Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity
ABSTRACT The genetic association between a variant in the Toll‐like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced “dry” age‐related macular degeneration) was controversial in previous studies. We per...
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| Veröffentlicht in: | The FASEB journal 2011-10, Vol.25 (10), p.3489-3495 |
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| creator | Zhou, Peng Fan, Lei Yu, Ke‐Da Zhao, Ming‐Wei Li, Xiao‐Xin |
| description | ABSTRACT
The genetic association between a variant in the Toll‐like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced “dry” age‐related macular degeneration) was controversial in previous studies. We performed a meta‐analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612‐0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double‐stranded RNA in the TLR3 protein was only 51.12 ± 3.96% (P |
| doi_str_mv | 10.1096/fj.11-189258 |
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The genetic association between a variant in the Toll‐like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced “dry” age‐related macular degeneration) was controversial in previous studies. We performed a meta‐analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612‐0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double‐stranded RNA in the TLR3 protein was only 51.12 ± 3.96% (P<0.001) of the wild‐type level. There was a consistently reduced TLR3‐mediated NF‐κB activation. Therefore, TLR3 C1234T (L412F in the protein) may protect against GA by reduced binding capacity of TLR3 to dsRNA This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.—Zhou, P., Fan, L., Yu, K. ‐D., Zhao, M. ‐W., Li, X. ‐X. Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity, FASEB J. 25, 3489–3495 (2011). www.fasebj.org</description><identifier>ISSN: 0892-6638</identifier><identifier>EISSN: 1530-6860</identifier><identifier>DOI: 10.1096/fj.11-189258</identifier><identifier>PMID: 21712495</identifier><language>eng</language><publisher>United States</publisher><subject>age‐related macular degeneration ; double‐stranded RNA ; Gene Expression Regulation - physiology ; Genetic Predisposition to Disease ; Geographic Atrophy - genetics ; Humans ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; RNA, Double-Stranded - genetics ; RNA, Double-Stranded - metabolism ; Toll-Like Receptor 3 - genetics ; Toll-Like Receptor 3 - metabolism</subject><ispartof>The FASEB journal, 2011-10, Vol.25 (10), p.3489-3495</ispartof><rights>FASEB</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4378-f50f83aa65f8504de364f6eafd6b6d6ea1e5de431a70efcfe1c981c45a9a6cb73</citedby><cites>FETCH-LOGICAL-c4378-f50f83aa65f8504de364f6eafd6b6d6ea1e5de431a70efcfe1c981c45a9a6cb73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1096%2Ffj.11-189258$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1096%2Ffj.11-189258$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21712495$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Peng</creatorcontrib><creatorcontrib>Fan, Lei</creatorcontrib><creatorcontrib>Yu, Ke‐Da</creatorcontrib><creatorcontrib>Zhao, Ming‐Wei</creatorcontrib><creatorcontrib>Li, Xiao‐Xin</creatorcontrib><title>Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity</title><title>The FASEB journal</title><addtitle>FASEB J</addtitle><description>ABSTRACT
The genetic association between a variant in the Toll‐like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced “dry” age‐related macular degeneration) was controversial in previous studies. We performed a meta‐analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612‐0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double‐stranded RNA in the TLR3 protein was only 51.12 ± 3.96% (P<0.001) of the wild‐type level. There was a consistently reduced TLR3‐mediated NF‐κB activation. Therefore, TLR3 C1234T (L412F in the protein) may protect against GA by reduced binding capacity of TLR3 to dsRNA This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.—Zhou, P., Fan, L., Yu, K. ‐D., Zhao, M. ‐W., Li, X. ‐X. Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity, FASEB J. 25, 3489–3495 (2011). www.fasebj.org</description><subject>age‐related macular degeneration</subject><subject>double‐stranded RNA</subject><subject>Gene Expression Regulation - physiology</subject><subject>Genetic Predisposition to Disease</subject><subject>Geographic Atrophy - genetics</subject><subject>Humans</subject><subject>Odds Ratio</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Risk Factors</subject><subject>RNA, Double-Stranded - genetics</subject><subject>RNA, Double-Stranded - metabolism</subject><subject>Toll-Like Receptor 3 - genetics</subject><subject>Toll-Like Receptor 3 - metabolism</subject><issn>0892-6638</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFu1DAQhi1ERbeFG2fkGxfSemLHsY9l1aWgCiRYzpbXHme9JJtgZ4Vy6yPwjDwJQbv0CKf5Nfr0aTQ_IS-BXQHT8jrsrgAKULqs1BOygIqzQirJnpIFm5eFlFydk4ucd4wxYCCfkfMSaiiFrhakW_dt--vhZxu_IU3ocBj7RDldQsnFmnZ2okPqR3QjtY2N-zzSBvsm2WEbHbVj6oftRMdt6g_Nlnp0CW1GT33-_PGGbuLex31DnR2si-P0nJwF22Z8cZqX5Ovqdr28K-4_vXu_vLkvnOC1KkLFguLWyiqoigmPXIog0QYvN9LPAbDyKDjYmmFwAcFpBU5UVlvpNjW_JK-P3vn27wfMo-lidti2do_9IRvNaqi10P8nlZalAODlTL45ki71OScMZkixs2kywMyfJkzYGQBzbGLGX53Eh02H_hH--_oZUEfgR2xx-qfMrL68LVcfAE7u3zVUll4</recordid><startdate>201110</startdate><enddate>201110</enddate><creator>Zhou, Peng</creator><creator>Fan, Lei</creator><creator>Yu, Ke‐Da</creator><creator>Zhao, Ming‐Wei</creator><creator>Li, Xiao‐Xin</creator><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>7X8</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope></search><sort><creationdate>201110</creationdate><title>Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity</title><author>Zhou, Peng ; Fan, Lei ; Yu, Ke‐Da ; Zhao, Ming‐Wei ; Li, Xiao‐Xin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4378-f50f83aa65f8504de364f6eafd6b6d6ea1e5de431a70efcfe1c981c45a9a6cb73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>age‐related macular degeneration</topic><topic>double‐stranded RNA</topic><topic>Gene Expression Regulation - physiology</topic><topic>Genetic Predisposition to Disease</topic><topic>Geographic Atrophy - genetics</topic><topic>Humans</topic><topic>Odds Ratio</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Risk Factors</topic><topic>RNA, Double-Stranded - genetics</topic><topic>RNA, Double-Stranded - metabolism</topic><topic>Toll-Like Receptor 3 - genetics</topic><topic>Toll-Like Receptor 3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhou, Peng</creatorcontrib><creatorcontrib>Fan, Lei</creatorcontrib><creatorcontrib>Yu, Ke‐Da</creatorcontrib><creatorcontrib>Zhao, Ming‐Wei</creatorcontrib><creatorcontrib>Li, Xiao‐Xin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Peng</au><au>Fan, Lei</au><au>Yu, Ke‐Da</au><au>Zhao, Ming‐Wei</au><au>Li, Xiao‐Xin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2011-10</date><risdate>2011</risdate><volume>25</volume><issue>10</issue><spage>3489</spage><epage>3495</epage><pages>3489-3495</pages><issn>0892-6638</issn><eissn>1530-6860</eissn><abstract>ABSTRACT
The genetic association between a variant in the Toll‐like receptor 3 (TLR3) gene (C1234T in mRNA, L412F in protein, Reference SNP Cluster Report rs3775291) and geographic atrophy (GA; also called advanced “dry” age‐related macular degeneration) was controversial in previous studies. We performed a meta‐analysis by pooling the current evidence in literature and found that the T allele of the TLR3 C1234T variant showed a summary odds ratio of 0.753 (95% confidence interval: 0.612‐0.927; P=0.007). Further experiments were performed to analyze how this mutant influences the function of TLR3. We found that this SNP did not affect mRNA, protein, or surface expression of TLR3. However, the binding capacity of L412F mutation of TLR3 for double‐stranded RNA in the TLR3 protein was only 51.12 ± 3.96% (P<0.001) of the wild‐type level. There was a consistently reduced TLR3‐mediated NF‐κB activation. Therefore, TLR3 C1234T (L412F in the protein) may protect against GA by reduced binding capacity of TLR3 to dsRNA This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.—Zhou, P., Fan, L., Yu, K. ‐D., Zhao, M. ‐W., Li, X. ‐X. Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity, FASEB J. 25, 3489–3495 (2011). www.fasebj.org</abstract><cop>United States</cop><pmid>21712495</pmid><doi>10.1096/fj.11-189258</doi><tpages>7</tpages></addata></record> |
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| subjects | age‐related macular degeneration double‐stranded RNA Gene Expression Regulation - physiology Genetic Predisposition to Disease Geographic Atrophy - genetics Humans Odds Ratio Polymorphism, Single Nucleotide Risk Factors RNA, Double-Stranded - genetics RNA, Double-Stranded - metabolism Toll-Like Receptor 3 - genetics Toll-Like Receptor 3 - metabolism |
| title | Toll‐like receptor 3 C1234T may protect against geographic atrophy through decreased dsRNA binding capacity |
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