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Myocilin mutations in patients with normal-tension glaucoma

Myocilin mutations in patients with normal-tension glaucoma
Myocilin mutations in patients with normal-tension glaucoma

Importance: Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated. Objective: To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG. Design, Setting, and Participants: In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018. Main Outcomes and Measures: Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test. Results: Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P =.03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P =.15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P =.04). Conclusions and Relevance: In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg..

2168-6165
Alward, Wallace L.M.
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Van Der Heide, Carly
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Khanna, Cheryl L.
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Roos, Ben R.
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Sivaprasad, Sobha
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Kam, Jason
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Ritch, Robert
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Lotery, Andrew
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Igo, Robert P.
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Cooke Bailey, Jessica N.
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Stone, Edwin M.
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Scheetz, Todd E.
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Kwon, Young H.
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Pasquale, Louis R.
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Wiggs, Janey L.
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Fingert, John H.
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Alward, Wallace L.M.
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Van Der Heide, Carly
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Khanna, Cheryl L.
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Roos, Ben R.
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Sivaprasad, Sobha
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Kam, Jason
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Ritch, Robert
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Lotery, Andrew
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Igo, Robert P.
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Cooke Bailey, Jessica N.
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Stone, Edwin M.
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Scheetz, Todd E.
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Kwon, Young H.
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Pasquale, Louis R.
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Wiggs, Janey L.
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Fingert, John H.
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Alward, Wallace L.M., Van Der Heide, Carly, Khanna, Cheryl L., Roos, Ben R., Sivaprasad, Sobha, Kam, Jason, Ritch, Robert, Lotery, Andrew, Igo, Robert P., Cooke Bailey, Jessica N., Stone, Edwin M., Scheetz, Todd E., Kwon, Young H., Pasquale, Louis R., Wiggs, Janey L. and Fingert, John H. (2019) Myocilin mutations in patients with normal-tension glaucoma. JAMA Ophthalmology. (doi:10.1001/jamaophthalmol.2019.0005).

Record type: Article

Abstract

Importance: Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated. Objective: To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG. Design, Setting, and Participants: In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018. Main Outcomes and Measures: Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test. Results: Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P =.03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P =.15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P =.04). Conclusions and Relevance: In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg..

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Accepted/In Press date: 22 December 2018
e-pub ahead of print date: 28 February 2019

Identifiers

Local EPrints ID: 431075
URI: http://eprints.soton.ac.uk/id/eprint/431075
ISSN: 2168-6165
PURE UUID: 8c3e96ac-0ba9-40ab-8cc9-7d4651282b77
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 22 May 2019 16:30
Last modified: 26 Nov 2021 02:47

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Contributors

Author: Wallace L.M. Alward
Author: Carly Van Der Heide
Author: Cheryl L. Khanna
Author: Ben R. Roos
Author: Sobha Sivaprasad
Author: Jason Kam
Author: Robert Ritch
Author: Andrew Lotery ORCID iD
Author: Robert P. Igo
Author: Jessica N. Cooke Bailey
Author: Edwin M. Stone
Author: Todd E. Scheetz
Author: Young H. Kwon
Author: Louis R. Pasquale
Author: Janey L. Wiggs
Author: John H. Fingert

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