Bioinformatics of Primary Open-Angle Glaucoma (POAG)
Have you ever heard of Glaucoma? It is an eye disease that leads to irreversible blindness. And
estimated to be the cause of blindness in 70 million people. Also the second cause of irreversible blindness in the world.
The statistics may be under-estimated, because, the folks in my ancestral village and environs were
not counted. So, this World Health organization statistics may be off the mark. Due to poor record-keeping in many parts of rural Africa. Secondly, there are many people walking around with glaucoma and don't even know it.
Many are unaware they already have the disease. It breaks my heart every time I have to tell a patient, "I'm sorry but the reason, you are losing vision is because you have glaucoma", and my heart breaks into tiny bits when I continue to say "This can be managed with medications and surgery but will not reverse the vision loss or halt the progression of the disease. But it will slow it.
Then, you find out that for some patients, there is a rapid deterioration and they do not respond well to medications. and these medications are expensive and many do not have health insurance coverage in many parts of Africa, The Caribbean, South America, Asia, and even the United States. In October, I attended to a 52-year-old lady, who was legally blind from glaucoma and had only been diagnosed five years prior apparently her previous doctor had not picked it up early enough, sometimes not surprising as she had what is referred to as normal-tension glaucoma.
Like many diseases, there is a genetic component to Glaucoma and specifically the most common subset, called Primary Open-angle Glaucoma. Recently. I got interested in Bioinformatics and how this science can be used in eye care.
Like many diseases, there is a genetic component to Glaucoma and specifically the most common subset, called Primary Open-angle Glaucoma. Recently. I got interested in Bioinformatics and how this science can be used in eye care.
Bioinformatics, as you know is an interdisciplinary science that combines biology, computer science, information engineering, mathematics, and statistics to analyze biological data. This my friends, should be the way for future research in healthcare and especially eye care and to "drill down" (my statistics professor's favorite phrase), certain diseases that have intrigued us but also are a bit of an enigma like Glaucoma and Primary Open-Angle glaucoma and it's many variants like Normal-tension glaucoma (NTG), High tension glaucoma (HTG), Juvenile open-angle glaucoma (JOAG), Primary congenital glaucoma (PCG), Ocular Hypertension (OHT).
Patients after diagnosis often ask "What causes glaucoma? and you give them the "layman's" " Oh the pressure in your eye is high and therefore causing damage to the optic nerve and vision loss" but the truth is that Glaucoma is so complex that even those researching glaucoma are often perplexed at this disease that is a public health issue.
Genomics is so complex, meaning that, when you "drill down" to the genetic components, you will be amazed at how complex this disease ravaging the world is, in both occurrence, pathogenesis, sensitivity to medication and prognosis.
This paper reviews the literature on current research development in the genetics of inheritance, presentation, and pathogenesis of primary open-angle glaucoma. Primary open-angle glaucoma the most common subset of glaucoma is a public health issue and the second cause of irreversible blindness in the world. It is a progressive genetically and phenotypically neuro-degenerative condition of the optic nerve with an insidious onset. Often presenting with elevated intraocular pressures (IOP), retinal ganglion cell death, thinning neuro-retinal rims of the optic nerve, and visual field defects. The anterior chamber angle (the angle formed between the cornea and iris) is open in POAG but aqueous humor, a transparent watery fluid that nourishes the cornea and lens does not drain properly due to morphological changes in the trabecular meshwork. There are several risk factors: Increasing age, high myopia, diabetes, family history especially in first-degree relatives influencing the inheritance and pathway of pathogenesis, and sensitivity to medications used in therapy and prognosis.
Articles of research studies from the years 2012 -2019 in the English language from PubMed Central, Medline, and Google scholar with the related terms bioinformatics; primary open-angle-glaucoma were used to write up this review. Studies have shown that several gene mutations and compromised molecular pathways are responsible for the development, disease pathway, and prognosis of POAG.
Basically, primary open-angle glaucoma is a progressive genetically and phenotypically neuro-degenerative condition of the optic nerve with an insidious onset. Often presenting with elevated intraocular pressures (IOP), retinal ganglion cell death, thinning neuro-retinal rims of the optic nerve, and visual field defects. The anterior chamber angle (the angle formed between the cornea and iris) is open in POAG but aqueous humor, a transparent watery fluid that nourishes the cornea and lens does not drain properly due to morphological changes in the trabecular meshwork. There are several risk factors: Increasing age, high myopia, diabetes, family history especially in first-degree relatives influencing the inheritance and pathway of pathogenesis, and sensitivity to medications used in therapy and prognosis.
There is a genetic and molecular component to both the predilection, sensitivity to medical therapy and prognosis. However, current studies and research implicate several gene mutations and molecular pathways as responsible for POAG and how the ocular structures involved are impacted. Calcification of the trabecular meshwork due to changes in the extracellular matrix leads to elevated intraocular pressure, causing axonal injury to a vulnerable optic nerve head (ONH) and progressive retinal ganglion cell loss. So, if calcification of trabecular meshwork can be prevented or reversed, improving aqueous outflow, then IOPs can be reduced, especially since the reduction of IOP levels is currently the only modifiable risk factor in the toolbox of treating POAG. The focus of glaucoma research should therefore be on how to prevent the changes that happen in the trabecular meshwork (TM). There is an urgency in this matter as most POAG is often not diagnosed early until there are significant deficits in visual fields and irreversible vision loss.
The pathogenesis, diagnosis, and prognosis of POAG is extremely complex as many genes, gene loci, and molecular pathways are involved in the various phenotypes. POAG can sometimes occur as a Mendelian inherited disease with complex genetic components impacting several ocular tissues, making it not only difficult to diagnose but to manage as well. The only modifiable risk factor is elevated intraocular pressures (IOP), although certain variants present with normal intraocular pressures (< 21 mm Hg). IOP is determined by the production and drainage of aqueous humor (AH) in the posterior chamber. AH is produced by the epithelial cell of the ciliary process in the ciliary body and drained through two pathways. A major and minor drainage system. Major IOP drainage is responsible for 90% of AH outflow through the trabecular meshwork, juxtacanalicular tissue, and Schlemm canal and is absorbed into the episcleral venous system. And, the minor pathway is through the uveoscleral drainage system via the ciliary muscle and suprachoroidal spaces, and choroidal vessels.
Since the major drainage pathway of (AH) is through the trabecular meshwork, its physiology plays a crucial role in the pathogenesis of POAG, biomarkers, genomics, proteomics, and gene regulation to identify the biomarkers for POAG by profiling the aqueous humor by Xie et al in a study, using long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in the aqueous humor (AH) from 10 POAG and 10 control patients and accessed by microarray analyses. It is important to note that the outflow of AH is crucial to maintaining normal IOP levels, which not only pose a risk factor for POAG development but a predictor of the progression of the disease. Coding-noncoding gene co-expression networks were drawn to predict potential lncRNA functions. lncRNA T267384, ENST00000607393, and T342877 expression levels were further tested by real-time quantitative PCR in AH from 29 POAG, 30 cataract patients, in iris tissue from 16 POAG patients and 10 controls, and in plasma from 49 POAG patients and 55 healthy controls [1]. 75% of the human genome can be transcribed into RNAs, > 95% of which are noncoding RNAs. lncRNA are non-protein-coding noncoding RNA often > 200 nucleotides, that can interact with mRNAs and other noncoding RNAs to regulate gene expression and are known to play a part in the incidence of neurogenerative diseases like glaucoma [1]. It was found that lncRNA T267384, ENST00000607393, and T342877 may be potential markers for POAG diagnosis and give an insight into the new management of POAG as ENST00000607393 affects the calcification of the trabecular meshwork, thereby impacting the outflow facility of aqueous humor.
It is important that emphasis on this study focused on the aqueous humor and the genetic factors that impact the trabecular meshwork as the drainage of aqueous through the TM is responsible for 90% of AH drainage and if TM is diseased, high IOPs occurs resulting in POAG, retinal ganglion cell death and eventually blindness. As we now know, IOP reduction is currently the only clinically proven treatment either by medical therapy or surgery. Family-based genome with linkage analysis genome loci that influence the variation of IOP has provided a better understanding of genes involved in POAG and why some cases are often severe and progress so quickly compared to others. As everyday clinicians are confronted with cases that are not so sensitive to medications and optic neuropathy and vision loss deteriorate rapidly. If a better knowledge of the genes involved and the molecular pathway is understood, surgery for such patients could be advised sooner than currently happens. Although, this may not currently be feasible in some parts of the world as genetic linkage analysis costs between $300-$3500 and is covered by insurance in the United States but not readily available in places like continental Africa, the Caribbean where there is elevated risks of POAG and incidence of the disease is highest.
A search in Gene Expression Omnibus, ArrayExpress conducted to find the molecular pathways implicated in the molecular pathogenesis of POAG using pathway databases like WikiPathways, Kyoto Encyclopedia of Genes and Genome (KEGG), Reactome using trabecular meshwork gene expression data yielded results of ninety-two pathways grouped onto five categories: Extracellular matrix (ECM), inflammation, complement activation, senescence, and RhoGTPase signaling. Clusters of ECM complement activation and senescence have multiple mutual genes with the inflammation group, showing the central role of inflammation in the connection (Liesenborghs et al 2019). Confirming many research studies' results on the complexity of POAG. However, knowing the pathways implicated gives an indication of known points of action of drugs (Liesenborghs et al 2019).
Mendelian traits are passed down by dominant and recessive alleles of a gene, Some of the Mendelian genes for POAG that have been identified through genetic linkage analysis are: MYOC, EFEMP1, IL2ORB, WDR36, ASB10, OPTN, TBK1, NTF4, and these are found on the loci GLCIA through GLCIP. MYOC pathogenesis mutation occurs in 3-5% of POAG. While elevated IOPs of > 21 mm hg are common in POAG, there are phenotypes of open-angle glaucoma (OHT) that have IOPs within the normal range of 10 mm hg-21 mm hg and are referred to as normal-tension glaucoma (NTG) where the optic nerve has a lower threshold for the development of pressure-induced retinal ganglion cell damage. It has been found that mutations of gene OPTN and TBK1 contribute to NTG. Although IOPs are within the clinically normal range in NTG, retina ganglion cell loss, excavation of the optic disc because of axonal injury and disruption and visual field deficit become obvious, and with anti-glaucoma medications to reduce IOP level, there is clinical improvement, which further confirms the extremely genetically complexity of the neurodegenerative disease- POAG.
While some phenotypes of POAG cause changes in RGCs making them susceptible to cell death, certain variants compromise the homeostasis of the axon-supporting optic nerve head glia leading to neuroinflammation (Danford el al 2017). African, the Caribbean, and African-American populations are often two to five times more than those of European/European descent, unfortunately, genome-wide association studies (GWAS) for POAG in Europeans and Asian are overrepresented while African and South American populations are underrepresented despite their elevated risks, this, of course, is due to locations where research studies are often conducted. However, there are a couple of African-American studies in progress as well as in two West African countries of Nigeria and Ghana (Danford et al 2017) Wang X et al focused on the gene expression profiling of the optic nerve head of patients with primary open-angle glaucoma may not help in addressing the crucial matter of better management and pathogenesis of POAG, while the ONH becomes vulnerable in POAG consequently becoming atrophied secondary to ganglion cell loss due to elevated IOPs, the ONH is not the pathway of drainage.
References
This paper reviews the literature on current research development in the genetics of inheritance, presentation, and pathogenesis of primary open-angle glaucoma. Primary open-angle glaucoma the most common subset of glaucoma is a public health issue and the second cause of irreversible blindness in the world. It is a progressive genetically and phenotypically neuro-degenerative condition of the optic nerve with an insidious onset. Often presenting with elevated intraocular pressures (IOP), retinal ganglion cell death, thinning neuro-retinal rims of the optic nerve, and visual field defects. The anterior chamber angle (the angle formed between the cornea and iris) is open in POAG but aqueous humor, a transparent watery fluid that nourishes the cornea and lens does not drain properly due to morphological changes in the trabecular meshwork. There are several risk factors: Increasing age, high myopia, diabetes, family history especially in first-degree relatives influencing the inheritance and pathway of pathogenesis, and sensitivity to medications used in therapy and prognosis.
Articles of research studies from the years 2012 -2019 in the English language from PubMed Central, Medline, and Google scholar with the related terms bioinformatics; primary open-angle-glaucoma were used to write up this review. Studies have shown that several gene mutations and compromised molecular pathways are responsible for the development, disease pathway, and prognosis of POAG.
Basically, primary open-angle glaucoma is a progressive genetically and phenotypically neuro-degenerative condition of the optic nerve with an insidious onset. Often presenting with elevated intraocular pressures (IOP), retinal ganglion cell death, thinning neuro-retinal rims of the optic nerve, and visual field defects. The anterior chamber angle (the angle formed between the cornea and iris) is open in POAG but aqueous humor, a transparent watery fluid that nourishes the cornea and lens does not drain properly due to morphological changes in the trabecular meshwork. There are several risk factors: Increasing age, high myopia, diabetes, family history especially in first-degree relatives influencing the inheritance and pathway of pathogenesis, and sensitivity to medications used in therapy and prognosis.
There is a genetic and molecular component to both the predilection, sensitivity to medical therapy and prognosis. However, current studies and research implicate several gene mutations and molecular pathways as responsible for POAG and how the ocular structures involved are impacted. Calcification of the trabecular meshwork due to changes in the extracellular matrix leads to elevated intraocular pressure, causing axonal injury to a vulnerable optic nerve head (ONH) and progressive retinal ganglion cell loss. So, if calcification of trabecular meshwork can be prevented or reversed, improving aqueous outflow, then IOPs can be reduced, especially since the reduction of IOP levels is currently the only modifiable risk factor in the toolbox of treating POAG. The focus of glaucoma research should therefore be on how to prevent the changes that happen in the trabecular meshwork (TM). There is an urgency in this matter as most POAG is often not diagnosed early until there are significant deficits in visual fields and irreversible vision loss.
The pathogenesis, diagnosis, and prognosis of POAG is extremely complex as many genes, gene loci, and molecular pathways are involved in the various phenotypes. POAG can sometimes occur as a Mendelian inherited disease with complex genetic components impacting several ocular tissues, making it not only difficult to diagnose but to manage as well. The only modifiable risk factor is elevated intraocular pressures (IOP), although certain variants present with normal intraocular pressures (< 21 mm Hg). IOP is determined by the production and drainage of aqueous humor (AH) in the posterior chamber. AH is produced by the epithelial cell of the ciliary process in the ciliary body and drained through two pathways. A major and minor drainage system. Major IOP drainage is responsible for 90% of AH outflow through the trabecular meshwork, juxtacanalicular tissue, and Schlemm canal and is absorbed into the episcleral venous system. And, the minor pathway is through the uveoscleral drainage system via the ciliary muscle and suprachoroidal spaces, and choroidal vessels.
Since the major drainage pathway of (AH) is through the trabecular meshwork, its physiology plays a crucial role in the pathogenesis of POAG, biomarkers, genomics, proteomics, and gene regulation to identify the biomarkers for POAG by profiling the aqueous humor by Xie et al in a study, using long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in the aqueous humor (AH) from 10 POAG and 10 control patients and accessed by microarray analyses. It is important to note that the outflow of AH is crucial to maintaining normal IOP levels, which not only pose a risk factor for POAG development but a predictor of the progression of the disease. Coding-noncoding gene co-expression networks were drawn to predict potential lncRNA functions. lncRNA T267384, ENST00000607393, and T342877 expression levels were further tested by real-time quantitative PCR in AH from 29 POAG, 30 cataract patients, in iris tissue from 16 POAG patients and 10 controls, and in plasma from 49 POAG patients and 55 healthy controls [1]. 75% of the human genome can be transcribed into RNAs, > 95% of which are noncoding RNAs. lncRNA are non-protein-coding noncoding RNA often > 200 nucleotides, that can interact with mRNAs and other noncoding RNAs to regulate gene expression and are known to play a part in the incidence of neurogenerative diseases like glaucoma [1]. It was found that lncRNA T267384, ENST00000607393, and T342877 may be potential markers for POAG diagnosis and give an insight into the new management of POAG as ENST00000607393 affects the calcification of the trabecular meshwork, thereby impacting the outflow facility of aqueous humor.
It is important that emphasis on this study focused on the aqueous humor and the genetic factors that impact the trabecular meshwork as the drainage of aqueous through the TM is responsible for 90% of AH drainage and if TM is diseased, high IOPs occurs resulting in POAG, retinal ganglion cell death and eventually blindness. As we now know, IOP reduction is currently the only clinically proven treatment either by medical therapy or surgery. Family-based genome with linkage analysis genome loci that influence the variation of IOP has provided a better understanding of genes involved in POAG and why some cases are often severe and progress so quickly compared to others. As everyday clinicians are confronted with cases that are not so sensitive to medications and optic neuropathy and vision loss deteriorate rapidly. If a better knowledge of the genes involved and the molecular pathway is understood, surgery for such patients could be advised sooner than currently happens. Although, this may not currently be feasible in some parts of the world as genetic linkage analysis costs between $300-$3500 and is covered by insurance in the United States but not readily available in places like continental Africa, the Caribbean where there is elevated risks of POAG and incidence of the disease is highest.
A search in Gene Expression Omnibus, ArrayExpress conducted to find the molecular pathways implicated in the molecular pathogenesis of POAG using pathway databases like WikiPathways, Kyoto Encyclopedia of Genes and Genome (KEGG), Reactome using trabecular meshwork gene expression data yielded results of ninety-two pathways grouped onto five categories: Extracellular matrix (ECM), inflammation, complement activation, senescence, and RhoGTPase signaling. Clusters of ECM complement activation and senescence have multiple mutual genes with the inflammation group, showing the central role of inflammation in the connection (Liesenborghs et al 2019). Confirming many research studies' results on the complexity of POAG. However, knowing the pathways implicated gives an indication of known points of action of drugs (Liesenborghs et al 2019).
Mendelian traits are passed down by dominant and recessive alleles of a gene, Some of the Mendelian genes for POAG that have been identified through genetic linkage analysis are: MYOC, EFEMP1, IL2ORB, WDR36, ASB10, OPTN, TBK1, NTF4, and these are found on the loci GLCIA through GLCIP. MYOC pathogenesis mutation occurs in 3-5% of POAG. While elevated IOPs of > 21 mm hg are common in POAG, there are phenotypes of open-angle glaucoma (OHT) that have IOPs within the normal range of 10 mm hg-21 mm hg and are referred to as normal-tension glaucoma (NTG) where the optic nerve has a lower threshold for the development of pressure-induced retinal ganglion cell damage. It has been found that mutations of gene OPTN and TBK1 contribute to NTG. Although IOPs are within the clinically normal range in NTG, retina ganglion cell loss, excavation of the optic disc because of axonal injury and disruption and visual field deficit become obvious, and with anti-glaucoma medications to reduce IOP level, there is clinical improvement, which further confirms the extremely genetically complexity of the neurodegenerative disease- POAG.
While some phenotypes of POAG cause changes in RGCs making them susceptible to cell death, certain variants compromise the homeostasis of the axon-supporting optic nerve head glia leading to neuroinflammation (Danford el al 2017). African, the Caribbean, and African-American populations are often two to five times more than those of European/European descent, unfortunately, genome-wide association studies (GWAS) for POAG in Europeans and Asian are overrepresented while African and South American populations are underrepresented despite their elevated risks, this, of course, is due to locations where research studies are often conducted. However, there are a couple of African-American studies in progress as well as in two West African countries of Nigeria and Ghana (Danford et al 2017) Wang X et al focused on the gene expression profiling of the optic nerve head of patients with primary open-angle glaucoma may not help in addressing the crucial matter of better management and pathogenesis of POAG, while the ONH becomes vulnerable in POAG consequently becoming atrophied secondary to ganglion cell loss due to elevated IOPs, the ONH is not the pathway of drainage.
CPDB analysis of several ocular tissue genes was done by
(Danford et al 2017) to find implicated pathways in POAG Pathogenesis.
Lamina Cribosa, of the 69 genes pathway
studied using LC tissues, ECM organization and fiber formation pathways were
most implicated.
In optic nerve tissue, out of the 62 genes
analyzed 24 were represented in the cytokine-cytokine pathway.
In isolated Optic Nerve Head astrocytes, 15
genes were implicated.
Retina and Retina Ganglion cells, twenty-one studies did show 47 genes were associated with POAG phenotypes OHT, NTG,
JOAG, and the most associated pathway was cell-cycle regulation with
IL-6-mediated signaling event.
Trabecular Meshwork: 139 genes analyzed
favored AP1 transcription factor network, TGF Beta signaling pathway, copper
homeostasis, and ECM organization, And this confirms that ECM regulation and
cell-cycle regulation are important processes in the TM.
In conclusion, the pathogenesis and inheritance pattern of POAG is
genetically complex but developments in bioinformatics have given us a better insight
into the genomics that affect this insidious disease. Several gene mutations, chromosome
loci, and multiple molecular pathways influence POAG and all its phenotypes:
OHT, HTG, NTG, JOAG, PCG, and the trabecular meshwork one crucial ocular
structure where changes impact the disease the most. The use of gene ontology
and pathway analysis using genomics and molecular pathway databases like GWAS,
Gene Expression Omnibus, ArrayExpress, Wikipathways, KEG, and Reactome confirms
abnormal ECF proteins and changes in the morphology of the trabecular meshwork
as in the genes involved in the formation of collagen, fibronectin, and
integrins. The molecular pathways TGF-β signaling regulate ECM turnover and
TGF-β2 involved in the extracellular matrix organization pathway regulates ECM
metabolism induces elastin and collagen cross-linking causing pathological
changes in TM (Liesenborghs I et al 2019) resulting in calcification of TM and
compromising the aqueous outflow, leading to elevated intraocular pressure.
POAG is a complex disease and the current practice of
lowering IOP is an important preventive and therapeutic protocol, future
treatment should reflect the multifaceted nature of the disease. Consideration
should be given to therapies that target neurotropic sustenance of the retinal
ganglion cells RGC (Danford et al 2017). Brain-derived neurotrophic factor
(BDNF) injected in the vitreous may be a promising option to regenerate retinal
ganglion cells. If more research is focused on axon-genesis of the RGC which
would mean that there could reversible points of the disease, this would be a
turning point in the management of POAG and all types of Glaucoma, giving hope
to millions of people around the world. And slowing this public health
nightmare that is Glaucoma
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References
1. Xie
L, Mao M, Wang C, et al: Potential Biomarkers for Primary Open-Angle glaucoma identified
by long noncoding RNA profiling in the Aqueous Humor. The American Journal of
Pathology, vol 189, No 4, April 2019
2. Danford
ID, Verkuil LD, Chan DJ et al. Characterizing the “POAGome” : A bioinformatics
driven approach to Primary Open-angle glaucoma.Pro Retin Res 2017 May;58:89-114
3. Liu
Y, Allingham RR: Major Review: Molecular Genetics of Primary Open-Angle
Glaucoma. Exp Eye Res . 2017 July; 160: 62–84. doi:10.1016/j.exer.2017.05.002.
4. Wang
X, Gong K, Li H, et al: Gene Expression Profiling of the Optic Nerve Head of
Patients with Primary Open-Angle Glaucoma. Journal of Ophthalmology, Volume
2017, Article ID 6896390, 7 pages https://doi.org/10.1155/2017/6896390
5. Wang
H, Sun B, Chen Y et al: Research Progress on Human Genes Involved in the
Pathogenesis of Glaucoma. MOLECULAR MEDICINE REPORTS 18:
656-674, 2018656
6. Liesenberglis
I, Eijssen LMT, et al: Comprehensive Bioinformatics Analysis of Trabecular
Meshwork Gene Expression data to uncover the Molecular Pathogenesis of Primary
Open-Angle Glaucoma. Acta Ophthalmologica June 2019 https://doi.org/10.1111/aos.14154
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