NOTCH3 Pathogenic Variant and Risk of Age-Related Macular Degeneration: Findings From the Taiwan Biobank and Small...

Age-related macular degeneration (AMD) is a leading cause of central vision loss involving retinal microvascular dysfunction. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary small vessel disease caused by NOTCH3 mutations, primarily affects the cerebral vasculature but may also involve the retinal microvasculature. This study investigated the association between the NOTCH3 R544C variant and AMD using the Taiwan Biobank and validated the findings in a hospital-based cohort.

In the Taiwan Biobank, individuals carrying the NOTCH3 R544C variant were matched with noncarriers (1:10) by demographic and cardiovascular factors. Odds ratios (ORs) for self-reported AMD and other eye diseases were calculated. Validation was performed in the Taiwan-Associated Genetic and Non-Genetic Small Vessel Disease (TAG-SVD) cohort, including 64 NOTCH3 R544C carriers and 84 age-matched controls who underwent ophthalmic evaluation.

In the Taiwan Biobank, NOTCH3 R544C carriers (n = 1134) had higher prevalence rates of stroke (OR = 2.23; 95% confidence interval [CI], 1.30-3.84), family history of stroke (OR = 2.05; 95% CI, 1.78-2.35), and AMD (OR = 2.26; 95% CI, 1.38-3.71) compared with matched controls (n = 11,340), but not of other eye diseases. Individuals with AMD were older and more likely to have diabetes, higher fasting glucose, HbA1c, total cholesterol, and low-density lipoprotein levels. Multivariate analysis identified age (OR = 1.06; 95% CI, 1.01-1.11) and diabetes (OR = 5.51; 95% CI, 1.84-14.79) as independent correlates. In the TAG-SVD cohort, AMD prevalence was higher in carriers (23.4%) than in controls (13.1%), although not statistically significant (P = 0.10).

The NOTCH3 R544C variant may be associated with an increased risk of AMD, warranting further studies to clarify the underlying mechanisms.