Common variants at CD40 and other loci confer risk of rheumatoid arthritis.
To identify rheumatoid arthritis risk loci in European populations, we conducted a meta-analysis of two published genome-wide association (GWA) studies totaling 3,393 cases and 12,462 controls. We genotyped 31 top-ranked SNPs not previously associated with rheumatoid arthritis in an independent replication of 3,929 autoantibody-positive rheumatoid arthritis cases and 5,807 matched controls from eight separate collections. We identified a common variant at the CD40 gene locus (rs4810485, P = 0.0032 replication, P = 8.2 x 10(-9) overall, OR = 0.87). Along with other associations near TRAF1 (refs. 2,3) and TNFAIP3 (refs. 4,5), this implies a central role for the CD40 signaling pathway in rheumatoid arthritis pathogenesis. We also identified association at the CCL21 gene locus (rs2812378, P = 0.00097 replication, P = 2.8 x 10(-7) overall), a gene involved in lymphocyte trafficking. Finally, we identified evidence of association at four additional gene loci: MMEL1-TNFRSF14 (rs3890745, P = 0.0035 replication, P = 1.1 x 10(-7) overall), CDK6 (rs42041, P = 0.010 replication, P = 4.0 x 10(-6) overall), PRKCQ (rs4750316, P = 0.0078 replication, P = 4.4 x 10(-6) overall), and KIF5A-PIP4K2C (rs1678542, P = 0.0026 replication, P = 8.8 x 10(-8) overall).
Raychaudhuri
Soumya
S
Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Remmers
Elaine F
EF
Lee
Annette T
AT
Hackett
Rachel
R
Guiducci
Candace
C
Burtt
Noël P
NP
Gianniny
Lauren
L
Korman
Benjamin D
BD
Padyukov
Leonid
L
Kurreeman
Fina A S
FA
Chang
Monica
M
Catanese
Joseph J
JJ
Ding
Bo
B
Wong
Sandra
S
van der Helm-van Mil
Annette H M
AH
Neale
Benjamin M
BM
Coblyn
Jonathan
J
Cui
Jing
J
Tak
Paul P
PP
Wolbink
Gert Jan
GJ
Crusius
J Bart A
JB
van der Horst-Bruinsma
Irene E
IE
Criswell
Lindsey A
LA
Amos
Christopher I
CI
Seldin
Michael F
MF
Kastner
Daniel L
DL
Ardlie
Kristin G
KG
Alfredsson
Lars
L
Costenbader
Karen H
KH
Altshuler
David
D
Huizinga
Tom W J
TW
Shadick
Nancy A
NA
Weinblatt
Michael E
ME
de Vries
Niek
N
Worthington
Jane
J
Seielstad
Mark
M
Toes
Rene E M
RE
Karlson
Elizabeth W
EW
Begovich
Ann B
AB
Klareskog
Lars
L
Gregersen
Peter K
PK
Daly
Mark J
MJ
Plenge
Robert M
RM
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D019013:CD40 Antigens
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