ABC Transporters and the Proteasome Complex Are Implicated in Susceptibility to Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis across Multiple Drugs
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{"title"=>"ABC transporters and the proteasome complex are implicated in susceptibility to Stevens-Johnson syndrome and Toxic Epidermal Necrolysis across multiple drugs", "type"=>"journal", "authors"=>[{"first_name"=>"Paola", "last_name"=>"Nicoletti", "scopus_author_id"=>"8328348000"}, {"first_name"=>"Mukesh", "last_name"=>"Bansal", "scopus_author_id"=>"15842904600"}, {"first_name"=>"Celine", "last_name"=>"Lefebvre", "scopus_author_id"=>"18536386900"}, {"first_name"=>"Paolo", "last_name"=>"Guarnieri", "scopus_author_id"=>"55278064300"}, {"first_name"=>"Yufeng", "last_name"=>"Shen", "scopus_author_id"=>"55882708800"}, {"first_name"=>"Itsik", "last_name"=>"Pe'er", "scopus_author_id"=>"6701594188"}, {"first_name"=>"Andrea", "last_name"=>"Califano", "scopus_author_id"=>"7005602032"}, {"first_name"=>"Aris", "last_name"=>"Floratos", "scopus_author_id"=>"6602572764"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84938336254", "pui"=>"605398455", "doi"=>"10.1371/journal.pone.0131038", "sgr"=>"84938336254", "pmid"=>"26110827"}, "id"=>"4f049717-9bd2-3b16-b45f-5cf890bb8215", "abstract"=>"Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug-specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at https://sourceforge.net/projects/pointergsa/.", "link"=>"http://www.mendeley.com/research/abc-transporters-proteasome-complex-implicated-susceptibility-stevensjohnson-syndrome-toxic-epiderma", "reader_count"=>12, "reader_count_by_academic_status"=>{"Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>3, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Postgraduate"=>3, "Student > Master"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>4, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Switzerland"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2150257"], "description"=>"<p>The enrichment score is computed by DAVID on the 200 DEGs from Chung et al. Abbreviations: #GENES (number of DEGs in the pathway), PV (p-value, Fisher Exact test), FE (Fold Enrichment), FDR (false discovery rate). A (*) next to a pathway name indicates that the pathway was found to be enriched by both Pointer and DAVID.</p><p>The top KEGG pathways enriched in differentially expressed genes from SJS/TEN active lesions and ranked by FDR (FDR<0.25).</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464717, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.t002", "stats"=>{"downloads"=>2, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_top_KEGG_pathways_enriched_in_differentially_expressed_genes_from_SJS_TEN_active_lesions_and_ranked_by_FDR_FDR_lt_0_25_/1464717", "title"=>"The top KEGG pathways enriched in differentially expressed genes from SJS/TEN active lesions and ranked by FDR (FDR<0.25).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150256"], "description"=>"<p>Abbreviations: #GSS (gene set size for the pathway); #GLE (number of pathway genes in GSEA leading edge); ES (enrichment score), NES (normalized enrichment score), PV (p-value of ES), FDR (false discovery rate).</p><p>The top enriched KEGG pathways for low risk genetic variants ranked by normalized enrichment score (NES).</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464716, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.t001", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_top_enriched_KEGG_pathways_for_low_risk_genetic_variants_ranked_by_normalized_enrichment_score_NES_/1464716", "title"=>"The top enriched KEGG pathways for low risk genetic variants ranked by normalized enrichment score (NES).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150252"], "description"=>"<p>Key steps of the Pointer algorithm.</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464712, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.g001", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Key_steps_of_the_Pointer_algorithm_/1464712", "title"=>"Key steps of the Pointer algorithm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150259"], "description"=>"<p>The enrichment score is computed by DAVID on the 200 DEGs from Chung et al. Abbreviations: #GENES (number of DEGs in the pathway), PV (p-value, Fisher Exact test), FE (Fold Enrichment), FDR (false discovery rate). A (*) next to a pathway name indicates that the pathway was found to be enriched by both Pointer and DAVID.</p><p>The top REACTOME pathways enriched in differentially expressed genes from SJS/TEN active lesions and ranked by FDR (FDR<0.25).</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464719, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.t004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_top_REACTOME_pathways_enriched_in_differentially_expressed_genes_from_SJS_TEN_active_lesions_and_ranked_by_FDR_FDR_lt_0_25_/1464719", "title"=>"The top REACTOME pathways enriched in differentially expressed genes from SJS/TEN active lesions and ranked by FDR (FDR<0.25).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150260"], "description"=>"<p>Abbreviations: FDR1 (FDR from the pathway analysis performed using physical distance only), FDR2 (FDR from the pathway analysis performed using LD-reconstruction), FDR3 (FDR from the pathway analysis performed with Pointer).</p><p>Comparison of False Discovery Rates from the pathway analysis performed with three SNP-to-gene mapping strategies.</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464720, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.t005", "stats"=>{"downloads"=>0, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_False_Discovery_Rates_from_the_pathway_analysis_performed_with_three_SNP_to_gene_mapping_strategies_/1464720", "title"=>"Comparison of False Discovery Rates from the pathway analysis performed with three SNP-to-gene mapping strategies.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150258"], "description"=>"<p>In capital letters, pathways that contain KEGG proteasome genes.</p><p>Abbreviations: GSS (pathway gene set size); GLE (number of genes in leading edge); ES (Enrichment score), NES (Normalized Enrichment score), PV (p-value), FDR (false discovery rate), SD (p-value of shadow analysis against KEGG proteasome pathway)</p><p>Enriched Reactome pathways ranked by FDR.</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464718, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.t003", "stats"=>{"downloads"=>3, "page_views"=>35, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Enriched_Reactome_pathways_ranked_by_FDR_/1464718", "title"=>"Enriched Reactome pathways ranked by FDR.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150255"], "description"=>"<p>The Hierarchical clustering analysis was performed on gene expression data from Chung et al., 2008. Individual gene-related signals are increased (red), unchanged (white), or decreased (blue). The analysis clearly separates cases (brown group) from controls (light blue group) and reveals the up-regulation of proteasome genes in the SJS/TEN lesions.</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464715, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.g003", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hierarchical_clustering_of_expression_profiles_for_genes_in_the_KEGG_proteasome_pathway_/1464715", "title"=>"Hierarchical clustering of expression profiles for genes in the KEGG proteasome pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150254"], "description"=>"<p>The QQ-plot is constructed using the genotyped SNPs whose snp-map contains at least one ABC transporter pathway gene. The GSEA plot shows the enrichment score of the ABC transporter pathway. The top portion of the plot shows the running enrichment score for the pathway genes as the analysis moves down the ranked list. The peak score is the enrichment score for the gene set. The bottom portion of the plot shows the value of the ranking metric as it moves down the list of ranked genes. The plots for the other two enriched pathways (Proteasome and Propanoate metabolism) look similar (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131038#pone.0131038.s002\" target=\"_blank\">S2 Fig</a>).</p>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464714, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0131038.g002", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_QQ_plot_panel_A_and_GSEA_plots_panel_B_of_the_KEGG_ABC_transporter_pathway_/1464714", "title"=>"QQ-plot (panel A) and GSEA plots (panel B) of the KEGG ABC transporter pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-25 04:19:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/2150275", "https://ndownloader.figshare.com/files/2150276", "https://ndownloader.figshare.com/files/2150277", "https://ndownloader.figshare.com/files/2150278", "https://ndownloader.figshare.com/files/2150279", "https://ndownloader.figshare.com/files/2150280", "https://ndownloader.figshare.com/files/2150281", "https://ndownloader.figshare.com/files/2150282"], "description"=>"<div><p>Stevens–Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug-specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at <a href=\"https://sourceforge.net/projects/pointergsa/\" target=\"_blank\">https://sourceforge.net/projects/pointergsa/</a>.</p></div>", "links"=>[], "tags"=>["Toxic Epidermal Necrolysis", "risk variants", "gene expression dataset", "snp", "Proteasome pathways", "hla", "ten", "adr", "pharmacogenetic GWAS data", "ld", "sjs", "abc", "enrichment"], "article_id"=>1464727, "categories"=>["Uncategorised"], "users"=>["Paola Nicoletti", "Mukesh Bansal", "Celine Lefebvre", "Paolo Guarnieri", "Yufeng Shen", "Itsik Pe’er", "Andrea Califano", "Aris Floratos"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0131038.s001", "https://dx.doi.org/10.1371/journal.pone.0131038.s002", "https://dx.doi.org/10.1371/journal.pone.0131038.s003", "https://dx.doi.org/10.1371/journal.pone.0131038.s004", "https://dx.doi.org/10.1371/journal.pone.0131038.s005", "https://dx.doi.org/10.1371/journal.pone.0131038.s006", "https://dx.doi.org/10.1371/journal.pone.0131038.s007", "https://dx.doi.org/10.1371/journal.pone.0131038.s008"], "stats"=>{"downloads"=>14, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ABC_Transporters_and_the_Proteasome_Complex_Are_Implicated_in_Susceptibility_to_Stevens_8211_Johnson_Syndrome_and_Toxic_Epidermal_Necrolysis_across_Multiple_Drugs_/1464727", "title"=>"ABC Transporters and the Proteasome Complex Are Implicated in Susceptibility to Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis across Multiple Drugs", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-25 04:19:43"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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