title: Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.
abstract: Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Saedis
authors.initials: S
authors.lastname: Saevarsdottir
authors.forename: Corinne
authors.initials: C
authors.lastname: Miceli
authors.forename: Dorothee
authors.initials: D
authors.lastname: Diogo
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Maša Umiċeviċ
authors.initials: MU
authors.lastname: Mirkov
authors.forename: Helena
authors.initials: H
authors.lastname: Canhao
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikari
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Sara
authors.initials: S
authors.lastname: Wedrén
authors.forename: Johan
authors.initials: J
authors.lastname: Askling
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Shigeki
authors.initials: S
authors.lastname: Momohara
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Manik
authors.initials: M
authors.lastname: Kuchroo
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Wilson
authors.forename: Kimme L
authors.initials: KL
authors.lastname: Hyrich
authors.forename: Marieke
authors.initials: M
authors.lastname: Herenius
authors.forename: Marieke E
authors.initials: ME
authors.lastname: Doorenspleet
authors.forename: Paul-Peter
authors.initials: PP
authors.lastname: Tak
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: Gert Jan
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: Piet L C M
authors.initials: PL
authors.lastname: van Riel
authors.forename: Mart
authors.initials: M
authors.lastname: van de Laar
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.forename: Cornelia F
authors.initials: CF
authors.lastname: Allaart
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Larry W
authors.initials: LW
authors.lastname: Moreland
authors.forename: João Eurico
authors.initials: JE
authors.lastname: Fonseca
authors.forename: Niek
authors.initials: N
authors.lastname: de Vries
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Xavier
authors.initials: X
authors.lastname: Mariette
authors.forename: Anne
authors.initials: A
authors.lastname: Barton
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018501:Antirheumatic Agents / Q000008:administration & dosage; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000503:physiopathology; D044466:Asian People / Q000235:genetics; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D000071176:Signaling Lymphocytic Activation Molecule Family; D014409:Tumor Necrosis Factor-alpha; D044465:White People / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018501:Antirheumatic Agents; D054316:Biomarkers, Pharmacological; C498970:CD84 protein, human; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000071176:Signaling Lymphocytic Activation Molecule Family; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
references.citation: Nat Genet. 2010 Jun;42(6):508-14
references.pmid: 20453842
references.citation: Pharmacogenomics. 2011 Nov;12(11):1571-85
references.pmid: 22044414
references.citation: PLoS Comput Biol. 2010 May 06;6(5):e1000770
references.pmid: 20463871
references.citation: Rheumatology (Oxford). 2005 Feb;44(2):172-5
references.pmid: 15509629
references.citation: Arthritis Rheum. 2005 Jan;52(1):61-72
references.pmid: 15641091
references.citation: Arthritis Care Res (Hoboken). 2012 Aug;64(8):1108-15
references.pmid: 22422731
references.citation: Genome Res. 2005 Jul;15(7):901-13
references.pmid: 15965027
references.citation: Ann Rheum Dis. 2003 Jun;62(6):526-9
references.pmid: 12759288
references.citation: PLoS One. 2010 Dec 15;5(12):e14326
references.pmid: 21179534
references.citation: Mol Med. 2008 Sep-Oct;14(9-10):575-81
references.pmid: 18615156
references.citation: Nat Genet. 2007 Jul;39(7):906-13
references.pmid: 17572673
references.citation: Ann Rheum Dis. 2008 Aug;67(8):1174-7
references.pmid: 18385279
references.citation: Clin Exp Rheumatol. 2004 Jan-Feb;22(1):118-24
references.pmid: 15005015
references.citation: Nat Genet. 2012 Mar 25;44(5):483-9
references.pmid: 22446960
references.citation: Cytokine. 2003 Aug 7;23(3):76-85
references.pmid: 12906870
references.citation: N Engl J Med. 2007 Sep 20;357(12):1199-209
references.pmid: 17804836
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
references.pmid: 22064851
references.citation: N Engl J Med. 2011 Dec 8;365(23):2205-19
references.pmid: 22150039
references.citation: Cytokine. 1995 Apr;7(3):251-9
references.pmid: 7640345
references.citation: Arthritis Rheum. 2012 Mar;64(3):665-70
references.pmid: 21952740
references.citation: Arthritis Rheum. 2010 Jul;62(7):1849-61
references.pmid: 20309874
references.citation: Lancet. 2010 Sep 25;376(9746):1094-108
references.pmid: 20870100
references.citation: Nat Genet. 2009 Jul;41(7):776-82
references.pmid: 19525953
references.citation: Arthritis Rheum. 2011 Mar;63(3):645-53
references.pmid: 21061259
references.citation: J Immunol. 2001 Oct 1;167(7):3668-76
references.pmid: 11564780
references.citation: Nat Genet. 2012 Mar 25;44(5):511-6
references.pmid: 22446963
references.citation: Genes Immun. 2005 Aug;6(5):388-97
references.pmid: 15973463
references.citation: Arthritis Rheum. 1996 Jan;39(1):34-40
references.pmid: 8546736
references.citation: Acta Reumatol Port. 2011 Jan-Mar;36(1):45-56
references.pmid: 21483280
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: J Rheumatol. 2007 Sep;34(9):1817-22
references.pmid: 17696278
references.citation: Lancet. 2009 Feb 21;373(9664):659-72
references.pmid: 19157532
references.citation: Ann Rheum Dis. 2008 Apr;67(4):478-84
references.pmid: 17673491
references.citation: Hum Mol Genet. 2008 Oct 15;17(R2):R122-8
references.pmid: 18852200
references.citation: Nature. 2011 May 5;473(7345):43-9
references.pmid: 21441907
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Theor Popul Biol. 2001 Nov;60(3):155-66
references.pmid: 11855950
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: J Immunol. 2003 Sep 1;171(5):2485-95
references.pmid: 12928397
references.citation: Autoimmun Rev. 2006 Oct;5(8):532-6
references.pmid: 17027888
references.citation: Arthritis Rheum. 1995 Jan;38(1):44-8
references.pmid: 7818570