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ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma
Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progres...
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| creator | Praveen, Kavita Patel, Gaurang C Gurski, Lauren Ayer, Ariane H Persaud, Trikaladarshi Still, Matthew D Miloscio, Lawrence Van Zyl, Tavé Di Gioia, Silvio Alessandro Brumpton, Ben Michael Krebs, Kristine Åsvold, Bjørn Olav Chen, Esteban Chavali, Venkata R M Fury, Wen Gudiseva, Harini V Hyde, Sarah Jorgenson, Eric Lefebvre, Stephanie Li, Dadong Li, Alexander Mclninch, James Patel, Brijeshkumar Rabinowitz, Jeremy S Salowe, Rebecca Schurmann, Claudia Seidelin, Anne-Sofie Stahl, Eli Sun, Dylan Teslovich, Tanya M Tybjærg-Hansen, Anne Willer, Cristen Waldron, Scott Walley, Sabrina Yang, Hua Zaveri, Sarthak Hu, Ying Hveem, Kristian Melander, Olle Milani, Lili Stender, Stefan O'Brien, Joan M Jones, Marcus B Abecasis, Gonçalo R Cantor, Michael N Weyne, Jonathan Karalis, Katia Economides, Aris Della Gatta, Giusy Ferreira, Manuel A Yancopoulos, George D Baras, Aris Romano, Carmelo Coppola, Giovanni |
| description | Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma. |
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Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.</description><language>eng</language><publisher>Nature Research</publisher><creationdate>2022</creationdate><rights>info:eu-repo/semantics/openAccess</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,783,888,26579</link.rule.ids><linktorsrc>$$Uhttp://hdl.handle.net/11250/3044878$$EView_record_in_NORA$$FView_record_in_$$GNORA$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>Praveen, Kavita</creatorcontrib><creatorcontrib>Patel, Gaurang C</creatorcontrib><creatorcontrib>Gurski, Lauren</creatorcontrib><creatorcontrib>Ayer, Ariane H</creatorcontrib><creatorcontrib>Persaud, Trikaladarshi</creatorcontrib><creatorcontrib>Still, Matthew D</creatorcontrib><creatorcontrib>Miloscio, Lawrence</creatorcontrib><creatorcontrib>Van Zyl, Tavé</creatorcontrib><creatorcontrib>Di Gioia, Silvio Alessandro</creatorcontrib><creatorcontrib>Brumpton, Ben Michael</creatorcontrib><creatorcontrib>Krebs, Kristine</creatorcontrib><creatorcontrib>Åsvold, Bjørn Olav</creatorcontrib><creatorcontrib>Chen, Esteban</creatorcontrib><creatorcontrib>Chavali, Venkata R M</creatorcontrib><creatorcontrib>Fury, Wen</creatorcontrib><creatorcontrib>Gudiseva, Harini V</creatorcontrib><creatorcontrib>Hyde, Sarah</creatorcontrib><creatorcontrib>Jorgenson, Eric</creatorcontrib><creatorcontrib>Lefebvre, Stephanie</creatorcontrib><creatorcontrib>Li, Dadong</creatorcontrib><creatorcontrib>Li, Alexander</creatorcontrib><creatorcontrib>Mclninch, James</creatorcontrib><creatorcontrib>Patel, Brijeshkumar</creatorcontrib><creatorcontrib>Rabinowitz, Jeremy S</creatorcontrib><creatorcontrib>Salowe, Rebecca</creatorcontrib><creatorcontrib>Schurmann, Claudia</creatorcontrib><creatorcontrib>Seidelin, Anne-Sofie</creatorcontrib><creatorcontrib>Stahl, Eli</creatorcontrib><creatorcontrib>Sun, Dylan</creatorcontrib><creatorcontrib>Teslovich, Tanya M</creatorcontrib><creatorcontrib>Tybjærg-Hansen, Anne</creatorcontrib><creatorcontrib>Willer, Cristen</creatorcontrib><creatorcontrib>Waldron, Scott</creatorcontrib><creatorcontrib>Walley, Sabrina</creatorcontrib><creatorcontrib>Yang, Hua</creatorcontrib><creatorcontrib>Zaveri, Sarthak</creatorcontrib><creatorcontrib>Hu, Ying</creatorcontrib><creatorcontrib>Hveem, Kristian</creatorcontrib><creatorcontrib>Melander, Olle</creatorcontrib><creatorcontrib>Milani, Lili</creatorcontrib><creatorcontrib>Stender, Stefan</creatorcontrib><creatorcontrib>O'Brien, Joan M</creatorcontrib><creatorcontrib>Jones, Marcus B</creatorcontrib><creatorcontrib>Abecasis, Gonçalo R</creatorcontrib><creatorcontrib>Cantor, Michael N</creatorcontrib><creatorcontrib>Weyne, Jonathan</creatorcontrib><creatorcontrib>Karalis, Katia</creatorcontrib><creatorcontrib>Economides, Aris</creatorcontrib><creatorcontrib>Della Gatta, Giusy</creatorcontrib><creatorcontrib>Ferreira, Manuel A</creatorcontrib><creatorcontrib>Yancopoulos, George D</creatorcontrib><creatorcontrib>Baras, Aris</creatorcontrib><creatorcontrib>Romano, Carmelo</creatorcontrib><creatorcontrib>Coppola, Giovanni</creatorcontrib><title>ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma</title><description>Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.</description><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>3HK</sourceid><recordid>eNqNyj0OwjAMQOEsDAi4g9lBamlRuyLEzwCIoXtkuW6JFJLKce4PAwdget_w5uZ-eFye3a3ZAIK-WHDirI5AUUZWGKKACySMifuvVDBS9igwCaeUhQFDD6PHTPGNSzMb0Cde_bow6_OpO163JC6pCzZEQVuWu31hq6Ku26at_nk-WuU1QQ</recordid><startdate>2022</startdate><enddate>2022</enddate><creator>Praveen, Kavita</creator><creator>Patel, Gaurang C</creator><creator>Gurski, Lauren</creator><creator>Ayer, Ariane H</creator><creator>Persaud, Trikaladarshi</creator><creator>Still, Matthew D</creator><creator>Miloscio, Lawrence</creator><creator>Van Zyl, Tavé</creator><creator>Di Gioia, Silvio Alessandro</creator><creator>Brumpton, Ben Michael</creator><creator>Krebs, 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Katia</au><au>Economides, Aris</au><au>Della Gatta, Giusy</au><au>Ferreira, Manuel A</au><au>Yancopoulos, George D</au><au>Baras, Aris</au><au>Romano, Carmelo</au><au>Coppola, Giovanni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma</atitle><date>2022</date><risdate>2022</risdate><abstract>Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2–4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.</abstract><pub>Nature Research</pub><oa>free_for_read</oa></addata></record> |
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| title | ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma |
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