title: Common variants at CD40 and other loci confer risk of rheumatoid arthritis.
abstract: 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).
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Rachel
authors.initials: R
authors.lastname: Hackett
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Lauren
authors.initials: L
authors.lastname: Gianniny
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Korman
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Fina A S
authors.initials: FA
authors.lastname: Kurreeman
authors.forename: Monica
authors.initials: M
authors.lastname: Chang
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Sandra
authors.initials: S
authors.lastname: Wong
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Jonathan
authors.initials: J
authors.lastname: Coblyn
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: J Bart A
authors.initials: JB
authors.lastname: Crusius
authors.forename: Irene E
authors.initials: IE
authors.lastname: van der Horst-Bruinsma
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Karen H
authors.initials: KH
authors.lastname: Costenbader
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Mark
authors.initials: M
authors.lastname: Seielstad
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
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* / 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*
chemical_list: D019013:CD40 Antigens
references.citation: Immunol Rev. 2005 Feb;203:48-66
references.pmid: 15661021
references.citation: Arthritis Rheum. 2000 Jan;43(1):30-7
references.pmid: 10643697
references.citation: N Engl J Med. 2007 Sep 20;357(12):1199-209
references.pmid: 17804836
references.citation: Genes Immun. 2007 Apr;8(3):205-14
references.pmid: 17344890
references.citation: Am J Hum Genet. 2005 Dec;77(6):1044-60
references.pmid: 16380915
references.citation: J Immunol. 1995 Dec 15;155(12):5527-35
references.pmid: 7499834
references.citation: Nat Genet. 2008 Oct;40(10):1156-9
references.pmid: 18794857
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Science. 1993 Sep 3;261(5126):1328-30
references.pmid: 7689748
references.citation: Nat Genet. 2007 Dec;39(12):1477-82
references.pmid: 17982456
references.citation: Mol Immunol. 2008 Jan;45(1):117-26
references.pmid: 17588663
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6721-5
references.pmid: 8692885
references.citation: PLoS Med. 2007 Sep;4(9):e278
references.pmid: 17880261
references.citation: Nat Genet. 2007 Dec;39(12):1431-3
references.pmid: 17982455
references.citation: Nat Genet. 2003 Aug;34(4):395-402
references.pmid: 12833157
references.citation: J Biol Chem. 1997 May 30;272(22):14029-32
references.pmid: 9162022
references.citation: N Engl J Med. 2007 Sep 6;357(10):977-86
references.pmid: 17804842
references.citation: Am J Hum Genet. 2007 Dec;81(6):1284-8
references.pmid: 17999365
references.citation: Sci STKE. 2004 Jun 09;2004(237):pe25
references.pmid: 15199223
references.citation: Clin Endocrinol (Oxf). 2004 Aug;61(2):269-72
references.pmid: 15272925
references.citation: J Immunol. 2006 May 1;176(9):5388-400
references.pmid: 16622006
references.citation: Thyroid. 2004 Jul;14(7):506-9
references.pmid: 15307939
references.citation: Eur J Immunol. 2005 May;35(5):1347-59
references.pmid: 15832291
references.citation: Am J Hum Genet. 2004 Aug;75(2):330-7
references.pmid: 15208781
references.citation: Nat Immunol. 2004 Jan;5(1):31-7
references.pmid: 14647273
references.citation: Biochem Soc Trans. 2004 Apr;32(Pt 2):326-9
references.pmid: 15046600
references.citation: Immunity. 1994 Jun;1(3):167-78
references.pmid: 7534202
references.citation: N Engl J Med. 1978 Apr 20;298(16):869-71
references.pmid: 147420
references.citation: Nat Genet. 2007 Jul;39(7):906-13
references.pmid: 17572673
references.citation: J Immunol. 1997 Nov 1;159(9):4620-7
references.pmid: 9379064