease, Colin T. ^{[5
,6
]}

Dasgupta, Bhaskar ^{[13
]}

Watts, Richard ^{[14
]}

Khalidi, Nader ^{[15
]}

Langford, Carol A. ^{[16
]}

Ytterberg, Steven ^{[17
]}

Boiardi, Luigi ^{[18
]}

Beretta, Lorenzo ^{[19
]}

Govoni, Marcello ^{[20
]}

Emmi, Giacomo ^{[21
]}

Bonatti, Francesco ^{[22
]}

Cimmino, Marco A. ^{[23
,24
]}

Witte, Torsten ^{[25
]}

Neumann, Thomas ^{[26
]}

Holle, Julia ^{[27
,28
]}

Schoenau, Verena ^{[29
]}

Sailler, Laurent ^{[30
]}

Papo, Thomas ^{[31
]}

Haroche, Julien ^{[32
,33
]}

Mahr, Alfred ^{[34
]}

Mouthon, Luc ^{[35
]}

Molberg, Oyvind ^{[36
]}

Diamantopoulos, Andreas P. ^{[37
]}

Voskuyl, Alexandre ^{[38
]}

Brouwer, Elisabeth ^{[39
]}

Daikeler, Thomas ^{[40
]}

Berger, Christoph T. ^{[41
,42
]}

Molloy, Eamonn S. ^{[43
]}

O'Neill, Lorraine ^{[43
]}

Blockmans, Daniel ^{[44
]}

Lie, Benedicte A. ^{[45
,46
]}

Mclaren, Paul ^{[47
]}

Vyse, Timothy J. ^{[48
,49
,50
]}

Wijmenga, Cisca ^{[51
]}

Allanore, Yannick ^{[52
]}

Koeleman, Bobby P. C. ^{[53
]}

Barrett, Jennifer H. ^{[5
,6
]}

Cid, Maria C. ^{[7
]}

Salvarani, Carlo ^{[18
]}

Merkel, Peter A. ^{[54
]}

机构：

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

[2] Univ Granada, Dept Genet, Granada 18016, Spain

[3] Univ Granada, Inst Biotecnol, Granada 18016, Spain

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

[5] Univ Leeds, Sch Med, Leeds LS7 4SA, W Yorkshire, England

[6] Leeds Teaching Hosp NHS Trust, NIHR Leeds Musculoskeletal Biomed Res Unit, Leeds LS7 4SA, W Yorkshire, England

[7] Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Vasculitis Res Unit,Dept Autoimmune Dis, E-08036 Barcelona, Spain

[8] Boston Univ, Sect Rheumatol, Boston, MA 02118 USA

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

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

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

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

[13] Southend Univ Hosp NHS Fdn Trust, Dept Rheumatol, Westcliff On Sea SS0 0RY, England

[14] Ipswich Hosp NHS Trust, Dept Rheumatol, Ipswich IP4 5PD, Suffolk, England

[15] McMaster Univ, Div Rheumatol, Hamilton, ON L8N 1Y2, Canada

[16] Cleveland Clin, Div Rheumatol, Cleveland, OH 44195 USA

[17] Mayo Clin, Div Rheumatol, Rochester, MN 55905 USA

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

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

[20] Univ Ferrara, Azienda Osped Univ S Anna, Dept Rheumatol, I-44121 Ferrara, Italy

[21] Univ Florence, Dept Expt & Clin Med, I-50134 Florence, Italy

[22] Univ Parma, Med Genet Unit, Dept Clin & Expt Med, I-43124 Parma, Italy

[23] Univ Genoa, Dept Internal Med, Res Lab, I-16132 Genoa, Italy

[24] Univ Genoa, Dept Internal Med, Acad Div Clin Rheumatol, I-16132 Genoa, Italy

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

[26] Univ Hosp Jena, Innere Med Klin 3, D-07743 Jena, 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 Toulouse, CHU Toulouse, INSERM, Serv Med Interne,Hop Purpan,UMR 1027, F-31059 Toulouse, France

[31] Univ Paris Diderot, Hop Bichat, Serv Med Interne, F-75018 Paris, France

[32] Hop La Pitie Salpetriere, AP HP, Dept Internal Med, F-75013 Paris, France

[33] Hop La Pitie Salpetriere, AP HP, French Reference Ctr Rare Autoimmune & Syst Dis, F-75013 Paris, France

[34] Univ Paris Diderot, Host St Louis, ECSTRA Team,UMR 1153, Sorbonne Paris Cite,Res Ctr,Dept Internal Med,Epi, F-75010 Paris, France

[35] Univ Paris 05, Cochin Hosp, AP HP, Natl Referral Ctr Rare Autoimmune & Syst Dis,Dept, F-75014 Paris, France

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

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

[38] Vrije Univ Amsterdam, Med Ctr, Amsterdam Rheumatol & Immunol Ctr, NL-1007 MB Amsterdam, Netherlands

[39] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, NL-9713 GZ Groningen, Netherlands

[40] Univ Hosp, Rheumatol Dept Internal Med, CH-4056 Basel, Switzerland

[41] Univ Hosp, Translat Immunol & Med Outpatient Clin, Dept Biomed, CH-4056 Basel, Switzerland

[42] Univ Hosp, Translat Immunol & Med Outpatient Clin, Dept Internal Med, CH-4056 Basel, Switzerland

[43] St Vincents Univ Hosp, Dublin Acad Med Ctr, Ctr Arthrit & Rheumat Dis, Dept Rheumatol, Dublin 4, Ireland

[44] Univ Hosp Gasthuisberg, Dept Gen Internal Med, B-3000 Leuven, Belgium

[45] Univ Oslo, Dept Med Genet, N-0450 Oslo, Norway

[46] Oslo Univ Hosp, N-0450 Oslo, Norway

[47] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[48] Kings Coll London, Div Genet, London SE1 9RT, England

[49] Kings Coll London, Div Mol Med, London SE1 9RT, England

[50] Kings Coll London, Div Immunol Infect & Inflammatory Dis, London SE1 9RT, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 100卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

FUNCTIONAL VARIATION; DISEASE; PATHOGENESIS; VARIANTS; INSIGHTS; HYPOXIA; GENES; TOOL;

D O I：

10.1016/j.ajhg.2016.11.013

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than SO years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 x 10(-54), per-allele OR = 1.79; and rs9275592, p = 1.14 x 10(-4), OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 x 10(-10), OR = 1.28; and rs128738, p = 4.60 x 10(-9), OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

引用

页码：64 / 74

页数：11

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