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Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r\u2009=\u2009\u22120.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r\u2009=\u20090.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P\u2009&amp;gt;\u20090.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm\u2019s canal (SC) cells (\u22122.4-fold-change, P\u2009=\u20090.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddad083","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T23:40:25Z","timestamp":1684885225000},"page":"2523-2531","source":"Crossref","is-referenced-by-count":15,"title":["Rare protective variants and glaucoma-relevant cell stressors modulate <i>Angiopoietin-like 7<\/i> expression"],"prefix":"10.1093","volume":"32","author":[{"given":"Inas F","family":"Aboobakar","sequence":"first","affiliation":[{"name":"Department of Ophthalmology , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Ryan A","family":"Collantes","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Hauser","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W Daniel","family":"Stamer","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Duke University School of Medicine , Durham, NC 27710 , USA"},{"name":"Department of Biomedical Engineering, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1890-3278","authenticated-orcid":false,"given":"Janey L","family":"Wiggs","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"},{"name":"Harvard Medical School , Massachusetts Eye and Ear, , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"2023072112072534500_ref1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The number&gt; of people with glaucoma worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. 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