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Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy
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نویسنده
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gorlova o. ,martin j.-e. ,rueda b. ,koeleman b.p.c. ,ying j. ,teruel m. ,diaz-gallo l.-m. ,broen j.c. ,vonk m.c. ,simeon c.p. ,alizadeh b.z. ,coenen m.j.h. ,voskuyl a.e. ,schuerwegh a.j. ,van riel p.l.c.m. ,vanthuyne m. ,van't slot r. ,italiaander a. ,ophoff r.a. ,hunzelmann n. ,fonollosa v. ,ortego-centeno n. ,gonzález-gay m.a. ,garcía-hernández f.j. ,gonzález-escribanomarí a.f. ,airo p. ,van laar j. ,worthington j. ,hesselstrand r. ,smith v. ,de keyser f. ,houssiau f. ,chee m.m. ,madhok r. ,shiels p.g. ,westhovens r. ,kreuter a. ,de baere e. ,witte t. ,padyukov l. ,nordin a. ,scorza r. ,lunardi c. ,lie b.a. ,hoffmann-vold a.-m. ,palm o. ,de la peña paloma g.p. ,carreira p. ,varga j. ,hinchcliff m. ,lee a.t. ,gourh p. ,amos c.i. ,wigley f.m. ,hummers l.k. ,hummers j. ,nelson j.l. ,riemekasten g. ,herrick a. ,beretta l. ,fonseca c. ,denton c.p. ,gregersen p.k. ,agarwal s. ,assassi s. ,tan f.k. ,arnett f.c. ,radstake t.r.d.j. ,mayes m.d. ,martin j.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 7
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چکیده
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The aim of this study was to determine,through a genome-wide association study (gwas),the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (ssc). we considered limited (lcssc) and diffuse (dcssc) cutaneous involvement,and the relationships with presence of the ssc-specific auto-antibodies,anti-centromere (aca),and anti-topoisomerase i (ata). four gwas cohorts,comprising 2,296 ssc patients and 5,171 healthy controls,were meta-analyzed looking for associations in the selected subgroups. eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 ssc patients and 4,971 controls. conditional analysis for associated snps in the hla region was performed to explore their independent association in antibody subgroups. overall analysis showed that non-hla polymorphism rs11642873 in irf8 gene to be associated at gwas level with lcssc (p = 2.32×10 -12,or = 0.75). also,rs12540874 in grb10 gene (p = 1.27 × 10 -6,or = 1.15) and rs11047102 in sox5 gene (p = 1.39×10 -7,or = 1.36) showed a suggestive association with lcssc and aca subgroups respectively. in the hla region,we observed highly associated allelic combinations in the hla-dqb1 locus with aca (p = 1.79×10 -61,or = 2.48),in the hla-dpa1/b1 loci with ata (p = 4.57×10 -76,or = 8.84),and in notch4 with aca p = 8.84×10 -21,or = 0.55) and ata (p = 1.14×10 -8,or = 0.54). we have identified three new non-hla genes (irf8,grb10,and sox5) associated with ssc clinical and auto-antibody subgroups. within the hla region,hla-dqb1,hla-dpa1/b1,and notch4 associations with ssc are likely confined to specific auto-antibodies. these data emphasize the differential genetic components of subphenotypes of ssc. © 2011 gorlova et al.
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آدرس
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department of epidemiology,m. d. anderson cancer center,houston,tx, United States, instituto de parasitología y biomedicina lópez-neyra,consejo superior de investigaciones científicas,granada, Spain, instituto de parasitología y biomedicina lópez-neyra,consejo superior de investigaciones científicas,granada, Spain, department of medical genetics,university medical center utrecht,utrecht, Netherlands, department of epidemiology,m. d. anderson cancer center,houston,tx, United States, instituto de parasitología y biomedicina lópez-neyra,consejo superior de investigaciones científicas,granada, Spain, instituto de parasitología y biomedicina lópez-neyra,consejo superior de investigaciones científicas,granada, Spain, department of rheumatology,radboud university nijmegen medical center,nijmegen, Netherlands, department of rheumatology,radboud university nijmegen medical center,nijmegen, Netherlands, servicio de medicina interna,hospital valle de hebron,barcelona, Spain, university medical centre groningen,department of epidemiology,groningen, Netherlands, department of human genetics,radboud university nijmegen medical center,nijmegen, Netherlands, vu university medical center,amsterdam, Netherlands, department of rheumatology,university of leiden,leiden, Netherlands, department of rheumatology,radboud university nijmegen medical center,nijmegen, Netherlands, cliniques universitaires saint-luc,université catholique de louvain,brussels, Belgium, department of medical genetics,university medical center utrecht,utrecht, Netherlands, department of medical genetics,university medical center utrecht,utrecht, Netherlands, department of medical genetics,university medical center utrecht,utrecht, Netherlands, department of dermatology,university of cologne,cologne, Germany, servicio de medicina interna,hospital valle de hebron,barcelona, Spain, servicio de medicina interna,hospital clínico universitario,granada, Spain, servicio de reumatología,hospital marqués de valdecilla,santander, Spain, servicio de medicina interna,hospital virgen del rocio,sevilla, Spain, servicio de inmunología,hospital virgen del rocío,sevilla, Spain, rheumatology unit and chair,spedali civili,università degli studi,brescia, Italy, institute of cellular medicine,newcastle university,newcastle upon tyne, United Kingdom, department of rheumatology and epidemiology,university of manchester,manchester academic health science centre,manchester, United Kingdom, department of clinical sciences,division of rheumatology,lund university,lund, Sweden, ghent university,ghent, Belgium, ghent university,ghent, Belgium, cliniques universitaires saint-luc,université catholique de louvain,brussels, Belgium, centre for rheumatic diseases,glasgow royal infirmary glasgow, United Kingdom, centre for rheumatic diseases,glasgow royal infirmary glasgow, United Kingdom, department of surgery,western infirmary glasgow,university of glasgow,glasgow, United Kingdom, katholieke universiteit leuven,leuven, Belgium, department of dermatology,josefs-hospital,ruhr university bochum, Germany, center for medical genetics,ghent university hospital,ghent, Belgium, hannover medical school,hannover, Germany, center for molecular medicine,karolinska institutet,stockholm, Sweden, center for molecular medicine,karolinska institutet,stockholm, Sweden, referral center for systemic autoimmune diseases,fondazione irccs ca' granda ospedale maggiore policlinico and university of milan,milan, Italy, department of medicine,policlinico gb rossi,university of verona, Italy, institute of immunology,oslo university hospital rikshospitalet,oslo, Norway, department of rheumatology,rikshospitalet,oslo university hospital,oslo, Norway, department of rheumatology,rikshospitalet,oslo university hospital,oslo, Norway, servicio de reumatología,hospital ramón y cajal,madrid, Spain, hospital 12 de octubre,madrid, Spain, northwestern university feinberg school of medicine,chicago,il, United States, northwestern university feinberg school of medicine,chicago,il, United States, feinstein institute of medical research,manhasset,ny, United States, the university of texas health science center-houston,houston,tx, United States, department of epidemiology,m. d. anderson cancer center,houston,tx, United States, the johns hopkins university medical center,baltimore,md, United States, fred hutchinson cancer research center,seattle,wa, United States, the johns hopkins university medical center,baltimore,md, United States, fred hutchinson cancer research center,seattle,wa, United States, department of rheumatology and clinical immunology,charité university hospital,berlin, Germany, department of rheumatology and epidemiology,university of manchester,manchester academic health science centre,manchester, United Kingdom, referral center for systemic autoimmune diseases,fondazione irccs ca' granda ospedale maggiore policlinico and university of milan,milan, Italy, centre for rheumatology,royal free and university college school,london, United Kingdom, centre for rheumatology,royal free and university college school,london, United Kingdom, feinstein institute of medical research,manhasset,ny, United States, the university of texas health science center-houston,houston,tx, United States, the university of texas health science center-houston,houston,tx, United States, the university of texas health science center-houston,houston,tx, United States, the university of texas health science center-houston,houston,tx, United States, department of rheumatology,radboud university nijmegen medical center,nijmegen, Netherlands, the university of texas health science center-houston,houston,tx, United States, instituto de parasitología y biomedicina lópez-neyra,consejo superior de investigaciones científicas,granada, Spain
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