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Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis
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نویسنده
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cui j. ,stahl e.a. ,saevarsdottir s. ,miceli c. ,diogo d. ,trynka g. ,raj t. ,mirkov m.u. ,canhao h. ,ikari k. ,terao c. ,okada y. ,wedrén s. ,askling j. ,yamanaka h. ,momohara s. ,taniguchi a. ,ohmura k. ,matsuda f. ,mimori t. ,gupta n. ,kuchroo m. ,morgan a.w. ,isaacs j.d. ,wilson a.g. ,hyrich k.l. ,herenius m. ,doorenspleet m.e. ,tak p.-p. ,crusius j.b.a. ,van der horst-bruinsma i.e. ,wolbink g.j. ,van riel p.l.c.m. ,van de laar m. ,guchelaar h.-j. ,shadick n.a. ,allaart c.f. ,huizinga t.w.j. ,toes r.e.m. ,kimberly r.p. ,bridges jr. s.l. ,criswell l.a. ,moreland l.w. ,fonseca j.e. ,de vries n. ,stranger b.e. ,de jager p.l. ,raychaudhuri s. ,weinblatt m.e. ,gregersen p.k. ,mariette x. ,barton a. ,padyukov l. ,coenen m.j.h. ,karlson e.w. ,plenge r.m.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 3
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چکیده
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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. © 2013 cui et al.
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آدرس
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division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma, United States, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma,united states,division of psychiatric genomics,mt. sinai school of medicine,new york,ny, United States, rheumatology unit,department of medicine,karolinska institutet and karolinska university hospital solna,stockholm,sweden,institute of environmental medicine,karolinska institutet,stockholm, Sweden, université paris-sud,orsay,france,aphp-hôpital bicêtre,inserm u1012,le kremlin bicêtre,paris, France, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States, division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma,united states,program in translational neuropsychiatric genomics,institute for the neurosciences,department of neurology,brigham and women's hospital,boston,ma, United States, department of human genetics,radboud university nijmegen medical centre,nijmegen, Netherlands, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,rheumatology research unit,instituto de medicina molecular,faculdade de medicina da universidade de lisboa,lisbon,portugal,rheumatology department,santa maria hospital-chln,lisbon, Portugal, institute of rheumatology,tokyo women's medical university,tokyo, Japan, department of rheumatology and clinical immunology,kyoto university graduate school of medicine,kyoto,japan,center for genomic medicine,kyoto university graduate school of medicine,kyoto, Japan, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States, rheumatology unit,department of medicine,karolinska institutet and karolinska university hospital solna,stockholm,sweden,institute of environmental medicine,karolinska institutet,stockholm, Sweden, rheumatology unit,department of medicine,karolinska institutet and karolinska university hospital solna,stockholm,sweden,clinical epidemiology unit,department of medicine,karolinska institute/karolinska university hospital,stockholm, Sweden, institute of rheumatology,tokyo women's medical university,tokyo, Japan, institute of rheumatology,tokyo women's medical university,tokyo, Japan, institute of rheumatology,tokyo women's medical university,tokyo, Japan, department of rheumatology and clinical immunology,kyoto university graduate school of medicine,kyoto, Japan, center for genomic medicine,kyoto university graduate school of medicine,kyoto, Japan, department of rheumatology and clinical immunology,kyoto university graduate school of medicine,kyoto, Japan, medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States, medical and population genetics program,chemical biology program,broad institute,cambridge,ma,united states,program in translational neuropsychiatric genomics,institute for the neurosciences,department of neurology,brigham and women's hospital,boston,ma, United States, nihr-leeds musculoskeletal biomedical research unit and leeds institute of molecular medicine,university of leeds,leeds, United Kingdom, musculoskeletal research group,institute of cellular medicine,newcastle upon tyne, United Kingdom, rheumatology unit,medical school,university of sheffield,sheffield, United Kingdom, school of translational medicine,arthritis research uk epidemiology unit,university of manchester,manchester, United Kingdom, department of clinical immunology and rheumatology,academic medical center/university of amsterdam,amsterdam, Netherlands, department of clinical immunology and rheumatology,academic medical center/university of amsterdam,amsterdam, Netherlands, department of clinical immunology and rheumatology,academic medical center/university of amsterdam,amsterdam,netherlands,glaxosmithkline,stevenage, United Kingdom, laboratory of immunogenetics,department of pathology,vrije universiteit medical center,amsterdam, Netherlands, department of rheumatology,vrije universiteit university medical center,amsterdam, Netherlands, sanquin research landsteiner laboratory,academic medical center,university of amsterdam,amsterdam,netherlands,school of medicine and biomedical sciences,sheffield university,sheffield,united kingdom,jan van breemen institute,amsterdam, Netherlands, department of human genetics,radboud university nijmegen medical centre,nijmegen, Netherlands, arthritis center twente,university twente and medisch spectrum twente,enschede, Netherlands, department of clinical pharmacy and toxicology,leiden university medical center,leiden, Netherlands, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma, United States, department of rheumatology,leiden university medical centre,leiden, Netherlands, department of rheumatology,leiden university medical centre,leiden, Netherlands, department of rheumatology,leiden university medical centre,leiden, Netherlands, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, rosalind russell medical research center for arthritis,division of rheumatology,department of medicine,university of california san francisco,san francisco,ca, United States, division of rheumatology and clinical immunology,university of pittsburgh,pittsburgh,pa, United States, rheumatology research unit,instituto de medicina molecular,faculdade de medicina da universidade de lisboa,lisbon,portugal,rheumatology department,santa maria hospital-chln,lisbon, Portugal, department of clinical immunology and rheumatology,academic medical center/university of amsterdam,amsterdam, Netherlands, division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States, division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma,united states,aphp-hôpital bicêtre,inserm u1012,le kremlin bicêtre,paris, France, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma,united states,nihr manchester musculoskeletal biomedical research unit,central manchester nhs foundation trust,manchester academic health sciences centre,manchester, United Kingdom, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma, United States, the feinstein institute for medical research,north shore-long island jewish health system,manhasset,ny, United States, université paris-sud,orsay,france,aphp-hôpital bicêtre,inserm u1012,le kremlin bicêtre,paris, France, arthritis research uk epidemiology unit,musculoskeletal research group,university of manchester,manchester academic health sciences centre,manchester, United Kingdom, institute of environmental medicine,karolinska institutet,stockholm, Sweden, department of human genetics,radboud university nijmegen medical centre,nijmegen, Netherlands, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma, United States, division of rheumatology,immunology,and allergy,brigham and women's hospital,harvard medical school,boston,ma,united states,division of genetics,brigham and women's hospital,harvard medical school,boston,ma,united states,medical and population genetics program,chemical biology program,broad institute,cambridge,ma, United States
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Authors
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