Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway
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{"title"=>"Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Gang", "last_name"=>"Li", "scopus_author_id"=>"55713456400"}, {"first_name"=>"Dorothée", "last_name"=>"Diogo", "scopus_author_id"=>"57193814311"}, {"first_name"=>"Di", "last_name"=>"Wu", "scopus_author_id"=>"56669013600"}, {"first_name"=>"Jim", "last_name"=>"Spoonamore", "scopus_author_id"=>"6506293432"}, {"first_name"=>"Vlado", "last_name"=>"Dancik", "scopus_author_id"=>"6603591172"}, {"first_name"=>"Lude", "last_name"=>"Franke", "scopus_author_id"=>"56310093600"}, {"first_name"=>"Fina", "last_name"=>"Kurreeman", "scopus_author_id"=>"6504447096"}, {"first_name"=>"Elizabeth J.", "last_name"=>"Rossin", "scopus_author_id"=>"16203933700"}, {"first_name"=>"Grant", "last_name"=>"Duclos", "scopus_author_id"=>"55608371000"}, {"first_name"=>"Cathy", "last_name"=>"Hartland", "scopus_author_id"=>"50161410500"}, {"first_name"=>"Xuezhong", "last_name"=>"Zhou", "scopus_author_id"=>"7410089554"}, {"first_name"=>"Kejie", "last_name"=>"Li", "scopus_author_id"=>"56297061300"}, {"first_name"=>"Jun", "last_name"=>"Liu", "scopus_author_id"=>"57196291819"}, {"first_name"=>"Philip L.", "last_name"=>"De Jager", "scopus_author_id"=>"7005494360"}, {"first_name"=>"Katherine A.", "last_name"=>"Siminovitch", "scopus_author_id"=>"35404700300"}, {"first_name"=>"Alexandra", "last_name"=>"Zhernakova", "scopus_author_id"=>"9737684500"}, {"first_name"=>"Soumya", "last_name"=>"Raychaudhuri", "scopus_author_id"=>"7006375923"}, {"first_name"=>"John", "last_name"=>"Bowes", "scopus_author_id"=>"56066311000"}, {"first_name"=>"Steve", "last_name"=>"Eyre", "scopus_author_id"=>"56066328600"}, {"first_name"=>"Leonid", "last_name"=>"Padyukov", "scopus_author_id"=>"6603725900"}, {"first_name"=>"Peter K.", "last_name"=>"Gregersen", "scopus_author_id"=>"7006364574"}, {"first_name"=>"Jane", "last_name"=>"Worthington", "scopus_author_id"=>"26322894900"}, {"first_name"=>"Namrata", "last_name"=>"Gupta", "scopus_author_id"=>"36930358000"}, {"first_name"=>"Paul A.", "last_name"=>"Clemons", "scopus_author_id"=>"6701589271"}, {"first_name"=>"Eli", "last_name"=>"Stahl", "scopus_author_id"=>"57031513200"}, {"first_name"=>"Nicola", "last_name"=>"Tolliday", "scopus_author_id"=>"6602651176"}, {"first_name"=>"Robert M.", "last_name"=>"Plenge", "scopus_author_id"=>"6602930396"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"doi"=>"10.1371/journal.pgen.1003487", "sgr"=>"84878492072", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"23696745", "issn"=>"15537390", "scopus"=>"2-s2.0-84878492072", "pui"=>"369039807"}, "id"=>"2a1b2917-f07f-34f8-8f75-8e61b4214af7", "abstract"=>"Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a CD40 risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the CD40 risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of CD40 coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, P = 1.4×10(-9)). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (P = 10(-9)), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA-approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA.", "link"=>"http://www.mendeley.com/research/human-genetics-rheumatoid-arthritis-guides-highthroughput-drug-screen-cd40-signaling-pathway", "reader_count"=>64, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Researcher"=>22, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>4, "Student > Bachelor"=>9, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>4, "Researcher"=>22, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>8, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>4, "Student > Bachelor"=>9, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>5, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>31, "Medicine and Dentistry"=>16, "Physics and Astronomy"=>1, "Psychology"=>1, "Chemistry"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>16}, "Chemistry"=>{"Chemistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>31}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>3, "China"=>1, "Finland"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1062453"], "description"=>"<p>For each compound, we calculate the maximum amount of inhibition observed at the highest concentration of drug relative to zero luciferase activity.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "inhibition", "compounds"], "article_id"=>704123, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.t002", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Percent_maximum_inhibition_for_two_8220_known_8221_and_two_8220_novel_8221_compounds_in_both_BL2_NF_954_B_Luc_and_Ramos_NF_954_B_Luc_cell_lines_/704123", "title"=>"Percent maximum inhibition for two “known” and two “novel” compounds in both BL2-NFκB-Luc and Ramos-NFκB-Luc cell lines.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-16 01:08:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062452"], "description"=>"<p>Purified human CD19+ primary B cells were incubated with 10 ng/ml IL4 alone (“No activation”) or IL4+64 ng/ml tCD40L (“Activation”), together with different concentrations of drugs for 48 hours. CD86 expression was measured by PE GeoMFI on CD19+ gated B cells. The chemical structure of each compound is shown.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "compounds", "cd86"], "article_id"=>704122, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.g004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_compounds_on_CD86_expression_in_primary_CD19_B_cells_/704122", "title"=>"Effect of compounds on CD86 expression in primary CD19+ B cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-16 01:08:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062456", "https://ndownloader.figshare.com/files/1062458", "https://ndownloader.figshare.com/files/1062459", "https://ndownloader.figshare.com/files/1062460", "https://ndownloader.figshare.com/files/1062465", "https://ndownloader.figshare.com/files/1062470", "https://ndownloader.figshare.com/files/1062473", "https://ndownloader.figshare.com/files/1062476", "https://ndownloader.figshare.com/files/1062479", "https://ndownloader.figshare.com/files/1062481", "https://ndownloader.figshare.com/files/1062482", "https://ndownloader.figshare.com/files/1062483", "https://ndownloader.figshare.com/files/1062484", "https://ndownloader.figshare.com/files/1062490"], "description"=>"<div><p>Although genetic and non-genetic studies in mouse and human implicate the CD40 pathway in rheumatoid arthritis (RA), there are no approved drugs that inhibit CD40 signaling for clinical care in RA or any other disease. Here, we sought to understand the biological consequences of a <i>CD40</i> risk variant in RA discovered by a previous genome-wide association study (GWAS) and to perform a high-throughput drug screen for modulators of CD40 signaling based on human genetic findings. First, we fine-map the <i>CD40</i> risk locus in 7,222 seropositive RA patients and 15,870 controls, together with deep sequencing of <i>CD40</i> coding exons in 500 RA cases and 650 controls, to identify a single SNP that explains the entire signal of association (rs4810485, <i>P</i> = 1.4×10<sup>−9</sup>). Second, we demonstrate that subjects homozygous for the RA risk allele have ∼33% more CD40 on the surface of primary human CD19+ B lymphocytes than subjects homozygous for the non-risk allele (<i>P</i> = 10<sup>−9</sup>), a finding corroborated by expression quantitative trait loci (eQTL) analysis in peripheral blood mononuclear cells from 1,469 healthy control individuals. Third, we use retroviral shRNA infection to perturb the amount of CD40 on the surface of a human B lymphocyte cell line (BL2) and observe a direct correlation between amount of CD40 protein and phosphorylation of RelA (p65), a subunit of the NF-κB transcription factor. Finally, we develop a high-throughput NF-κB luciferase reporter assay in BL2 cells activated with trimerized CD40 ligand (tCD40L) and conduct an HTS of 1,982 chemical compounds and FDA–approved drugs. After a series of counter-screens and testing in primary human CD19+ B cells, we identify 2 novel chemical inhibitors not previously implicated in inflammation or CD40-mediated NF-κB signaling. Our study demonstrates proof-of-concept that human genetics can be used to guide the development of phenotype-based, high-throughput small-molecule screens to identify potential novel therapies in complex traits such as RA.</p></div>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "rheumatoid", "arthritis", "guides", "high-throughput", "cd40"], "article_id"=>704125, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003487.s001", "https://dx.doi.org/10.1371/journal.pgen.1003487.s002", "https://dx.doi.org/10.1371/journal.pgen.1003487.s003", "https://dx.doi.org/10.1371/journal.pgen.1003487.s004", "https://dx.doi.org/10.1371/journal.pgen.1003487.s005", "https://dx.doi.org/10.1371/journal.pgen.1003487.s006", "https://dx.doi.org/10.1371/journal.pgen.1003487.s007", "https://dx.doi.org/10.1371/journal.pgen.1003487.s008", "https://dx.doi.org/10.1371/journal.pgen.1003487.s009", "https://dx.doi.org/10.1371/journal.pgen.1003487.s010", "https://dx.doi.org/10.1371/journal.pgen.1003487.s011", "https://dx.doi.org/10.1371/journal.pgen.1003487.s012", "https://dx.doi.org/10.1371/journal.pgen.1003487.s013", "https://dx.doi.org/10.1371/journal.pgen.1003487.s014"], "stats"=>{"downloads"=>2, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_Genetics_in_Rheumatoid_Arthritis_Guides_a_High_Throughput_Drug_Screen_of_the_CD40_Signaling_Pathway_/704125", "title"=>"Human Genetics in Rheumatoid Arthritis Guides a High-Throughput Drug Screen of the CD40 Signaling Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-05-16 01:08:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062454"], "description"=>"<p>Relative IC<sub>50</sub> is the concentration required to bring the dose-response curve to the halfway point between the top and bottom plateaus of the curve.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "compounds"], "article_id"=>704124, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.t001", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relative_IC_50_for_two_8220_known_8221_and_two_8220_novel_8221_compounds_in_both_BL2_NF_954_B_Luc_and_Ramos_NF_954_B_Luc_cell_lines_/704124", "title"=>"Relative IC<sub>50</sub> for two “known” and two “novel” compounds in both BL2-NFκB-Luc and Ramos-NFκB-Luc cell lines.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-16 01:08:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062450"], "description"=>"<p>(A) Results from duplicate experiments screening 1,982 compounds. Red circles are our positive control (IKK inhibitor VII); grey circles are our neutral controls (DMSO only); and blue circles are test compounds. The red dashed line indicates >2SD from the mean of the neutral controls, which defines our “hit” compounds (n = 81 compounds). (B) Dose-response curves for two compounds known to inhibit inflammation [CID = 5282230 (tranilast)] or NF-|B signaling [CID = 5282360 (4-hydroxy-estradiol)] in the BL2-NF|B-Luc cell lines. (C) Dose-response curves for two compounds not previously implicated in inflammation, NF-κB signaling, CD40 signaling, or other biological pathways related to rheumatoid arthritis: CID = 306804, [4-(1-acetyl-4-oxo-2H-3,1-benzoxazin-2-yl)phenyl] acetate; and CID = 7309015, 8-[(Z)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]-7-hydroxy-4-methylchromen-2-one. Red line = cells activated with tCD40L; black line = cells activated with either CD40 or LPS (in BL2-TLR4-NFκB-Luc cells); green line = cell toxicity, as measured by CellTiter-Glo.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "cd40-mediated", "nf-kb", "bl2"], "article_id"=>704121, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.g003", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Small_molecule_screen_of_CD40_mediated_NF_kB_signaling_in_BL2_cells_/704121", "title"=>"Small molecule screen of CD40-mediated NF-kB signaling in BL2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-16 01:08:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062447"], "description"=>"<p>(A) Schematic of the canonical CD40 – NF-|B signaling pathway in B cells. (B) RNAi perturbation of <i>CD40</i> in two distinct clones derived from BL2 cells decreases CD40 protein levels by 55% (left) and 40% (middle) compared to the BL2 parent line (black, right); (C) More CD40 on the surface of BL2 cells increases RelA (p65) phosphorylation following activation with tCD40L, as measured by Western blot, with maximum activation at 15 minutes. Results are shown for the same two shRNA lines and parental BL2 cell line as in (B). This is a representative example of multiple experiments. (D) Titration of tCD40L leads to increased luciferase activity. Each experiment was performed in triplicate. The red circle represents ∼80% maximum luciferase activity (64 ng/ml tCD40L). Luciferase activity at baseline (i.e., no tCD40L activation) was subtracted from each measurement to plot results. (E) Titration of IKK inhibitor VII leads to inhibition of luciferase activity following tCD40L activation. Each experiment was performed in duplicate. (F) The luciferase assay is robust, with Z'-factor>0.80 and >60-fold inhibition of luciferase activity without killing cells across different plates.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "knockdown", "cd40-luciferase", "assay", "bl2"], "article_id"=>704119, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.g002", "stats"=>{"downloads"=>1, "page_views"=>37, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD40_knockdown_and_CD40_luciferase_assay_in_BL2_cells_/704119", "title"=>"CD40 knockdown and CD40-luciferase assay in BL2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-16 01:08:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/1062446"], "description"=>"<p>(A) The regional association plot from analysis of Immunochip (iChip) data in 7,222 CCP+ cases and 15,870 controls. Gene location is shown along the bottom of the graph, with observed –log(P) value along the left Y-axis and recombination rate along the right Y-axis. Each SNP is plotted is a circle, with color scheme (red to white) in reference to the extent of linkage disequilibrium with the index SNP, rs4810485 (labeled as a diamond). (B) The regional association plot from analysis of iChip data and CD40 protein levels in 90 healthy control individuals. (C) A box-whisker's plot of SNP (rs4810485) and CD40 protein levels in B cells from healthy control individuals, where T = non-risk allele and G = risk allele. (D) A box-whisker's plot of SNP (rs4810485) and <i>CD40</i> mRNA levels in PBMC's from two separate collections (total of 1,441 healthy control individuals); T = non-risk allele and G = risk allele.</p>", "links"=>[], "tags"=>["genetics", "Genetics of disease", "Genome-wide association studies", "Clinical immunology", "Autoimmune diseases", "rheumatoid arthritis", "Immune cells", "b cells", "Genetics of the immune system", "Drugs and devices", "Drug research and development", "drug discovery", "ra", "cd40"], "article_id"=>704118, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Gang Li", "Dorothée Diogo", "Di Wu", "Jim Spoonamore", "Vlado Dancik", "Lude Franke", "Fina Kurreeman", "Elizabeth J. Rossin", "Grant Duclos", "Cathy Hartland", "Xuezhong Zhou", "Kejie Li", "Jun Liu", "Philip L. De Jager", "Katherine A. Siminovitch", "Alexandra Zhernakova", "Soumya Raychaudhuri", "John Bowes", "Steve Eyre", "Leonid Padyukov", "Peter K. Gregersen", "Jane Worthington", "Namrata Gupta", "Paul A. Clemons", "Eli Stahl", "Nicola Tolliday", "Robert M. Plenge"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003487.g001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_data_on_risk_of_RA_and_CD40_protein_levels_/704118", "title"=>"Genetic data on risk of RA and CD40 protein levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-16 01:08:38"}

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Relative Metric

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