Roshni Sengupta, M.Optom

Assistant Professor, Department of Optometry, GD Goenka University, Haryana, India



Ophthalmic conditions constitute a considerable global health burden, affecting diverse populations. Conditions like age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR), alongside less common hereditary disorders such as retinitis pigmentosa and congenital cataracts, detrimentally affect vision, diminishing quality of life and productivity. Vision is influenced not only by environmental factors but also by genetic predispositions. Recent investigations have illuminated the intricate interplay between genetics and eye diseases, with a specific focus on prevalent, irreversible hereditary causes of blindness.

Understanding the Basics of Genetic Inheritance:
Before delving into eye diseases, understanding genetic inheritance is crucial. Genes, units of heredity, dictate traits, including those relevant to eye health. Genetic variations or mutations within genes can affect susceptibility to certain eye diseases. In this complexity, alleles, alternate gene forms on a chromosome, hold significance, influencing individual traits. Linkage analysis examines co-inheritance patterns of alleles, identifying genetic loci associated with specific traits or diseases. This sheds light on the genetic linkage of adjacent genes on the same chromosome.

Macular Degeneration: A Genetic Perspective

AMD stands as a prominent global cause of irreversible blindness. In the early stages of AMD, the pathogenesis is intricately tied to inflammation, with aging individuals facing increased oxidative stress and complement dysregulation. The interplay of genetic and environmental factors contributes to the accumulation of toxic elements (drusen), activating sustained pro-inflammatory pathways. In geographic atrophy (GA), persistent damage to retinal pigment epithelium (RPE) causes RPE and choriocapillaris degeneration. Neovascular AMD involves the breakdown of the outer blood–retinal barrier, prompting immune cell influx, VEGF-dependent neovascularization, and eventual photoreceptor damage, culminating in visual impairment.(1)

Recent extensive genetic association studies with substantial case–control cohorts have delineated AMD pathogenesis. Associations within oxidative stress and lipid peroxidation (e.g., complement factor H or CFH), complement (CFH, C3, complement factor I, C2, complement factor B), and neovascularization (vascular endothelial growth factor A, high-temperature requirement factor A1) genes have been consistently replicated across diverse global populations. (2)

Glaucoma: Unraveling the Genetic Web

Genome-wide association studies (GWAS), have expedited the identification of genes contributing to glaucoma, a leading cause of irreversible global blindness. Various disease-causing mutations in optineurin (OPTN), myocilin (MYOC), and WD-repeat domain 36 (WDR36), and TANK-binding kinase 1 (TBK1) genes have been long identified as the cause of familial forms of POAG with 10-fold risk. Diagnostic genetic tests using early-onset glaucoma genes aid pre-symptomatic disease detection and genetic counseling. Endophenotypes for POAG include IOP, CCT, cup area (CA), vertical cup–disc ratio (VCDR), and disc area (DA) with very high heritability: 0.55 for IOP, 0.85 for CCT, 0.72 for DA, 0.75 for CA, and between 0.48 and 0.66 for VCDR (3) (as shown in Fig 1). Recent GWAS for three common adult-onset glaucoma uncovered novel loci, including ABCA1, AFAP1, GMDS, PMM2, TGFBR3, FNDC3B, ARHGEF12, GAS7, FOXC1, ATXN2, and TXNRD2 for primary open-angle glaucoma(POAG); EPDR1, CHAT, GLIS3, FERMT2, DPM2-FAM102 for primary angle-closure glaucoma(PACG); and CACNA1A for exfoliation syndrome (XFS) glaucoma, totaling 16 genomic regions for POAG (including normal tension glaucoma), 8 for PACG, and 2 for XFS. (4)

Figure 1: Genes implicated in glaucoma and endophenotypes

Genetic Influence on Diabetic Retinopathy

The heritability of diabetic retinopathy is estimated to be as high as 27% for any diabetic retinopathy and 52% for proliferative diabetic retinopathy (PDR). (5) Prolonged exposure to elevated glucose levels and sensing danger signals from infections can heighten inflammation in diabetic patients’ ocular compartments. This inflammation upregulates mediators, activating NF-κB and inducing transcription of factors like TNF, iNOS, IL-1β, IL-6, IL-8, IL-17A, ICAM-1, Cox-2, and MMP-9. Consequently, compromised tight junctions disrupt communication between ocular cells, leading to blood-retinal barrier breakdown and affecting proteins like occluding, ZO-1, connexin 43, and 26. This complex process involves various molecular entities, including Cox-2, HMGB1, iNOS, IL-1β, ICAM-1, MMP-9, TLR4, TNF, RBP-4, and ZO-1. (2)

Various genes associated with an elevated risk of DR involve inflammation, oxidative stress, and angiogenesis. Noteworthy genes include VEGF, pivotal in abnormal blood vessel development; ACE, linked to blood pressure regulation and retinal complications; and those related to the renin-angiotensin-aldosterone system (RAAS), impacting vascular function. Epigenetic mechanisms, like histone modifications and DNA methylation, significantly contribute to DR progression, influencing gene expression and sustaining pro-inflammatory pathways. Researchers are investigating “epi-drugs,” such as histone demethylases and DNA methylation inhibitors, for potential therapeutic applications. (6)

The Promise of Genetic Research in Eye Health

Genes associated with the disease are elucidating pertinent biological pathways, potentially serving as targets for innovative gene-based therapies. Additionally, the identification of these genes facilitates the creation of gene-based tests for identifying individuals at risk before irreversible blindness sets in. Further research is essential to thoroughly characterize the genetic architecture specific to the disease, a prerequisite for comprehensive genetic testing and the implementation of targeted gene-based therapies.



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  2. Zhou P, Li XX. Role of genetic factors in the pathogenesis of exudative age-related macular degeneration. Taiwan Journal of Ophthalmology. 2014 Dec 1;4(4):152-5.
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  6. Homme RP, Singh M, Majumder A, George AK, Nair K, Sandhu HS, Tyagi N, Lominadze D, Tyagi SC. Remodeling of retinal architecture in diabetic retinopathy: disruption of ocular physiology and visual functions by inflammatory gene products and pyroptosis. Frontiers in Physiology. 2018 Sep 5; 9:1268.