{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T06:15:22Z","timestamp":1778220922389,"version":"3.51.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["1R01EY023557"],"award-info":[{"award-number":["1R01EY023557"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["P30 EY001583"],"award-info":[{"award-number":["P30 EY001583"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001205","name":"F. M. Kirby Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001205","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008556","name":"Paul MacKall and Evanina Bell MacKall Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008556","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      variants, which regulate the RhoA\/ROCK pathway, are associated with primary open-angle glaucoma (POAG) in individuals of African ancestry and may influence response to Rho-kinase inhibitors such as netarsudil.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed 1,844 African ancestry subjects with POAG, comparing baseline demographic and ocular phenotypes across\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      genotype groups (non-carriers, heterozygous carriers, and homozygous carriers). Netarsudil response was evaluated in a subset of 66 subjects (114 eyes). Generalized estimating equations were used to compare the change in intraocular pressure (IOP) and other ocular measures from baseline to 12 months across the\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      genotype groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Baseline glaucoma severity and ocular phenotypes including IOP were similar across all\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      genotype groups (all\n                      <jats:italic>p<\/jats:italic>\n                      &amp;gt; 0.05). Among netarsudil-treated eyes, mean IOP reduction at 12 months was \u22121.77 \u00b1 5.06\u00a0mmHg (SD) in non-carriers and 1.58 \u00b1 6.25\u00a0mmHg (SD) in combined heterozygous\/homozygous carriers. A \u226520% IOP reduction at 12 months was achieved in 29.8% of non-carrier eyes and 34.6% of variant-carrier eyes (aOR 1.31, 95% CI 0.42\u20134.10,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.64). Among the netarsudil treated eyes, no statistically significant differences were observed across genotype groups for other ocular measures, including cup-to-disc ratio, retinal nerve fiber layer thickness, and visual field mean deviation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Despite a strong biological rationale linking\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      to Rho\/ROCK signaling and aqueous humor outflow, these preliminary findings suggest that\n                      <jats:italic>ARHGEF12<\/jats:italic>\n                      variant status does not strongly predict netarsudil response, suggesting that variability in ROCK inhibitor efficacy likely reflects multifactorial and pathway-level influences beyond single-gene variation. These results should therefore be considered exploratory. Future studies with larger, treatment-na\u00efve cohorts are needed to evaluate pharmacogenetic associations.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1803432","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:51:24Z","timestamp":1778219484000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating therapeutic response to netarsudil in glaucoma subjects with the ARHGEF12 risk variant"],"prefix":"10.3389","volume":"17","author":[{"given":"Anusha","family":"Mamidipaka","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Di Rosa","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marine-Ayan","family":"Ibrahim Aibo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangming","family":"Jin","sequence":"additional","affiliation":[{"name":"Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Salowe","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Halimitabrizi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leila","family":"Ghaffari","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Addis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laxmi","family":"Moksha","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gui-Shuang","family":"Ying","sequence":"additional","affiliation":[{"name":"Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan M.","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Genetics of Complex Disease, Scheie Eye Institute, University of Pennsylvania","place":["Philadelphia, PA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1016\/j.ogla.2023.01.008","article-title":"Associations between socioeconomic factors and visit adherence among patients with glaucoma in the all of Us Research Program","volume":"6","author":"Acuff","year":"2023","journal-title":"Ophthalmol. 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