ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma
Authors: 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 , Krebs Kristi , 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 ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Abecasis Goncalo R. , Cantor Michael , Deubler Andrew , Economides Aris , Lotta Luca A. , Overton John D. , Reid Jeffrey G. , Shuldiner Alan , Siminovitch Katherine ,   Sequencing and Lab Operations, Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Schleicher Thomas D. , Padilla Maria Sotiropoulos , Widom Louis , Wolf Sarah E. , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H. ,   Genome Informatics, Bai Xiaodong , Balasubramanian Suganthi , Bao Suying , Boutkov Boris , Chen Siying , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Maxwell Evan K. , Nafde Mona , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Salerno William , Sun Kathie ,   Clinical Informatics, Averitt Amelia , Banerjee Nilanjana , Malhotra Sameer , Sharma Deepika , Staples Jeffery C. , Yadav Ashish ,   Translational and Analytical Genetics, Backman Joshua , Damask Amy , Dobbyn Lee , Ferreira Manuel Allen Revez , Ghosh Arkopravo , Gillies Christopher , Kang Hyun Min , Kessler Michael , Kosmicki Jack , Lin Nan , Liu Daren , Locke Adam , Marchini Jonathan , Marcketta Anthony , Mbatchou Joelle , Moscati Arden , Paulding Charles , Sidore Carlo , Watanabe Kyoko , Bin Ye  , Zhang Blair , Ziyatdinov Andrey ,   Research Program Management, LeBlanc Michelle G. , Mighty Jason , Mitnaul Lyndon J. , Nishtala Nirupama , Rana Nadia ,   GHS-RGC DiscovEHR Collaboration, Adams Lance J. , Blank Jackie , Bodian Dale , Boris Derek , Buchanan Adam , Carey David J. , Colonie Ryan D. , Davis F. Daniel , Hartzel Dustin N. , Kelly Melissa , Kirchner H. Lester , Leader Joseph B. , Ledbetter David H. , Manus J. Neil , Martin Christa L. , Metpally Raghu P. , Meyer Michelle , Mirshahi Tooraj , Oetjens Matthew , Person Thomas Nate , Still Christopher , Strande Natasha , Sturm Amy , Wagner Jen , Williams Marc ,   Estonian Biobank Research Team, Metspalu Andres , Nelis Mari , Mägi Reedik , Esko Tõnu , 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 
Published: October 2022

AbstractGlaucoma 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 thatAngptl7knockout 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 acuteAngptl7 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.