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PMID: 19898481 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.

Nature genetics ·Vol. 41 ·No. 12 ·2009-12-00 ·Pages 1313-8

Raychaudhuri S, Thomson BP, Remmers EF, Eyre S, Hinks A, Guiducci C, Catanese JJ, Xie G, Stahl EA, Chen R, Alfredsson L, Amos CI, Ardlie KG, BIRAC Consortium, Barton A, Bowes J, Burtt NP, Chang M, Coblyn J, Costenbader KH, Criswell LA, Crusius JB, Cui J, De Jager PL, Ding B, Emery P, Flynn E, Harrison P, Hocking LJ, Huizinga TW, Kastner DL, Ke X, Kurreeman FA, Lee AT, Liu X, Li Y, Martin P, Morgan AW, Padyukov L, Reid DM, Seielstad M, Seldin MF, Shadick NA, Steer S, Tak PP, Thomson W, van der Helm-van Mil AH, van der Horst-Bruinsma IE, Weinblatt ME, Wilson AG, Wolbink GJ, Wordsworth P, YEAR Consortium, Altshuler D, Karlson EW, Toes RE, de Vries N, Begovich AB, Siminovitch KA, Worthington J, Klareskog L, Gregersen PK, Daly MJ, Plenge RM

Abstract

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 x 10(-6) replication, P = 1 x 10(-9) overall), CD28 (rs1980422, P = 5 x 10(-6) replication, P = 1 x 10(-9) overall) and PRDM1 (rs548234, P = 1 x 10(-5) replication, P = 2 x 10(-8) overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 x 10(-7) overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 x 10(-7) overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 x 10(-6) overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 x 10(-5) overall). Many of these loci are also associated to other immunologic diseases.

MeSH Terms
Arthritis, Rheumatoid/genetics CD2 Antigens/genetics CD28 Antigens/genetics CD58 Antigens/genetics Case-Control Studies Genetic Predisposition to Disease Genetic Variation Genotype Humans Polymorphism, Single Nucleotide Positive Regulatory Domain I-Binding Factor 1 Repressor Proteins/genetics Risk Factors
Chemicals
CD2 Antigens CD28 Antigens CD58 Antigens Repressor Proteins PRDM1 protein, human Positive Regulatory Domain I-Binding Factor 1
Authors & Affiliations
64 authors, click to expand affiliations / ORCID
Raychaudhuri Soumya
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broad.mit.edu
Thomson Brian P
Remmers Elaine F
Eyre Stephen
Hinks Anne
Guiducci Candace
Catanese Joseph J
Xie Gang
Stahl Eli A
Chen Robert
Alfredsson Lars
Amos Christopher I
Ardlie Kristin G
BIRAC Consortium
Barton Anne
Bowes John
Burtt Noel P
Chang Monica
Coblyn Jonathan
Costenbader Karen H
Criswell Lindsey A
Crusius J Bart A
Cui Jing
De Jager Phillip L
Ding Bo
Emery Paul
Flynn Edward
Harrison Pille
Hocking Lynne J
Huizinga Tom W J
Kastner Daniel L
Ke Xiayi
Kurreeman Fina A S
Lee Annette T
Liu Xiangdong
Li Yonghong
Martin Paul
Morgan Ann W
Padyukov Leonid
Reid David M
Seielstad Mark
Seldin Michael F
Shadick Nancy A
Steer Sophia
Tak Paul P
Thomson Wendy
van der Helm-van Mil Annette H M
van der Horst-Bruinsma Irene E
Weinblatt Michael E
Wilson Anthony G
Wolbink Gert Jan
Wordsworth Paul
YEAR Consortium
Altshuler David
Karlson Elizabeth W
Toes Rene E M
de Vries Niek
Begovich Ann B
Siminovitch Katherine A
Worthington Jane
Klareskog Lars
Gregersen Peter K
Daly Mark J
Plenge Robert M
Investigators
141 investigators, click to expand
Bruce I N
Hyrich K
Ho P
Gorodkin R
Badcock L J
Deighton C M
O'Reilly S C
Raj N
Regan M R
Summers G D
Williams R A
Barton A
Knight S M
Symmons D P M
Sanders P
Pal B
Gaffney K
Macgregor A J
Marshall T
Merry P
Scott D G I
Porter D
Madok R
Gordon M
McInnes I
Sturrock R
Field M
Harrison B
Pattrick M
Snowden H N
Bowden A P
Smith E E
Klimiuk P
Speden D J
Thompson P W
Richards S C M
Hull R G
Ledingham J M
Mccrae F
Shaban M R
Thomas A L
Young Min S A
Herrick A L
Cooper R G
Benitha R
Jones A K P
O'Neill T W
Abernethy V E
Clewes A R
Dawson J K
Lynch M
Kitas G
Delamere J P
Erb N
Klocke R
Whallett A J
Dawes P T
Dowson C M
Hassell A
Hay E M
Kamath S
Packham J
Sandhu R S
Shadforth M F
Bingham S
Emery P
Morgan A
Bird H A
Conaghan P G
Pease C T
Wakefield R J
Chalam S V
Mulherin D
Price T
Sheeran T
Venkatachalam S
Crook P
Foster H E
Griffiths B
Griffiths I D
Grove M L
Isaacs J D
Kay L
Ng W F
Myers A
Platt P N
Walker D J
Lim K L
Walsh D A
Carter N D
Holt M
Fawthrop F W
Smith G W
Emery Paul
Conaghan Philip
Morgan Ann
Quinn Mark
Keenan Anne-Maree
Hensor Elizabeth
Gough Andrew
Green Michael
Reece Richard
Hordon Lesley
Helliwell Philip
Melsom Richard
Doherty Sheelagh
Adebajo Ade
Harvey Andrew
Jarrett Steve
Huson Gareth
Isdale Amanda
Martin Mike
Karim Zunaid
McGonagle Dennis
Pease Colin
Cox Sally
Bejarano Victoria
Nam Jackie
Brown Claire
Thomas Christine
Pickles David
Hammond Alison
Neville Beverley
Fairclough Alan
Nunns Caroline
Gill Anne
Green Julie
Rhys-Evans Belinda
Padwell Barbara
Madden Julie
Taylor Lynda
Smith Sally
King Heather
Firth Jill
Heard Jayne
Sigsworth Linda
Corscadden Diane
Henshaw Karen
Rashid Lubna-Haroon
Martin Stephen G
Robinson James I
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.479
Email
soumya@broad.mit.edu
Published
2009-12-00
Epub
2009-00-08
Pages
1313-8
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3142887
Subset
IM
Grants
CIHR · MOP79321 · Canada
Versus Arthritis · 18475 · United Kingdom
NIDDK NIH HHS · R01 DK64869 · United States
NHGRI NIH HHS · U01 HG004171 · United States
NIAMS NIH HHS · K08 AR055688-02 · United States
NIDDK NIH HHS · R01 DK083756-1 · United States
NHLBI NIH HHS · R01HL087676 · United States
NIAMS NIH HHS · R01 AR44422 · United States
Intramural NIH HHS · United States
NIAMS NIH HHS · N01-AR-2-2263 · United States
NIAMS NIH HHS · K08 AR055688-04 · United States
NIAMS NIH HHS · K08 AR055688 · United States
NIAID NIH HHS · K08 AI055314 · United States
NCRR NIH HHS · U54 RR020278 · United States
NIAMS NIH HHS · K08 AR055688-03 · United States
NIAMS NIH HHS · R01 AR044422-10 · United States
NIAMS NIH HHS · R01 AR044422 · United States
NHLBI NIH HHS · R01 HL087676 · United States
NIAMS NIH HHS · K08 AR055688-01A1 · United States
NIDDK NIH HHS · U01 DK062432 · United States
NIAMS NIH HHS · 1K08AR055688-01A1 · United States
Arthritis Research UK · 17552 · United Kingdom
NIDDK NIH HHS · R01 DK064869 · United States
NIAMS NIH HHS · K08 AR055688-01A1S1 · United States
Arthritis Research UK · 18475 · United Kingdom
CIHR · IIN-84042 · Canada
NIAMS NIH HHS · R01 AR056768 · United States
NIDDK NIH HHS · R01 DK083756 · United States
NIAID NIH HHS · K08 AI55314-3 · United States
NIDDK NIH HHS · U01 DK62432 · United States
External Links
PubMed source DOI: 10.1038/ng.479 PMC Full Text View journal details
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