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Genome-Wide scan identifies TNIP1,PSORS1C1,and RHOB as novel risk loci for systemic sclerosis
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نویسنده
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allanore y. ,saad m. ,dieudé p. ,avouac j. ,distler j.h.w. ,amouyel p. ,matucci-cerinic m. ,riemekasten g. ,airo p. ,melchers i. ,hachulla e. ,cusi d. ,wichmann h.-e. ,wipff j. ,lambert j.-c. ,hunzelmann n. ,tiev k. ,caramaschi p. ,diot e. ,kowal-bielecka o. ,valentini g. ,mouthon l. ,czirják l. ,damjanov n. ,salvi e. ,conti c. ,müller m. ,müller-ladner u. ,riccieri v. ,ruiz b. ,cracowski j.-l. ,letenneur l. ,dupuy a.m. ,meyer o. ,kahan a. ,munnich a. ,boileau c. ,martinez m.
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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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Systemic sclerosis (ssc) is an orphan,complex,inflammatory disease affecting the immune system and connective tissue. ssc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease,with a largely unknown pathogenesis. we have designed a two-stage genome-wide association study of ssc using case-control samples from france,italy,germany,and northern europe. the initial genome-wide scan was conducted in a french post quality-control sample of 564 cases and 1,776 controls,using almost 500 k snps. two snps from the mhc region,together with the 6 loci outside mhc having at least one snp with a p<10 -5 were selected for follow-up analysis. these markers were genotyped in a post-qc replication sample of 1,682 ssc cases and 3,926 controls. the three top snps are in strong linkage disequilibrium and located on 6p21,in the hla-dqb1 gene: rs9275224,p = 9.18×10 -8,or = 0.69,95% ci [0.60-0.79]; rs6457617,p = 1.14×10 -7 and rs9275245,p = 1.39×10 -7. within the mhc region,the next most associated snp (rs3130573,p = 1.86×10 -5,or = 1.36 [1.18-1.56]) is located in the psors1c1 gene. outside the mhc region,our gwas analysis revealed 7 top snps (p<10 -5) that spanned 6 independent genomic regions. follow-up of the 17 top snps in an independent sample of 1,682 ssc and 3,926 controls showed associations at psors1c1 (overall p = 5.70×10 -10,or:1.25),tnip1 (p = 4.68×10 -9,or:1.31),and rhob loci (p = 3.17×10 -6,or:1.21). because of its biological relevance,and previous reports of genetic association at this locus with connective tissue disorders,we investigated tnip1 expression. a markedly reduced expression of the tnip1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from ssc patients. furthermore,tnip1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. the genetic signal of association with tnip1 variants,together with tissular and cellular investigations,suggests that this pathway has a critical role in regulating autoimmunity and ssc pathogenesis. © 2011 allanore et al.
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آدرس
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université paris descartes,rhumatologie a,inserm,u1016,hôpital cochin,aphp,paris,france,inserm,u781,université paris descartes,hôpital necker,paris, France, inserm,u563,chu purpan,université paul sabatier,toulouse, France, université paris diderot,rhumatologie,inserm,u699,hôpital bichat claude-bernard,paris, France, université paris descartes,rhumatologie a,inserm,u1016,hôpital cochin,aphp,paris,france,inserm,u781,université paris descartes,hôpital necker,paris, France, department for internal medicine 3,institute for clinical immunology friedrich-alexander-university erlangen-nuremberg,nuremberg, Germany, inserm,u744,institut pasteur de lille,université de lille nord,lille, France, department of biomedicine,division of rheumatology aouc,denothe centre,university of florence,florence, Italy, department of rheumatology and clinical immunology,charité university hospital,berlin, Germany, rheumatology and clinical immunology,spedali civili,brescia, Italy, clinical research unit for rheumatology,university medical center,freiburg, Germany, lille ii university,internal medecine department,lille, France, university of milano,department of medicine,surgery,and dentistry san paolo school of medicine,italy,genomics and bioinformatics platform,fondazione filarete,milan, Italy, institute of epidemiology i,helmholtz zentrum münchen - german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry,and epidemiology,chair of epidemiology,ludwig-maximilians-universität and klinikum grosshadern,munich, Germany, université paris descartes,rhumatologie a,inserm,u1016,hôpital cochin,aphp,paris,france,inserm,u781,université paris descartes,hôpital necker,paris, France, inserm,u744,institut pasteur de lille,université de lille nord,lille, France, department of dermatology,university of cologne,köln, Germany, université pierre et marie curie,service de médecine interne,hôpital saint antoine,paris, France, rheumatology unit,university of verona,verona, Italy, inserm,u618,ifr 135,chu bretonneau,tours, France, department of rheumatology and internal medicine,medical university of bialystok,bialystok, Poland, department of clinical and experimental medicine,rheumatology unit,second university of naples,naples, Italy, université paris descartes,médecine interne,hôpital cochin,aphp,paris, France, department of immunology and rheumatology,university of pécs,pécs, Hungary, institute of rheumatology,school of medicine,university of belgrade,belgrade, Serbia, university of milano,department of medicine,surgery,and dentistry san paolo school of medicine,italy,genomics and bioinformatics platform,fondazione filarete,milan, Italy, kos genetic srl,milano, Italy, institute of genetic epidemiology,helmholtz zentrum münchen - german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry,and epidemiology,chair of epidemiology,chair of genetic epidemiology,ludwig-maximilians-universität and department of medicine i,university hospital grosshadern,ludwig-maximilians-universität,munich, Germany, university of giessen,department of rheumatology and clinical immunology kerckhoff-klinik,bad nauheim, Germany, division of rheumatology,department of internal medicine and medical specialities,university sapienza,rome, Italy, inserm,u781,université paris descartes,hôpital necker,paris, France, inserm,cic3,chu grenoble, France, inserm,u897,bordeaux,france,université bordeaux segalen,bordeaux, France, inserm,u888,hôpital de la colombière,montpellier, France, université paris diderot,rhumatologie,inserm,u699,hôpital bichat claude-bernard,paris, France, université paris descartes,rhumatologie a,inserm,u1016,hôpital cochin,aphp,paris, France, inserm,u781,université paris descartes,hôpital necker,paris, France, inserm,u781,université paris descartes,hôpital necker,paris,france,université versailles-sqy,laboratoire de biochimie,d'hormonologie et de génétique moléculaire,hôpital ambroise paré,ap-hp,boulogne, France, inserm,u563,chu purpan,université paul sabatier,toulouse, France
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Authors
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