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Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes
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نویسنده
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taylor k.e. ,chung s.a. ,graham r.r. ,ortmann w.a. ,lee a.t. ,langefeld c.d. ,jacob c.o. ,kamboh m.i. ,alarcón-riquelme m.e. ,tsao b.p. ,moser k.l. ,gaffney p.m. ,harley j.b. ,petri m. ,manzi s. ,gregersen p.k. ,behrens t.w. ,criswell l.a.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 2
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چکیده
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Systemic lupus erythematosus (sle) is a genetically complex disease with heterogeneous clinical manifestations. recent studies have greatly expanded the number of established sle risk alleles,but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. we studied 22 sle susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10-8) in 1919 sle cases from 9 independent caucasian sle case series and 4813 independent controls. the mean number of risk alleles in cases was 15.1 (sd 3.1) while the mean in controls was 13.1 (sd 2.8),with trend p = 4×10-128. we defined a genetic risk score (grs) for sle as the number of risk alleles with each weighted by the sle risk odds ratio (or). the or for high-low grs tertiles,adjusted for intra-european ancestry,sex,and parent study,was 4.4 (95% ci 3.8-5.1). we studied associations of individual snps and the grs with clinical manifestations for the cases: age at diagnosis,the 11 american college of rheumatology classification criteria,and double-stranded dna antibody (anti-dsdna) production. six subphenotypes were significantly associated with the grs,most notably anti-dsdna (orhigh-low = 2.36,p = 9e-9),the immunologic criterion (orhigh-low = 2.23,p = 3e-7),and age at diagnosis (orhigh-low = 1.45,p = 0.0060). finally,we developed a subphenotype-specific grs (sub-grs) for each phenotype with more power to detect cumulative genetic associations. the sub-grs was more strongly associated than any single snp effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers),while single loci are more significantly associated with renal disease (hla-drb1,or = 1.37,95% ci 1.14-1.64) and arthritis (itgam,or = 0.72,95% ci 0.59-0.88). we did not observe significant associations for other subphenotypes,for individual loci or the sub-grs. thus our analysis categorizes sle subphenotypes into three groups: those having cumulative,single,and no known genetic association with respect to the currently established sle risk loci.
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آدرس
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rosalind russell medical research center for arthritis,department of medicine,university of california san francisco,san francisco,ca, United States, rosalind russell medical research center for arthritis,department of medicine,university of california san francisco,san francisco,ca, United States, itgr human genetics,genentech,south san francisco,ca, United States, itgr human genetics,genentech,south san francisco,ca, United States, robert s. boas center for genomics and human genetics,feinstein institute for medical research,manhasset,ny, United States, department of biostatistical sciences,wake forest university health sciences,wake forest,nc, United States, department of medicine,keck school of medicine,university of southern california,los angeles,ca, United States, department of human genetics,university of pittsburgh graduate school of public health,pittsburgh,pa, United States, arthritis and immunology research program,oklahoma medical research foundation,oklahoma city,ok,united states,center for genomics and oncological research,pfizer-university of granada-junta de andalucia,granada, Spain, department of medicine,university of california los angeles,los angeles,ca, United States, arthritis and immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, arthritis and immunology research program,oklahoma medical research foundation,oklahoma city,ok, United States, u.s. department of veterans affairs medical center cincinnati,ohio,united states,cincinnati children's hospital medical center,cincinnati,oh, United States, division of rheumatology,johns hopkins university school of medicine,baltimore,md, United States, allegheny-singer research institute,pittsburgh,pa, United States, robert s. boas center for genomics and human genetics,feinstein institute for medical research,manhasset,ny, United States, itgr human genetics,genentech,south san francisco,ca, United States, rosalind russell medical research center for arthritis,department of medicine,university of california san francisco,san francisco,ca, United States
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Authors
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