Age-Related Macular Degeneration and Diabetic Nephropathy: Is there a Connection?

Both diabetic nephropathy and age-related macular degeneration (AMD) are prominent causes of serious complications; diabetic nephropathy leads to end-stage renal failure and AMD to visual impairment and blindness.¹ Known risk factors for diabetic nephropathy are hyperglycemia, hypertension, abnormal lipid levels, increased urate, and obesity. Risk factors for AMD are age, sex, race, smoking, alcohol consumption, dietary patterns, and obesity. Previous studies have investigated the association between diabetic nephropathy and the risk of AMD. While some studies have shown a correlation between risk factors for diabetic nephropathy and AMD, none have established causation.^2-5

The investigators of a recent study have explored whether causation exists. Using Mendelian randomization, first author, Xiaxue Chen, and corresponding author, Guangyu Li, both from the Department of Ophthalmology, The Second Hospital of Jilin University, Changchun City, Jilin, China, and colleagues, attempted to find a causal relationship between diabetic nephropathy and both wet and dry forms of AMD. Their efforts were aided by the growth of genome-wide association studies (GWAS), which helped to provide more robust data. Their study was published online in Gene.¹

Mendelian randomization and the causal link

The investigators performed 2-sample Mendelian randomization analyses to investigate the contribution of exposure to AMD and then performed multivariable analyses for validation. They used single nucleotide polymorphisms derived from GWAS data for the instrumental variables.¹

Data from patients with diabetic neuropathy and AMD were obtained from the FinnGen Biobank GWAS. The risk factors associated with diabetic nephropathy that were tracked were glycemic traits (2-hour glucose post-challenge, fasting glucose, fasting insulin, and glycated hemoglobin [HbA1c]), blood pressure, urate, and obesity. The lipid phenotypes were high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein (LDL)-C, total cholesterol, and triglycerides.¹

The authors found that a significant increase in the risk of wet and dry AMD (both overall and individually) associated with genetically predicted diabetic nephropathy (P = 1.03 x 10-8, P = 5.15 x 10-6, and P = 2.27 x 10-4, respectively).¹ They did not find a significant association with AMD (overall) and most of the glycemic traits (2-hour glucose post-challenge, fasting glucose, fasting insulin, HbA1c, blood pressure, urate, and obesity).¹

They did find that an increase in HDL-C of 1 standard deviation increased the AMD risk (P = 2.69 x 10-3). Conversely, lower levels of triglycerides were associated with an increased risk of AMD (P = .02).¹ These associations were also found in the European EYE-RISK project of the European Eye Epidemiology consortium. The EYE-RISK project found that increased HDL-C was associated with larger drusen areas. Additionally, that project found that an increased level of triglycerides was associated with smaller drusen.²

Drusen and the hypothesis

The authors had a hypothesis for their findings. Drusen are known to be rich in lipids. The macula has a hypermetabolic state, which may lead to increased levels of reactive oxygen species. HDL-C can then transform into “dysfunctional pro-oxidant and proinflammatory granules.”¹ This can then impede the ability for cholesterol to leave and aid the oxidation of LDL in the retinal pigment epithelium (RPE). The oxidation byproducts then accumulate in the retina and Bruch’s membrane, leading to inflammation and deposition of drusen. Then, this promotes the progression of AMD. There are also genes related to lipid metabolism that might be associated with AMD. Additionally, both glomerular basement membranes and the RPE/Bruch’s membrane complex have similar structures, and both are exposed to immune complexes in the systemic circulation.¹

Advantages and limitations

An advantage to this study was that Mendelian randomization can be used to infer causation and showed evidence of a causal link between diabetic nephropathy and AMD, which has not been demonstrated in the past. Additionally, AMD was grouped into 3 subgroups, overall, wet, and dry AMD, and these were looked at individually. The large sample size improves the statistical power and reliability of their results.¹

The fact that all participants included in the study were of European descent had both an advantage and a limitation. The advantage is that it mitigated potential bias from population stratification. A limitation is generalizability; as their study used GWAS data only from patients of European descent, their findings may not apply to other populations.¹

Other limitations were mentioned by the authors. They stated that there may have been some horizontal pleiotropy issues affecting their study. Additionally, as they only had individual-level data, there may have been biases from the selection and exclusion restrictions. Finally, they mention that the “environmental exposures investigated in [Mendelian randomization] studies are determined by genetic variants, which may not be entirely equivalent to conventional exposures. Consequently, our study is susceptible to producing null or negative results.”¹

In summary

The authors stated “…our study represents the pioneering investigation into the causal relationship between [diabetic nephropathy] and AMD using [Mendelian randomization] analysis. The results revealed a significant and robust causal association between them. Additionally, we explored the causal relationship between risk factors for [diabetic nephropathy] and AMD in our study. These findings underscore the importance of enhancing awareness regarding the fundus conditions in individuals with [diabetic nephropathy]. Furthermore, our study highlights the necessity for further evaluation of these findings in larger and more diverse datasets. Moreover, our findings are worth evaluating further in larger datasets, and additional experimental studies are also warranted.”¹

Published: April 10, 2024