gms | German Medical Science

Background: Inflammation and angiogenesis are the key pathophysiological mechanisms of neovascular age-related macular degeneration (nAMD). Both mechanisms are not specific to the eye, yet general mechanisms of the organism. Hence, the BIOMAC study investigated the influence of systemic factors on the course and treatment response in a multi-omics approach.

Methods: BIOMAC is a cohort of 46 nAMD subjects. Twenty-one subjects had well controlled choroidal neovascularization (CNV) under anti-VEGF treatment (LF cluster). In the remaining 25 subjects, CNV activity was poorly controlled despite injections every 4–6 weeks (HF cluster). Proteomic profiles in peripheral blood samples were determined by LC-MS/MS mass spectrometry. Extensive in-silico modelling was performed to identify potential proteomic signatures underlying the clinical phenotype.

Results: Both strata were well balanced regarding age (HF 78.4±8.14; LF 79.7±7.00 years), gender (HF 40% LF 61.9% female) and BCVA (HF 61.4±15.7; LF 65.0±12.4). Due to the group definition, central retinal thickness differed between HF and LF (HF 352.2±98.0 vs. LF 274.8±45.7µm. Descriptively, 6 proteins were up- and 3 downregulated in HF vs. LF. Up-regulated proteins: complement c1q subcomponent subunit b (ratio HF/LF=1.84), cytosol aminopeptidase (ratio HF/LF=1.54), and insulin-like growth factor-binding protein 3 (ratio HF/LF=4.1496). Down-regulated proteins: Acidic leucine-rich nuclear phosphoprotein 32 family member A (ratio HF/LF=0.67). Applying advanced statistics, proteome-based clustering results in two distinct clusters of nAMD. One cluster exhibits a strong signature for oxidative stress response. If matched to clinical features, pulmonary dysfunction is identified as underlying health condition in these patients. In contrast, applying a non-linear machine-learning model identifies complex molecular patterns hidden in a high number of proteomic dimensions determining macular disease expression.

Conclusions: So far not considered systemic signals in the peripheral blood proteome contribute to the clinically observed phenotype of nAMD, which should be considered in future translational research on AMD.