|
|
|
|
Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis,Inflammation,and Autoantibody Production
|
|
|
|
|
|
|
|
نویسنده
|
molineros j.e. ,maiti a.k. ,sun c. ,looger l.l. ,han s. ,kim-howard x. ,glenn s. ,adler a. ,kelly j.a. ,niewold t.b. ,gilkeson g.s. ,brown e.e. ,alarcón g.s. ,edberg j.c. ,petri m. ,ramsey-goldman r. ,reveille j.d. ,vilá l.m. ,freedman b.i. ,tsao b.p. ,criswell l.a. ,jacob c.o. ,moore j.h. ,vyse t.j. ,langefeld c.l. ,guthridge j.m. ,gaffney p.m. ,moser k.l. ,scofield r.h. ,alarcón-riquelme m.e. ,williams s.m. ,merrill j.t. ,james j.a. ,kaufman k.m. ,kimberly r.p. ,harley j.b. ,nath s.k.
|
|
منبع
|
plos genetics - 2013 - دوره : 9 - شماره : 2
|
|
چکیده
|
Systemic lupus erythematosus (sle) is an inflammatory autoimmune disease with a strong genetic component. african-americans (aa) are at increased risk of sle,but the genetic basis of this risk is largely unknown. to identify causal variants in sle loci in aa,we performed admixture mapping followed by fine mapping in aa and european-americans (ea). through genome-wide admixture mapping in aa,we identified a strong sle susceptibility locus at 2q22-24 (lod = 6.28),and the admixture signal is associated with the european ancestry (ancestry risk ratio ~1.5). large-scale genotypic analysis on 19,726 individuals of african and european ancestry revealed three independently associated variants in the ifih1 gene: an intronic variant,rs13023380 [pmeta = 5.20×10-14; odds ratio,95% confidence interval = 0.82 (0.78-0.87)],and two missense variants,rs1990760 (ala946thr) [pmeta = 3.08×10-7; 0.88 (0.84-0.93)] and rs10930046 (arg460his) [pdom = 1.16×10-8; 0.70 (0.62-0.79)]. both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. we experimentally validated function of the intronic snp by dna electrophoresis,protein identification,and in vitro protein binding assays. dna carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen ku70/80,and showed reduced transcriptional activity in vivo. thus,in sle patients,genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin,ku70/80,or other nucleic acid regulatory proteins. this could promote antibody hypermutation and auto-antibody generation,further destabilizing the cellular network. together with molecular modeling,our results establish a distinct role for ifih1 in apoptosis,inflammation,and autoantibody production,and explain the molecular basis of these three risk alleles for sle pathogenesis. © 2013 molineros et al.
|
|
|
|
|
آدرس
|
arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, howard hughes medical institute,janelia farm research campus,ashburn,va, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok,united states,department of psychiatry,yale school of medicine,new haven,ct, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, mayo clinic,division of rheumatology and department of immunology,rochester,mn, United States, division of rheumatology,medical university of south carolina,charleston,sc, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, department of medicine,johns hopkins university school of medicine,baltimore,md, United States, division of rheumatology,northwestern university feinberg school of medicine,chicago,il, United States, department of rheumatology and clinical immunogenetics,university of texas health science center at houston,houston,tx, United States, department of medicine,division of rheumatology,university of puerto rico medical sciences campus,san juan, Puerto Rico, department of internal medicine,wake forest school of medicine,winston-salem,nc, United States, division of rheumatology,department of medicine,university of california los angeles,los angeles,ca, United States, rosalind russell medical research center for arthritis,university of california san francisco,san francisco,ca, United States, department of medicine,university of southern california,los angeles,ca, United States, department of genetics,dartmouth medical school,lebanon,nh, United States, division of genetics and molecular medicine,king's college london,london,united kingdom,division of immunology,infection and inflammatory diseases,kings college london,london, United Kingdom, department of biostatistical sciences,wake forest university health sciences,wake forest,nc, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok,united states,college of medicine,university of oklahoma health sciences center,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok,united states,centro de genómica e investigación oncológica (genyo)-pfizer,universidad de granada/junta de andalucía,granada, Spain, department of genetics,geisel school of medicine,dartmouth college,hanover,nh, United States, clinical pharmacology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok,united states,college of medicine,university of oklahoma health sciences center,oklahoma city,ok, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, department of medicine,university of alabama at birmingham,birmingham,al, United States, cincinnati children's hospital medical center,u.s. department of veterans affairs medical center,cincinnati,oh, United States, arthritis and clinical immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|