Update on the genetic architecture of rheumatoid arthritis
Key Points The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA developme...
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| Veröffentlicht in: | Nature reviews. Rheumatology 2017-01, Vol.13 (1), p.13-24 |
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| creator | Kim, Kwangwoo Bang, So-Young Lee, Hye-Soon Bae, Sang-Cheol |
| description | Key Points
The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported
Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations
The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4
+
T cells
Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data
RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems
Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing
Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs. |
| doi_str_mv | 10.1038/nrrheum.2016.176 |
| format | Article |
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The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported
Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations
The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4
+
T cells
Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data
RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems
Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing
Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.</description><identifier>ISSN: 1759-4790</identifier><identifier>EISSN: 1759-4804</identifier><identifier>DOI: 10.1038/nrrheum.2016.176</identifier><identifier>PMID: 27811914</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/420/2489/144 ; 692/499 ; 692/699/1670/498 ; Amino acids ; Antigens ; Arthritis, Rheumatoid - drug therapy ; Arthritis, Rheumatoid - genetics ; Arthritis, Rheumatoid - immunology ; Autoantibodies - blood ; Disease ; Disease susceptibility ; Drug Repositioning ; Genetic aspects ; Genetic Loci ; Genetic Predisposition to Disease ; HLA Antigens - genetics ; Humans ; Major Histocompatibility Complex - genetics ; Medicine & Public Health ; Pathogenesis ; Peptides ; Peptides, Cyclic - immunology ; Pharmacogenetics ; Phenotype ; Polymorphism, Single Nucleotide ; Regression analysis ; review-article ; Rheumatoid arthritis ; Rheumatology ; Risk factors ; Signal Transduction - genetics ; Single nucleotide polymorphisms</subject><ispartof>Nature reviews. Rheumatology, 2017-01, Vol.13 (1), p.13-24</ispartof><rights>Springer Nature Limited 2016</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c603t-f51b8b98ae3e5b1edc722258b4844f51714a3bf7fd8b99e4404a39a1d0c118593</citedby><cites>FETCH-LOGICAL-c603t-f51b8b98ae3e5b1edc722258b4844f51714a3bf7fd8b99e4404a39a1d0c118593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nrrheum.2016.176$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nrrheum.2016.176$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27811914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Kwangwoo</creatorcontrib><creatorcontrib>Bang, So-Young</creatorcontrib><creatorcontrib>Lee, Hye-Soon</creatorcontrib><creatorcontrib>Bae, Sang-Cheol</creatorcontrib><title>Update on the genetic architecture of rheumatoid arthritis</title><title>Nature reviews. Rheumatology</title><addtitle>Nat Rev Rheumatol</addtitle><addtitle>Nat Rev Rheumatol</addtitle><description>Key Points
The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported
Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations
The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4
+
T cells
Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data
RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems
Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing
Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.</description><subject>692/420/2489/144</subject><subject>692/499</subject><subject>692/699/1670/498</subject><subject>Amino acids</subject><subject>Antigens</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Arthritis, Rheumatoid - genetics</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Autoantibodies - blood</subject><subject>Disease</subject><subject>Disease susceptibility</subject><subject>Drug Repositioning</subject><subject>Genetic aspects</subject><subject>Genetic Loci</subject><subject>Genetic Predisposition to Disease</subject><subject>HLA Antigens - genetics</subject><subject>Humans</subject><subject>Major Histocompatibility Complex - genetics</subject><subject>Medicine & Public Health</subject><subject>Pathogenesis</subject><subject>Peptides</subject><subject>Peptides, Cyclic - immunology</subject><subject>Pharmacogenetics</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Regression analysis</subject><subject>review-article</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatology</subject><subject>Risk factors</subject><subject>Signal Transduction - genetics</subject><subject>Single nucleotide polymorphisms</subject><issn>1759-4790</issn><issn>1759-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc1v3CAQxVHVqkmT3nuKLFWqetktY7CB3FZRv6RIvTRnhPF4TWTDBvCh_33Z7qb5UCsOMLzfGxg9Qt4BXQNl8pOPccRlXtcU2jWI9gU5BdGoFZeUv7w_C0VPyJuUbilteSvVa3JSCwmggJ-Sy5tdbzJWwVd5xGqLHrOzlYl2dBltXmLRhurPMyYH1xcpj9Fll87Jq8FMCd8e9zNy8-Xzz6tvq-sfX79fba5XtqUsr4YGOtkpaZBh0wH2VtR13ciOS86LKIAb1g1i6AulkHNaamWgpxZANoqdkY-HvrsY7hZMWc8uWZwm4zEsSYNkrWBMtKyg75-ht2GJvvyuUE2rAHhNH6itmVA7P4Qcjd031RsuOFeMN7xQ639QZfU4Oxs8Dq7cPzF8eGQY0Ux5TGFasgs-PQXpAbQxpBRx0LvoZhN_aaB6n6s-5qr3ueqSa7FcHAdbuhn7v4b7IAsAByAVyW8xPpr8f01_Ay3FrNs</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Kim, Kwangwoo</creator><creator>Bang, So-Young</creator><creator>Lee, Hye-Soon</creator><creator>Bae, Sang-Cheol</creator><general>Nature Publishing Group UK</general><general>Nature 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>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>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20170101</creationdate><title>Update on the genetic architecture of rheumatoid arthritis</title><author>Kim, Kwangwoo ; Bang, So-Young ; Lee, Hye-Soon ; Bae, Sang-Cheol</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c603t-f51b8b98ae3e5b1edc722258b4844f51714a3bf7fd8b99e4404a39a1d0c118593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>692/420/2489/144</topic><topic>692/499</topic><topic>692/699/1670/498</topic><topic>Amino acids</topic><topic>Antigens</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Arthritis, Rheumatoid - genetics</topic><topic>Arthritis, Rheumatoid - immunology</topic><topic>Autoantibodies - blood</topic><topic>Disease</topic><topic>Disease susceptibility</topic><topic>Drug Repositioning</topic><topic>Genetic aspects</topic><topic>Genetic Loci</topic><topic>Genetic Predisposition to Disease</topic><topic>HLA Antigens - genetics</topic><topic>Humans</topic><topic>Major Histocompatibility Complex - genetics</topic><topic>Medicine & Public Health</topic><topic>Pathogenesis</topic><topic>Peptides</topic><topic>Peptides, Cyclic - immunology</topic><topic>Pharmacogenetics</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Regression analysis</topic><topic>review-article</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatology</topic><topic>Risk factors</topic><topic>Signal Transduction - genetics</topic><topic>Single nucleotide polymorphisms</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Kwangwoo</creatorcontrib><creatorcontrib>Bang, So-Young</creatorcontrib><creatorcontrib>Lee, Hye-Soon</creatorcontrib><creatorcontrib>Bae, Sang-Cheol</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>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>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>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical 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>MEDLINE - Academic</collection><jtitle>Nature reviews. Rheumatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Kwangwoo</au><au>Bang, So-Young</au><au>Lee, Hye-Soon</au><au>Bae, Sang-Cheol</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Update on the genetic architecture of rheumatoid arthritis</atitle><jtitle>Nature reviews. Rheumatology</jtitle><stitle>Nat Rev Rheumatol</stitle><addtitle>Nat Rev Rheumatol</addtitle><date>2017-01-01</date><risdate>2017</risdate><volume>13</volume><issue>1</issue><spage>13</spage><epage>24</epage><pages>13-24</pages><issn>1759-4790</issn><eissn>1759-4804</eissn><abstract>Key Points
The highly polygenic aetiology of rheumatoid arthritis (RA) is well characterized in population genetic studies, with >100 susceptibility loci reported
Genetic variants affecting the structure of epitope-binding sites of HLA molecules exhibit the strongest contributions to RA development; log-additive and non-log-additive effects of HLA alleles explain HLA–RA associations
The majority of non-HLA associations are mapped at noncoding variants that colocalize with cell-type-specific characteristics (for example, histone markers or enhancers) in CD4
+
T cells
Pinpointing a single causal gene in a locus that contains multiple genes usually requires additional 'omics' data
RA-risk loci generally contain genes related to T-cell and B-cell pathways, cytokine signalling pathways, proliferation and/or impaired haematopoietic and immune systems
Many proteins encoded within RA-risk loci, and their interaction partners, are the targets of currently approved therapies, implicating a potential guiding role for human RA genetics data in drug discovery and repurposing
Genetic association studies have uncovered more than 100 genetic loci related to susceptibility to rheumatoid arthritis. This Review discusses the latest insights into rheumatoid arthritis pathogenesis gained from genetic studies and their application for drug discovery and development.
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27811914</pmid><doi>10.1038/nrrheum.2016.176</doi><tpages>12</tpages></addata></record> |
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| subjects | 692/420/2489/144 692/499 692/699/1670/498 Amino acids Antigens Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - genetics Arthritis, Rheumatoid - immunology Autoantibodies - blood Disease Disease susceptibility Drug Repositioning Genetic aspects Genetic Loci Genetic Predisposition to Disease HLA Antigens - genetics Humans Major Histocompatibility Complex - genetics Medicine & Public Health Pathogenesis Peptides Peptides, Cyclic - immunology Pharmacogenetics Phenotype Polymorphism, Single Nucleotide Regression analysis review-article Rheumatoid arthritis Rheumatology Risk factors Signal Transduction - genetics Single nucleotide polymorphisms |
| title | Update on the genetic architecture of rheumatoid arthritis |
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