Distinct Genetic Profiles Associated With Subretinal Drusenoid Deposits and Cardiovascular Risk in Age-Related...

Subretinal drusenoid deposits (SDDs) are increasingly recognized as a distinct phenotype in age-related macular degeneration (AMD) and may be linked to cardiovascular disease (CVD). This study aims to explore whether AMD patients with SDDs carry a distinct genetic profile related to CVD risk compared to those without SDDs.

In a retrospective cohort of 459 AMD patients with genotyping and spectral-domain OCT data, we annotated SDD status and extracted cardiovascular diagnoses and procedures from electronic medical records. Fifty-two AMD-associated single-nucleotide polymorphisms (SNPs) were used to calculate weighted genetic risk scores (GRSs), and minor allele frequencies (MAFs) were compared between groups. Principal component analysis (PCA) was performed to assess clustering by SDD status within CVD subgroups.

Patients with SDDs exhibited distinct MAFs in several SNPs, including CFH, ARMS2, COL4A3, and ARHGAP21. Certain variants were more strongly associated with cardiovascular subtypes in patients with SDDs compared to those without. GRSs related to lipid metabolism and complement pathways were higher among SDD-positive patients within selected CVD subgroups. PCA suggested modest but significant separation between genetic profiles of patients with and without SDDs.

AMD patients with SDDs show distinct genetic signatures potentially relevant to cardiovascular health. These findings suggest that SDDs may represent a genetically and systemically unique AMD phenotype. Further investigation is warranted to understand the shared pathophysiology and potential for systemic risk stratification.

Integrating OCT phenotyping and genomic profiling in AMD may uncover systemic disease associations with implications for precision medicine.