Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus
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{"title"=>"Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus", "type"=>"journal", "authors"=>[{"first_name"=>"Kimberly E.", "last_name"=>"Taylor", "scopus_author_id"=>"23480943300"}, {"first_name"=>"Elaine F.", "last_name"=>"Remmers", "scopus_author_id"=>"7006767926"}, {"first_name"=>"Annette T.", "last_name"=>"Lee", "scopus_author_id"=>"7405628593"}, {"first_name"=>"Ward A.", "last_name"=>"Ortmann", "scopus_author_id"=>"6603452467"}, {"first_name"=>"Robert M.", "last_name"=>"Plenge", "scopus_author_id"=>"6602930396"}, {"first_name"=>"Chao", "last_name"=>"Tian", "scopus_author_id"=>"24342219800"}, {"first_name"=>"Sharon A.", "last_name"=>"Chung", "scopus_author_id"=>"35271403400"}, {"first_name"=>"Joanne", "last_name"=>"Nititham", "scopus_author_id"=>"18437876200"}, {"first_name"=>"Geoffrey", "last_name"=>"Hom", "scopus_author_id"=>"23766819400"}, {"first_name"=>"Amy H.", "last_name"=>"Kao", "scopus_author_id"=>"7102711462"}, {"first_name"=>"F. Yesim", "last_name"=>"Demirci", "scopus_author_id"=>"56753143900"}, {"first_name"=>"M. Ilyas", "last_name"=>"Kamboh", "scopus_author_id"=>"7006868487"}, {"first_name"=>"Michelle", "last_name"=>"Petri", "scopus_author_id"=>"15830375100"}, {"first_name"=>"Susan", "last_name"=>"Manzi", "scopus_author_id"=>"7006852559"}, {"first_name"=>"Daniel L.", "last_name"=>"Kastner", "scopus_author_id"=>"34770920900"}, {"first_name"=>"Michael F.", "last_name"=>"Seldin", "scopus_author_id"=>"7102528398"}, {"first_name"=>"Peter K.", "last_name"=>"Gregersen", "scopus_author_id"=>"7006364574"}, {"first_name"=>"Timothy W.", "last_name"=>"Behrens", "scopus_author_id"=>"7005294636"}, {"first_name"=>"Lindsey A.", "last_name"=>"Criswell", "scopus_author_id"=>"54790563400"}], "year"=>2008, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-44949149145", "sgr"=>"44949149145", "pui"=>"351811493", "isbn"=>"1553-7404 (Electronic)", "pmid"=>"18516230", "doi"=>"10.1371/journal.pgen.1000084"}, "id"=>"6b539770-88c2-3fcc-bff2-e227b96a1a79", "abstract"=>"Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10(-16)). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p<10(-11)), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.", "link"=>"http://www.mendeley.com/research/specificity-stat4-genetic-association-severe-disease-manifestations-systemic-lupus-erythematosus", "reader_count"=>36, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>6, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>7}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>6, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>7}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>13, "Medicine and Dentistry"=>16, "Arts and Humanities"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>16}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>13}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Brazil"=>1, "Germany"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/930194"], "description"=>"<p>See <a href=\"http://www.rheumatology.org/publications/classification/SLE/sle.asp\" target=\"_blank\">http://www.rheumatology.org/publications/classification/SLE/sle.asp</a> for phenotype definitions.</p><p>See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t001\" target=\"_blank\">Table 1</a> cohort definitions.</p><p>Global exact test for association between phenotype status and cohort membership.</p>†<p>Historical presence of positive anti-dsDNA test.</p>‡<p>Presence of end-stage renal disease or histopathologic evidence of severe, progressive renal disease on renal biopsy.</p>", "links"=>[], "tags"=>["phenotype"], "article_id"=>600620, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_SLE_phenotype_status_by_cohort_/600620", "title"=>"SLE phenotype status by cohort.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:10:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/930055"], "description"=>"<p>Results are 2×2 odds ratios with two-sided Fisher’s exact p-values.</p>§<p>See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t001\" target=\"_blank\">Table 1</a> for phenotype definitions.</p><p>Subset with nephritis detail (UCSF and ABCoN).</p><p>First principal component of phenotypes.</p>", "links"=>[], "tags"=>["mafs", "associations", "subphenotype", "cases"], "article_id"=>600489, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t006", "stats"=>{"downloads"=>2, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_rs7574865_MAFs_and_associations_in_subphenotype_cases_vs_controls_/600489", "title"=>"rs7574865 MAFs and associations in subphenotype cases vs. controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/930146"], "description"=>"<p>Significance is p<0.0001 for all pairs shown. Blank cells are given in the lower triangular matrix.</p><p>See <a href=\"http://www.rheumatology.org/publications/classification/SLE/sle.asp\" target=\"_blank\">http://www.rheumatology.org/publications/classification/SLE/sle.asp</a> for phenotype definitions.</p><p>PC = principal component.</p>", "links"=>[], "tags"=>["coefficient", "rho", "phenotype", "pairs"], "article_id"=>600565, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlation_coefficient_rho_for_phenotype_pairs_with_rho_gt_0_1_and_first_two_principal_components_/600565", "title"=>"Correlation coefficient rho for phenotype pairs with rho>0.1 and first two principal components.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:09:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/929962"], "description"=>"§<p>See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t001\" target=\"_blank\">Table 1</a> for phenotype definitions.</p><p>Mantel-Haenzel odds ratio (OR) and p-value combined across cohorts.</p><p>Multivariate logistic regression adjusting for sex; ancestry as a categorical variable (90% or greater Northern European, 90% or greater European but <90% Northern European, not 90% or greater European); and disease duration for all outcomes except age of diagnosis.</p>‡<p>UCSF and ABCoN only (see definitions <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t001\" target=\"_blank\">Table 1</a>): homogeneous n = 461, multivariate n = 790.</p>†<p>First principal component of phenotypes (see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#s2\" target=\"_blank\">Methods</a>).</p>", "links"=>[], "tags"=>["phenotype", "cases", "homogeneous", "subset", "multivariate"], "article_id"=>600386, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t005", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_rs7574865_association_with_phenotype_status_of_cases_in_homogeneous_subset_n_8202_8202_751_and_multivariate_analyses_/600386", "title"=>"rs7574865 association with phenotype status of cases in homogeneous subset (n = 751) and multivariate analyses.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:06:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/930002"], "description"=>"<p>Allelic odds ratios (ORs) and p-values from PLINK, p-values conditional on bold SNPs from Whap <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen.1000084-Purcell2\" target=\"_blank\">[14]</a>. Subjects with <90% genotyping are excluded for each analysis. For (C) and (D), the four top SNPs in bold are indistinguishable, i.e. any one fully determines the others in >99% of haplotypes.</p>", "links"=>[], "tags"=>["conditional", "snps"], "article_id"=>600431, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t004", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Allelic_and_conditional_tests_for_all_SNPs_with_p_lt_0_005_/600431", "title"=>"Allelic and conditional tests for all SNPs with p<0.005.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:07:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/930094"], "description"=>"<p>After removal of duplicate samples and first-degree relatives, but prior to other quality control filters.</p><p>UCSF = University of California, San Francisco; ABCoN = Autoimmune Biomarkers Collaborative Network; MADGC = Multiple Autoimmune Disease Genetics Consortium; NYHP = New York Health Project.</p>", "links"=>[], "tags"=>["genotype", "phenotype", "cohort", "genotyping"], "article_id"=>600526, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.t001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_available_genotype_and_phenotype_data_by_cohort_and_genotyping_platform_/600526", "title"=>"Summary of available genotype and phenotype data<sup>*</sup> by cohort and genotyping platform.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2008-05-30 00:08:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/929826"], "description"=>"<p>(A) Green markers are in STAT1 and STAT4 genes as indicated. Four SNPs comprising the top SLE risk haplotype, from allelic and conditional analyses (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t004\" target=\"_blank\">Table 4</a> (C)), are circled. (B) Haploview linkage disequilibrium map of D’ for 91 Illumina 550K STAT1/STAT4 extended region SNPs in 3138 study subjects. Green markers are in STAT1 and STAT4 genes as indicated. The top SLE risk SNP rs7574865 from allelic and conditional analyses (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1000084#pgen-1000084-t004\" target=\"_blank\">Table 4</a> (A)) is circled.</p>", "links"=>[], "tags"=>["linkage", "disequilibrium", "67", "sequenom", "snps", "2278"], "article_id"=>600248, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1000084.g001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Haploview_linkage_disequilibrium_map_of_D_8217_for_67_Sequenom_STAT1_STAT4_SNPs_in_2278_study_subjects_/600248", "title"=>"Haploview linkage disequilibrium map of D’ for 67 Sequenom STAT1/STAT4 SNPs in 2278 study subjects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2008-05-30 00:04:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/458722", "https://ndownloader.figshare.com/files/458755", "https://ndownloader.figshare.com/files/458847", "https://ndownloader.figshare.com/files/458890", "https://ndownloader.figshare.com/files/458929"], "description"=>"<div><p>Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the <em>STAT4</em> gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the <em>STAT4</em> region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant <em>STAT4</em> haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r<sup>2</sup> = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the <em>STAT4</em> region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10<sup>−16</sup>). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10<sup>−19</sup>), nephritis (MAF = 34.3%, OR = 1.80, p<10<sup>−11</sup>), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10<sup>−13</sup>). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10<sup>−4</sup> in the homogeneous subset of subjects). In contrast, <em>STAT4</em> was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of <em>STAT4</em> contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.</p></div>", "links"=>[], "tags"=>["specificity", "manifestations", "systemic", "lupus", "erythematosus"], "article_id"=>150367, "categories"=>["Neuroscience", "Genetics", "Medicine"], "users"=>["Kimberly E. Taylor", "Elaine F. Remmers", "Annette T. Lee", "Ward A. Ortmann", "Robert M. Plenge", "Chao Tian", "Sharon A. Chung", "Joanne Nititham", "Geoffrey Hom", "Amy H. Kao", "F. Yesim Demirci", "M. Ilyas Kamboh", "Michelle Petri", "Susan Manzi", "Daniel L. Kastner", "Michael F. Seldin", "Peter K. Gregersen", "Timothy W. Behrens", "Lindsey A. Criswell"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1000084.s001", "https://dx.doi.org/10.1371/journal.pgen.1000084.s002", "https://dx.doi.org/10.1371/journal.pgen.1000084.s003", "https://dx.doi.org/10.1371/journal.pgen.1000084.s004", "https://dx.doi.org/10.1371/journal.pgen.1000084.s005"], "stats"=>{"downloads"=>9, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Specificity_of_the_STAT4_Genetic_Association_for_Severe_Disease_Manifestations_of_Systemic_Lupus_Erythematosus/150367", "title"=>"Specificity of the <em>STAT4</em> Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2008-05-30 00:06:07"}

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Relative Metric

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