ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma
Kavita Praveen, Gaurang Patel, Lauren Gurski, Ariane Ayer, Trikaladarshi Persaud, Matthew Still, Lawrence Miloscio, Tavé van Zyl, Silvio Alessandro Di Gioia, Ben Brumpton, Kristi Krebs, Bjørn Olav Åsvold, Esteban Chen, Venkata Ramana Murthy Chavali, Wen Fury, Harini V. Gudiseva, Sarah Hyde, Eric Jorgenson, Stéphanie Lefebvre, Dadong Li, Alexander Li, James Mclninch, Brijeshkumar Patel, Jeremy S. Rabinowitz, Rebecca Salowe, Claudia Schurmann, Anne-Sofie Seidelin, Eli A. Stahl, Dylan Sun, Tanya M. Teslovich, Anne Tybjærg‐Hansen, Cristen J. Willer, Scott Waldron, Sabrina Walley, Hua Yang, Sarthak Zaveri, RGC Management and Leadership Team, Gonçalo R. Abecasis, Michael Cantor, Andrew Deubler, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Katherine Siminovitch, Sequencing and Lab Operations, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Genome Informatics, Xiaodong Bai, Suganthi Balasubramanian, Suying Bao, Boris Boutkov, Siying Chen, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Olga Krasheninina, Rouel Lanche, Adam J. Mansfield, Evan K. Maxwell, Mona Nafde, Sean O’Keeffe, Max Orelus, Razvan Panea, Tommy Polanco, Ayesha Rasool, William Salerno, Kathie Sun, Amelia Averitt, Nilanjana Banerjee, Sameer Malhotra, Deepika Sharma, Jeffery C. Staples, Ashish Yadav, Translational and Analytical Genetics, Joshua Backman, Amy Damask, Lee Dobbyn, Manuel Allen Revez Ferreira, Arkopravo Ghosh, Christopher E. Gillies, Hyun Min Kang, Michael D. Kessler, Jack A. Kosmicki, Nan Lin, Daren Liu
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.