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Genetic and Molecular Advances in Glaucoma

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 January 2024) | Viewed by 5151

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Prof. Dr. Vicente Zanón-Moreno

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Facultad de Ciencias de la Salud, Universidad International de Valencia - VIU, 46002 Valencia, Spain
Interests: ophthalmic research; glaucomatous blindness
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Glaucoma is the leading cause of irreversible blindness worldwide. According to the WHO, just over 4.5 million people are blind due to glaucoma, and it is estimated that its prevalence will increase in the coming years.

An early diagnosis of glaucoma is essential to prevent glaucomatous blindness. However, despite the efforts of ophthalmologists, glaucoma is a highly underdiagnosed disease. In developed countries, the proportion of undiagnosed cases can reach 50%, while in developing countries, this figure can be as high as 90%.

A study of the genetic and molecular bases of glaucoma will allow us to deepen our knowledge and understanding of the etiopathogenic mechanisms of this disease. Likewise, this study will help ophthalmologists and vision science researchers to identify new genetic and molecular biomarkers for the early diagnosis and prognosis of glaucoma and to design and develop new therapeutic strategies that can better control glaucoma progression. In this way, it will be possible to prevent glaucomatous blindness and improve the quality of life of these patients.

This Special Issue, entitled "Genetic and Molecular Advances in Glaucoma", aims to collect original articles and review articles on biomarkers for the early diagnosis and prognosis of glaucomatous disease, as well as new therapeutic targets for any type of glaucoma.

Prof. Dr. Vicente Zanón-Moreno
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

glaucoma
biomarkers
genetics
molecular
diagnosis
therapeutic target
prevention of blindness

Published Papers (3 papers)

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Research

17 pages, 1137 KiB

Open AccessArticle

Differential Gene and Protein Expression of Conjunctival Bleb Hyperfibrosis in Early Failure of Glaucoma Surgery

by Elena Millá, Néstor Ventura-Abreu, Cristina Vendrell, Maria Jesús Muniesa, Marta Pazos, Xavier Gasull and Núria Comes

Int. J. Mol. Sci. 2023, 24(15), 11949; https://doi.org/10.3390/ijms241511949 - 26 Jul 2023

Cited by 1 | Viewed by 855

Abstract

The early failure of glaucoma surgery is mainly caused by over-fibrosis at the subconjunctival space, causing obliteration of the filtration bleb. Because fibrosis has a suspected basis of genetic predisposition, we have undertaken a prospective study to identify upregulated profibrotic genes in a population of glaucoma patients with signs of conjunctival fibrosis and early postoperative surgical failure. Clinical data of re-operated fibrosis patients, hyperfibrosis patients who re-operated more than once in a short time, and control patients with no fibrosis were recorded and analyzed at each follow-up visit. Conjunctival-Tenon surgical specimens were obtained intraoperatively to evaluate the local expression of a panel of genes potentially associated with fibrosis. In order to correlate gene expression signatures with protein levels, we quantified secreted proteins in primary cultures of fibroblasts from patients. Expression of VEGFA, CXCL8, MYC, and CDKN1A was induced in the conjunctiva of hyperfibrosis patients. VEGFA and IL8 protein levels were also increased in fibroblast supernatants. We propose that an increase in these proteins could be useful in detecting conjunctival fibrosis in glaucoma patients undergoing filtering surgery. Molecular markers could be crucial for early detection of patients at high risk of failure of filtration surgery, leading to more optimal and personalized treatments. Full article

(This article belongs to the Special Issue Genetic and Molecular Advances in Glaucoma)

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13 pages, 313 KiB

Open AccessArticle

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence

by Julie L. Barr, Michael Feehan, Casey Tak, Leah A. Owen, Robert C. Finley, Parker A. Cromwell, John H. Lillvis, Patrice M. Hicks, Elizabeth Au, Michael H. Farkas, Asher Weiner, Andrew L. Reynolds, Sandra F. Sieminski, Richard M. Sherva, Mark A. Munger, Murray H. Brilliant and Margaret M. DeAngelis

Int. J. Mol. Sci. 2023, 24(6), 5636; https://doi.org/10.3390/ijms24065636 - 15 Mar 2023

Cited by 3 | Viewed by 1894

Abstract

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41–71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients’ glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System’s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10⁻³) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10⁻³) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer’s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62–5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10^–6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11–0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47–58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings. Full article

(This article belongs to the Special Issue Genetic and Molecular Advances in Glaucoma)

13 pages, 304 KiB

Open AccessArticle

Genotype and Phenotype Influence the Personal Response to Prostaglandin Analogues and Beta-Blockers in Spanish Glaucoma and Ocular Hypertension Patients

by Valeria Opazo-Toro, Virginia Fortuna, Wladimiro Jiménez, Marta Pazos López, María Jesús Muniesa Royo, Néstor Ventura-Abreu, Mercè Brunet and Elena Milla

Int. J. Mol. Sci. 2023, 24(3), 2093; https://doi.org/10.3390/ijms24032093 - 20 Jan 2023

Cited by 1 | Viewed by 1750

Abstract

Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (p = 0.031). The MD values presented significant differences between wildtype rs3766355 (−2 ± 2.2 dB), HT (−3.87 ± 4 dB), and HM carriers (−9.37 ± 9.51 dB) (p = 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (−6.1 ± 8.67 dB), HT (−9.02 ± 8.63 dB), and HM carriers (−9.51 ± 7.44 dB) (p = 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles. Full article

(This article belongs to the Special Issue Genetic and Molecular Advances in Glaucoma)

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