Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases
ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we p...
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| Veröffentlicht in: | Annals of the rheumatic diseases 2019-03, Vol.78 (3), p.311-319 |
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| container_title | Annals of the rheumatic diseases |
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| creator | Acosta-Herrera, Marialbert Kerick, Martin González-Serna, David Wijmenga, Cisca Franke, Andre Gregersen, Peter K Padyukov, Leonid Worthington, Jane Vyse, Timothy James Alarcón-Riquelme, Marta Eugenia Mayes, Maureen D Martin, Javier |
| description | ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs. |
| doi_str_mv | 10.1136/annrheumdis-2018-214127 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_D8T</sourceid><recordid>TN_cdi_swepub_primary_oai_swepub_ki_se_483250</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2159985709</sourcerecordid><originalsourceid>FETCH-LOGICAL-b626t-1dbe50fa3e62a7710c77eaa200d87b1e1422dab1cfabfb84b69fb42367b6fa003</originalsourceid><addsrcrecordid>eNqNksFu1DAQhi0EokvhFcASl_YQsJ3Edi5IVUVbpJW4wBFZ42TCeknixU52tW-PQ5aq7YmTPTPf_J6Rf0LecfaB81x-hGEIG5z6xsVMMK4zwQsu1DOy4oVMEZPsOVkxxvKsqKQ6I69i3KaQaa5fkrOclSqXZbkiP25x8D1mB9cg7XGEDAbojtFFGnCP0EUaNxCwoQMeaOdrR91A4zGO2LuaRgx-56Mb3R7p34lgTOk0FkLE-Jq8aJMEvjmd5-T7zedv13fZ-uvtl-urdWalkGPGG4slayFHKUApzmqlEEAw1mhlOfJCiAYsr1uwrdWFlVVrC5FLZWULaclzki268YC7yZpdcD2Eo_HgzCn1K93QFDoX5cx_WvhU6bGpcRgDdI_aHlcGtzE__d5IzZhgOglcLgKbJ213V2sz5xJV8kqJPU_sxemx4H9PGEfTu1hj18GAfopG8LKqdKlYldD3T9Ctn0L6kJnSXDFZ5iJRaqHq4GMM2N5PwJmZ7WEe2MPM9jCLPVLn24d73_f980MCxALYfvvfqn8A7BTMiw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2181706532</pqid></control><display><type>article</type><title>Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases</title><source>SWEPUB Freely available online</source><creator>Acosta-Herrera, Marialbert ; Kerick, Martin ; González-Serna, David ; Wijmenga, Cisca ; Franke, Andre ; Gregersen, Peter K ; Padyukov, Leonid ; Worthington, Jane ; Vyse, Timothy James ; Alarcón-Riquelme, Marta Eugenia ; Mayes, Maureen D ; Martin, Javier</creator><creatorcontrib>Acosta-Herrera, Marialbert ; Kerick, Martin ; González-Serna, David ; Wijmenga, Cisca ; Franke, Andre ; Gregersen, Peter K ; Padyukov, Leonid ; Worthington, Jane ; Vyse, Timothy James ; Alarcón-Riquelme, Marta Eugenia ; Mayes, Maureen D ; Martin, Javier ; Scleroderma Genetics Consortium ; Myositis Genetics Consortium</creatorcontrib><description>ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.</description><identifier>ISSN: 0003-4967</identifier><identifier>EISSN: 1468-2060</identifier><identifier>DOI: 10.1136/annrheumdis-2018-214127</identifier><identifier>PMID: 30573655</identifier><language>eng</language><publisher>England: Elsevier Limited</publisher><subject>Adult ; alpha Karyopherins - immunology ; Arthritis, Rheumatoid - genetics ; Arthritis, Rheumatoid - immunology ; Autoimmunity ; Chromatin ; Cytoskeleton ; Deoxyribonuclease ; Disease ; Epidermal growth factor ; Female ; Gene expression ; Gene loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomes ; Growth factors ; Haplotypes ; Health risk assessment ; Human health and pathology ; Humans ; Hypersensitivity ; Hypertension ; Immunosuppressive agents ; Inflammatory diseases ; Interferon ; Kinases ; Life Sciences ; LIM kinase ; Lim Kinases - immunology ; Lupus ; Lupus Erythematosus, Systemic - genetics ; Lupus Erythematosus, Systemic - immunology ; Male ; Membrane Proteins - immunology ; Meta-analysis ; Methotrexate ; Myositis - genetics ; Myositis - immunology ; Parasitology ; Polymorphism, Single Nucleotide ; Population ; Proteins ; Quality control ; Quantitative trait loci ; Quantitative Trait Loci - genetics ; Quantitative Trait Loci - immunology ; Repressor Proteins - immunology ; Rheumatic diseases ; Rheumatic Diseases - genetics ; Rheumatic Diseases - immunology ; Rheumatoid arthritis ; Rheumatology ; Rhumatology and musculoskeletal system ; Scleroderma ; Scleroderma, Systemic - genetics ; Scleroderma, Systemic - immunology ; Single-nucleotide polymorphism ; Software ; Studies ; Systemic lupus erythematosus ; Systemic sclerosis ; Whites - genetics</subject><ispartof>Annals of the rheumatic diseases, 2019-03, Vol.78 (3), p.311-319</ispartof><rights>Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2019 Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b626t-1dbe50fa3e62a7710c77eaa200d87b1e1422dab1cfabfb84b69fb42367b6fa003</citedby><cites>FETCH-LOGICAL-b626t-1dbe50fa3e62a7710c77eaa200d87b1e1422dab1cfabfb84b69fb42367b6fa003</cites><orcidid>0000-0003-1613-1518 ; 0000-0001-7287-5541</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,550,776,881</link.rule.ids><linktorsrc>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:141150866$$EView_record_in_Swedish_Publication_Index_(SWEPUB)$$FView_record_in_$$GSwedish_Publication_Index_(SWEPUB)$$Hfree_for_read</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30573655$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.univ-brest.fr/hal-02051972$$DView record in HAL$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:141150866$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Acosta-Herrera, Marialbert</creatorcontrib><creatorcontrib>Kerick, Martin</creatorcontrib><creatorcontrib>González-Serna, David</creatorcontrib><creatorcontrib>Wijmenga, Cisca</creatorcontrib><creatorcontrib>Franke, Andre</creatorcontrib><creatorcontrib>Gregersen, Peter K</creatorcontrib><creatorcontrib>Padyukov, Leonid</creatorcontrib><creatorcontrib>Worthington, Jane</creatorcontrib><creatorcontrib>Vyse, Timothy James</creatorcontrib><creatorcontrib>Alarcón-Riquelme, Marta Eugenia</creatorcontrib><creatorcontrib>Mayes, Maureen D</creatorcontrib><creatorcontrib>Martin, Javier</creatorcontrib><creatorcontrib>Scleroderma Genetics Consortium</creatorcontrib><creatorcontrib>Myositis Genetics Consortium</creatorcontrib><title>Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases</title><title>Annals of the rheumatic diseases</title><addtitle>Ann Rheum Dis</addtitle><description>ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.</description><subject>Adult</subject><subject>alpha Karyopherins - immunology</subject><subject>Arthritis, Rheumatoid - genetics</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Autoimmunity</subject><subject>Chromatin</subject><subject>Cytoskeleton</subject><subject>Deoxyribonuclease</subject><subject>Disease</subject><subject>Epidermal growth factor</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene loci</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Growth factors</subject><subject>Haplotypes</subject><subject>Health risk assessment</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Hypersensitivity</subject><subject>Hypertension</subject><subject>Immunosuppressive agents</subject><subject>Inflammatory diseases</subject><subject>Interferon</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>LIM kinase</subject><subject>Lim Kinases - immunology</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - genetics</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Male</subject><subject>Membrane Proteins - immunology</subject><subject>Meta-analysis</subject><subject>Methotrexate</subject><subject>Myositis - genetics</subject><subject>Myositis - immunology</subject><subject>Parasitology</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Population</subject><subject>Proteins</subject><subject>Quality control</subject><subject>Quantitative trait loci</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Quantitative Trait Loci - immunology</subject><subject>Repressor Proteins - immunology</subject><subject>Rheumatic diseases</subject><subject>Rheumatic Diseases - genetics</subject><subject>Rheumatic Diseases - immunology</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatology</subject><subject>Rhumatology and musculoskeletal system</subject><subject>Scleroderma</subject><subject>Scleroderma, Systemic - genetics</subject><subject>Scleroderma, Systemic - immunology</subject><subject>Single-nucleotide polymorphism</subject><subject>Software</subject><subject>Studies</subject><subject>Systemic lupus erythematosus</subject><subject>Systemic sclerosis</subject><subject>Whites - genetics</subject><issn>0003-4967</issn><issn>1468-2060</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>D8T</sourceid><recordid>eNqNksFu1DAQhi0EokvhFcASl_YQsJ3Edi5IVUVbpJW4wBFZ42TCeknixU52tW-PQ5aq7YmTPTPf_J6Rf0LecfaB81x-hGEIG5z6xsVMMK4zwQsu1DOy4oVMEZPsOVkxxvKsqKQ6I69i3KaQaa5fkrOclSqXZbkiP25x8D1mB9cg7XGEDAbojtFFGnCP0EUaNxCwoQMeaOdrR91A4zGO2LuaRgx-56Mb3R7p34lgTOk0FkLE-Jq8aJMEvjmd5-T7zedv13fZ-uvtl-urdWalkGPGG4slayFHKUApzmqlEEAw1mhlOfJCiAYsr1uwrdWFlVVrC5FLZWULaclzki268YC7yZpdcD2Eo_HgzCn1K93QFDoX5cx_WvhU6bGpcRgDdI_aHlcGtzE__d5IzZhgOglcLgKbJ213V2sz5xJV8kqJPU_sxemx4H9PGEfTu1hj18GAfopG8LKqdKlYldD3T9Ctn0L6kJnSXDFZ5iJRaqHq4GMM2N5PwJmZ7WEe2MPM9jCLPVLn24d73_f980MCxALYfvvfqn8A7BTMiw</recordid><startdate>20190301</startdate><enddate>20190301</enddate><creator>Acosta-Herrera, Marialbert</creator><creator>Kerick, Martin</creator><creator>González-Serna, David</creator><creator>Wijmenga, Cisca</creator><creator>Franke, Andre</creator><creator>Gregersen, Peter K</creator><creator>Padyukov, Leonid</creator><creator>Worthington, Jane</creator><creator>Vyse, Timothy James</creator><creator>Alarcón-Riquelme, Marta Eugenia</creator><creator>Mayes, Maureen D</creator><creator>Martin, Javier</creator><general>Elsevier Limited</general><general>BMJ Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0003-1613-1518</orcidid><orcidid>https://orcid.org/0000-0001-7287-5541</orcidid></search><sort><creationdate>20190301</creationdate><title>Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases</title><author>Acosta-Herrera, Marialbert ; Kerick, Martin ; González-Serna, David ; Wijmenga, Cisca ; Franke, Andre ; Gregersen, Peter K ; Padyukov, Leonid ; Worthington, Jane ; Vyse, Timothy James ; Alarcón-Riquelme, Marta Eugenia ; Mayes, Maureen D ; Martin, Javier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b626t-1dbe50fa3e62a7710c77eaa200d87b1e1422dab1cfabfb84b69fb42367b6fa003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>alpha Karyopherins - immunology</topic><topic>Arthritis, Rheumatoid - genetics</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Autoimmunity</topic><topic>Chromatin</topic><topic>Cytoskeleton</topic><topic>Deoxyribonuclease</topic><topic>Disease</topic><topic>Epidermal growth factor</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene loci</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Growth factors</topic><topic>Haplotypes</topic><topic>Health risk assessment</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Hypersensitivity</topic><topic>Hypertension</topic><topic>Immunosuppressive agents</topic><topic>Inflammatory diseases</topic><topic>Interferon</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>LIM kinase</topic><topic>Lim Kinases - immunology</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - genetics</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Male</topic><topic>Membrane Proteins - immunology</topic><topic>Meta-analysis</topic><topic>Methotrexate</topic><topic>Myositis - genetics</topic><topic>Myositis - immunology</topic><topic>Parasitology</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Population</topic><topic>Proteins</topic><topic>Quality control</topic><topic>Quantitative trait loci</topic><topic>Quantitative Trait Loci - genetics</topic><topic>Quantitative Trait Loci - immunology</topic><topic>Repressor Proteins - immunology</topic><topic>Rheumatic diseases</topic><topic>Rheumatic Diseases - genetics</topic><topic>Rheumatic Diseases - immunology</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatology</topic><topic>Rhumatology and musculoskeletal system</topic><topic>Scleroderma</topic><topic>Scleroderma, Systemic - genetics</topic><topic>Scleroderma, Systemic - immunology</topic><topic>Single-nucleotide polymorphism</topic><topic>Software</topic><topic>Studies</topic><topic>Systemic lupus erythematosus</topic><topic>Systemic sclerosis</topic><topic>Whites - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Acosta-Herrera, Marialbert</creatorcontrib><creatorcontrib>Kerick, Martin</creatorcontrib><creatorcontrib>González-Serna, David</creatorcontrib><creatorcontrib>Wijmenga, Cisca</creatorcontrib><creatorcontrib>Franke, Andre</creatorcontrib><creatorcontrib>Gregersen, Peter K</creatorcontrib><creatorcontrib>Padyukov, Leonid</creatorcontrib><creatorcontrib>Worthington, Jane</creatorcontrib><creatorcontrib>Vyse, Timothy James</creatorcontrib><creatorcontrib>Alarcón-Riquelme, Marta Eugenia</creatorcontrib><creatorcontrib>Mayes, Maureen D</creatorcontrib><creatorcontrib>Martin, Javier</creatorcontrib><creatorcontrib>Scleroderma Genetics Consortium</creatorcontrib><creatorcontrib>Myositis Genetics Consortium</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Annals of the rheumatic diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Acosta-Herrera, Marialbert</au><au>Kerick, Martin</au><au>González-Serna, David</au><au>Wijmenga, Cisca</au><au>Franke, Andre</au><au>Gregersen, Peter K</au><au>Padyukov, Leonid</au><au>Worthington, Jane</au><au>Vyse, Timothy James</au><au>Alarcón-Riquelme, Marta Eugenia</au><au>Mayes, Maureen D</au><au>Martin, Javier</au><aucorp>Scleroderma Genetics Consortium</aucorp><aucorp>Myositis Genetics Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases</atitle><jtitle>Annals of the rheumatic diseases</jtitle><addtitle>Ann Rheum Dis</addtitle><date>2019-03-01</date><risdate>2019</risdate><volume>78</volume><issue>3</issue><spage>311</spage><epage>319</epage><pages>311-319</pages><issn>0003-4967</issn><eissn>1468-2060</eissn><abstract>ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.</abstract><cop>England</cop><pub>Elsevier Limited</pub><pmid>30573655</pmid><doi>10.1136/annrheumdis-2018-214127</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-1613-1518</orcidid><orcidid>https://orcid.org/0000-0001-7287-5541</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of the rheumatic diseases, 2019-03, Vol.78 (3), p.311-319 |
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| recordid | cdi_swepub_primary_oai_swepub_ki_se_483250 |
| source | SWEPUB Freely available online |
| subjects | Adult alpha Karyopherins - immunology Arthritis, Rheumatoid - genetics Arthritis, Rheumatoid - immunology Autoimmunity Chromatin Cytoskeleton Deoxyribonuclease Disease Epidermal growth factor Female Gene expression Gene loci Genetic Predisposition to Disease Genome-Wide Association Study Genomes Growth factors Haplotypes Health risk assessment Human health and pathology Humans Hypersensitivity Hypertension Immunosuppressive agents Inflammatory diseases Interferon Kinases Life Sciences LIM kinase Lim Kinases - immunology Lupus Lupus Erythematosus, Systemic - genetics Lupus Erythematosus, Systemic - immunology Male Membrane Proteins - immunology Meta-analysis Methotrexate Myositis - genetics Myositis - immunology Parasitology Polymorphism, Single Nucleotide Population Proteins Quality control Quantitative trait loci Quantitative Trait Loci - genetics Quantitative Trait Loci - immunology Repressor Proteins - immunology Rheumatic diseases Rheumatic Diseases - genetics Rheumatic Diseases - immunology Rheumatoid arthritis Rheumatology Rhumatology and musculoskeletal system Scleroderma Scleroderma, Systemic - genetics Scleroderma, Systemic - immunology Single-nucleotide polymorphism Software Studies Systemic lupus erythematosus Systemic sclerosis Whites - genetics |
| title | Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T10%3A04%3A24IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_D8T&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20meta-analysis%20reveals%20shared%20new%20loci%20in%20systemic%20seropositive%20rheumatic%20diseases&rft.jtitle=Annals%20of%20the%20rheumatic%20diseases&rft.au=Acosta-Herrera,%20Marialbert&rft.aucorp=Scleroderma%20Genetics%20Consortium&rft.date=2019-03-01&rft.volume=78&rft.issue=3&rft.spage=311&rft.epage=319&rft.pages=311-319&rft.issn=0003-4967&rft.eissn=1468-2060&rft_id=info:doi/10.1136/annrheumdis-2018-214127&rft_dat=%3Cproquest_D8T%3E2159985709%3C/proquest_D8T%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2181706532&rft_id=info:pmid/30573655&rfr_iscdi=true |