Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk.
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.
Raychaudhuri
Soumya
S
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. soumya@broad.mit.edu
Thomson
Brian P
BP
Remmers
Elaine F
EF
Eyre
Stephen
S
Hinks
Anne
A
Guiducci
Candace
C
Catanese
Joseph J
JJ
Xie
Gang
G
Stahl
Eli A
EA
Chen
Robert
R
Alfredsson
Lars
L
Amos
Christopher I
CI
Ardlie
Kristin G
KG
Barton
Anne
A
Bowes
John
J
Burtt
Noel P
NP
Chang
Monica
M
Coblyn
Jonathan
J
Costenbader
Karen H
KH
Criswell
Lindsey A
LA
Crusius
J Bart A
JB
Cui
Jing
J
De Jager
Phillip L
PL
Ding
Bo
B
Emery
Paul
P
Flynn
Edward
E
Harrison
Pille
P
Hocking
Lynne J
LJ
Huizinga
Tom W J
TW
Kastner
Daniel L
DL
Ke
Xiayi
X
Kurreeman
Fina A S
FA
Lee
Annette T
AT
Liu
Xiangdong
X
Li
Yonghong
Y
Martin
Paul
P
Morgan
Ann W
AW
Padyukov
Leonid
L
Reid
David M
DM
Seielstad
Mark
M
Seldin
Michael F
MF
Shadick
Nancy A
NA
Steer
Sophia
S
Tak
Paul P
PP
Thomson
Wendy
W
van der Helm-van Mil
Annette H M
AH
van der Horst-Bruinsma
Irene E
IE
Weinblatt
Michael E
ME
Wilson
Anthony G
AG
Wolbink
Gert Jan
GJ
Wordsworth
Paul
P
Altshuler
David
D
Karlson
Elizabeth W
EW
Toes
Rene E M
RE
de Vries
Niek
N
Begovich
Ann B
AB
Siminovitch
Katherine A
KA
Worthington
Jane
J
Klareskog
Lars
L
Gregersen
Peter K
PK
Daly
Mark J
MJ
Plenge
Robert M
RM
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
D018801:CD2 Antigens; D018106:CD28 Antigens; D018968:CD58 Antigens; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1