Genetic Research into Diabetic Retinopathy Care

Kristi Sharma, M. Optom

Education Engagement Manager, Vision Science Academy

 

Genetic research is transforming the understanding and management of Diabetic Retinopathy (DR) by identifying individuals at higher risk, uncovering new molecular targets, and paving the way for personalised medicine and novel therapeutics. The field has moved from simply recognising that diabetes runs in families to pinpointing specific genetic variants that dictate disease susceptibility, progression, and treatment response.

The Genetic Landscape of Diabetic Retinopathy

DR is the most common microvascular complication of diabetes and the leading cause of blindness in working-age adults worldwide. ⁽¹⁾ While poor glycaemic control and high blood pressure are known risk factors, the fact that some patients with years of poor control never develop DR, while others with well-controlled diabetes do, strongly suggests a significant genetic component. Heritability studies, especially in twins and families, estimate that genetic factors account for a large portion of the risk (≈25%–50%, varying by population and severity). ⁽²⁾

Key Genetic Study Approaches

The search for the genes that contribute to DR susceptibility has used three main research strategies:

1) Candidate Gene Studies

These were the earliest approach, focusing on genes thought to be involved in the known biochemical pathways of DR:

• Angiogenesis & Vascular Function (VEGFA):

  Vascular Endothelial Growth Factor (VEGF) drives the growth of new, abnormal blood vessels in advanced DR (Proliferative DR). Researchers have examined multiple single nucleotide polymorphisms (SNPs) in the VEGFA gene. The C allele has been linked to higher serum levels of VEGF and an increased risk of developing DR and Diabetic Macular Edema (DME) in some populations. ⁽³⁾ Understanding a patient’s VEGFA genotype could help predict the severity of their disease and their response to anti-VEGF treatments

• Metabolic Pathways (ALR2/AKR1B1):

  Aldose Reductase Gene (ALR2 or AKR1B1) enzyme is the first and rate-limiting step in the polyol pathway, which becomes overly active in high blood sugar. ⁽⁴⁾ ALR2 converts glucose to sorbitol, leading to cellular osmotic stress, damage, and loss of pericytes, key features of early DR. ^(4,5) A polymorphism involving an (A-C) repeat in the ALR2 gene has been significantly associated with DR susceptibility across different ethnic groups. ⁽⁴⁾

• Inflammation & Oxidative Stress:

  Genes that encode inflammatory cytokines (e.g., TNF-alpha, IL-6) and components of the Angiotensin-Converting Enzyme (ACE) system have also been widely investigated. Inflammation and poor blood flow regulation play a key role in DR pathology. ⁽⁶⁾

2) Genome-Wide Association Studies (GWAS)

GWAS offer a more unbiased approach by scanning the entire human genome for SNPs linked to the disease. The challenge with DR GWAS has been reaching the necessary sample size and standardising the definition of the disease, such as distinguishing between non-proliferative and proliferative DR.

• T1D-related DR: Recent large-scale GWAS in T1D groups have identified significant susceptibility loci, including a new genomic risk locus in the region between the CCDC7 and ITGB1 genes. ⁽⁷⁾ The proteins produced by these genes are involved in cell adhesion and signalling, suggesting new ways retinal damage could occur.
• T2D-related DR: GWAS in T2D populations have found other important loci, such as those near the genes EYA2, MPDZ, and NTNG1, which are involved in developmental processes and nerve guidance. ⁽⁸⁾ Another study confirmed the association of SNPs near the STT3B and PALM2 genes in Japanese populations, although these findings often show racial and ethnic differences, highlighting the need for diverse study groups. ⁽⁹⁾

3) Mendelian Randomisation (MR)

MR is a useful epidemiological method that uses genetic variants as tools to test the causal relationship between a changeable factor (like a circulating protein or a physiological trait) and a disease outcome (DR). This method reduces confounding factors and reverse causation bias that affect traditional observational studies.

• Identifying causal targets: MR studies have helped establish the causal link between prolonged high blood sugar (measured by HbA1c) and DR risk. More recently, MR analysis has been applied to proteomic data, identifying specific plasma proteins (e.g., SIRPG, GSTA1, MAPK13) whose genetically predicted high levels are causally linked to an increased risk of DR. ⁽¹⁰⁾ These proteins are promising new targets for drugs.
• Validating drug pathways: MR can also validate drug targets. For instance, studies have used MR to explore the causal effects of genetically determined differences in the GLP-1 receptor pathway, which GLP-1 receptor agonists (a class of diabetes drugs) target. ⁽¹¹⁾ This provides strong genetically-supported evidence for the safety or effectiveness of these treatments.

Figure 1: Mendelian Randomisation

Bridging Genetics with Clinical Practice

1) Improved Risk Stratification & Screening

• One important application is the creation of personalised risk scores. (12) A patient’s genetic profile, along with traditional clinical data (duration of diabetes, HbA1c, blood pressure), can form an algorithm to:
• Identify High-Risk Individuals: Diabetic patients with a high genetic risk score may be placed on a more intensive monitoring schedule. They will receive retinal screenings earlier and more often than standard guidelines suggest. ⁽¹²⁾
• Stronger PreventionFor these high-risk individuals, aggressive targets for controlling blood sugar and blood pressure may be set to reduce their genetic risk. This proactive approach aims to intervene before irreversible micro-vascular damage from DR occurs. ⁽¹²⁾

2) Pharmacogenomics & Treatment Response Prediction

Genetics can predict how a patient will respond to current and future treatments, improving the choice of therapy and dosage. ⁽¹²⁾

Treatment Class	Genetic Target	Clinical Implication
Anti-VEGF Agents	VEGFA polymorphisms	High-VEGF variants may predict need for more frequent injections or specific anti-VEGF choice; early non-responders can pivot to steroids/laser sooner. (13)
Aldose Reductase Inhibitors	ALR2 polymorphisms	Despite past trial failures, a high-risk ALR2 genotype subgroup may benefit—supports targeted trials. (14)
Inflammatory Modulators	Cytokine/Inflammatory SNPs	Genetic profiles indicating dominant inflammation may favour anti-inflammatory agents alongside/instead of anti-VEGF. (15)

Table 1: Pharmacogenomics and Clinical Implications

3) Novel Therapeutic Development

Genetic research drives the discovery of new drug targets by validating the roles of specific molecules in disease pathways:

• Neuroprotection: Identifying genes related to neuro-degeneration in the retina, like MAPK, suggests that DR is not only a vascular disease but also a primary neuro-degenerative condition. This has increased interest in developing therapies aimed at preserving retinal neuronal health in the early stages of diabetes. ⁽¹⁶⁾
• Targeting New pathways:New targets identified through MR and GWAS, such as the plasma proteins GFRA2 or DKK3, offer direct, genetically validated starting points for drug development. This could lead to the next generation of non-VEGF-dependent DR therapies. ⁽¹⁷⁾

Figure 2: Intravitreal Anti-VEGF Drug Delivery in Diabetic Retinopathy

Future Directions: Gene Therapy and Gene Editing

The most ground-breaking advances from genetic research are in direct genetic manipulation. This offers the potential for a one-time treatment for DR. The eye is an excellent target for these therapies due to its small size, easy accessibility for injection, and immune-privileged status, which lowers the risk of rejection.

1. Gene Augmentation Therapy (Anti-VEGF Sustained Release) Current gene therapy trials for DR and DME focus on providing a long-term, sustained release of anti-angiogenic agents.
2. Precision genome editing (CRISPR/Cas9): Beyond sustained protein expression, gene editing technologies provide the possibility to correct or modify the expression of disease-causing genes. ⁽¹⁸⁾

Challenges and the Path Forward

Despite rapid progress, several challenges remain:

• Replication and heterogeneity: Many initial candidate gene findings have not replicated across different ethnic groups. This highlights the genetic diversity of DR. Future studies must include large, diverse ethnic cohorts to find globally relevant and strong genetic markers. ⁽¹⁹⁾
• Missing heritability:While genetics plays a big role, the specific variants found so far explain only a small part of the total heritability. This suggests that rarer variants, interactions between genes, or epigenetic factors, changes in gene expression that do not involve the DNA sequence are also important. ⁽²⁰⁾
• Translation to Clinic: Creating affordable, scalable, and clinically reliable genetic tests for DR risk and treatment response is a major challenge before personalised DR care can become routine.

Conclusion

Genetic research has clearly shifted DR care into a new phase. By highlighting the complex interactions of genes involved in vascular damage, inflammation, and neuro-degeneration, researchers are not only enhancing risk prediction but also driving the development of targeted drugs and innovative gene therapies. The future of DR care will be characterised by a truly personalised, genetically-informed approach, resulting in better diagnosis and treatment outcomes for diabetic patients around the world.

 

References

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18. Kolanu ND. CRISPR-Cas9 & inherited epigenetic modifications. Global Med Genet. 2024;11(1):113-122.
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About the Author

 

Kristi Sharma is a Master of Optometry with a clinical research expertise in Teleophthalmology. She currently works as the Education Engagement Manager at Vision Science Academy and has curated and tutored extensive courses at the Vision Science Academy Learning Centre. She is actively engaged in developing the research forum of Vision Science Academy, in addition to the ongoing and upcoming educational events in the Academy. She has published a number of scientific blog articles in the past 5 years and aspires to continue contributing significantly in the domain of vision research and writing.