Systemic and Genetic Risk Factors for Reticular Macular Disease and Soft Drusen in Age- Related Macular Degeneration

PurposeSoft drusen and subretinal drusenoid deposits (SDD) aka reticular macular disease (RMD) characterize two pathways to advanced age-related macular degeneration (AMD). We propose these pathways are distinct diseases, with distinct genetic risks, serum risks and associated systemic diseases. Methods126 Subjects with AMD had: retinal imaging for RMD status, serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. Results62 subjects had RMD, 64 were nonRMD (drusen only), 51 had CVD or Stroke. RMD correlated significantly with: ARMS2 risk allele (p= 0.019); lower mean serum HDL (61{+/-}18 vs. 69{+/-}22 mg/dl, p= 0.038, t test); CVD and troke (34/51 RMD, p= 0.001).NonRMD correlated/trended with APOE2 (p= 0.032) and CETP (p= 0.072) risk alleles. 97 subjects total had some drusen, which correlated with CFH risk (p= 0.016). Multivariate independent risks for RMD were: CVD and Stroke (p= 0.008), and ARMS2 homozygous risk (p= 0.038). ConclusionThe RMD and soft drusen AMD pathways have distinct systemic associations, serum and genetic risks. RMD is associated with CVD and stroke, ARMS2 risk, and lower HDL; drusen with CFH risk and two lipid risk genes. These pathways appear to be distinct diseases leading to advanced AMD. Summary StatementTwo phenotypes of age-related macular degeneration, soft drusen and reticular macular disease (the combination of subretinal drusenoid deposits and choriocapillaris insufficiency), are shown here to have distinct systemic vascular, serum, and genetic risks. These findings support the concept that these phenotypes actually represent distinct disease processes.