title: Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.
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.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broad.mit.edu
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Brian P
authors.initials: BP
authors.lastname: Thomson
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Stephen
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authors.forename: Candace
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authors.lastname: Catanese
authors.forename: Gang
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authors.lastname: Xie
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authors.lastname: Stahl
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authors.lastname: Chen
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authors.lastname: Alfredsson
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Anne
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authors.lastname: Barton
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authors.lastname: Chang
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authors.lastname: Coblyn
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authors.initials: KH
authors.lastname: Costenbader
authors.forename: Lindsey A
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authors.lastname: Crusius
authors.forename: Jing
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authors.forename: Phillip L
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authors.lastname: De Jager
authors.forename: Bo
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authors.lastname: Ding
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authors.lastname: Emery
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authors.lastname: Flynn
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authors.lastname: Harrison
authors.forename: Lynne J
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authors.lastname: Hocking
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Daniel L
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authors.lastname: Kastner
authors.forename: Xiayi
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authors.forename: Fina A S
authors.initials: FA
authors.lastname: Kurreeman
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Li
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authors.initials: P
authors.lastname: Martin
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: David M
authors.initials: DM
authors.lastname: Reid
authors.forename: Mark
authors.initials: M
authors.lastname: Seielstad
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.forename: Sophia
authors.initials: S
authors.lastname: Steer
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Wendy
authors.initials: W
authors.lastname: Thomson
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.forename: Irene E
authors.initials: IE
authors.lastname: van der Horst-Bruinsma
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: Paul
authors.initials: P
authors.lastname: Wordsworth
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D018801:CD2 Antigens / Q000235:genetics*; D018106:CD28 Antigens / Q000235:genetics*; D018968:CD58 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: D018801:CD2 Antigens; D018106:CD28 Antigens; D018968:CD58 Antigens; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1