Metabolic vulnerability index and MetaboHealth score as risk factors for age-related macular degeneration in a large-scale prospective cohort

Age-related macular degeneration (AMD) imposes a substantial burden of disability. Metabolic disturbances are associated with increased AMD risk. Here we evaluate the metabolic vulnerability index (MVX), derived from inflammation- and malnutrition-related markers, and MetaboHealth score, developed from metabolomics-based biological aging, as biomarkers for AMD incidence. UK Biobank participants with metabolomic data and no AMD at baseline were included. Cox proportional hazards models were used to estimate the associations of MVX and MetaboHealth with incident AMD, adjusting for demographic, socioeconomic, lifestyle, and comorbidity factors. Interactions between AMD polygenic risk score (PRS, field 26,204) and both scores were evaluated on both multiplicative and additive scales using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Cross-sectional linear models were adopted to assess the associations of both scores with AMD-related retinal traits, including photoreceptor segment (PS) and retinal pigment epithelium–Bruch’s membrane thicknesses. Over a median follow-up of 13.66 years, AMD occurred in 5509 of 265,133 participants for MVX analysis and in 5498 of 264,352 participants for MetaboHealth analysis. Higher quintiles of MVX and the MetaboHealth score demonstrated a dose-dependent association with increased AMD risk (P for trends < 0.001), with hazard ratios (HRs) of 1.17 (95% CI 1.06–1.30) and 1.32 (1.20–1.45) for the highest quintiles, respectively. Both associations were stronger in those with specific comorbidities compared with their respective reference groups (multiplicative p < 0.05). The highest risk was observed for individuals with jointly high PRS and MVX or MetaboHealth score (HR 2.53 [2.06–3.10]; HR 3.14 [2.54–3.89], respectively). AMD PRS interacted with MVX on AMD risk (multiplicative p < 0.05, RERI = 0.27 [0.13–0.41], AP = 0.16 [0.08–0.23], and SI = 1.58 [1.10–2.05]). This multiplicative interaction was further supported by genetic variants in the complement factor H gene. Both higher MVX and MetaboHealth scores were inversely associated with PS thickness (β = −0.09 µm and β = −0.22 µm, both p < 0.05). MVX and the MetaboHealth score are associated with AMD risk, especially in individuals with comorbidities. Further studies are needed to elucidate the underlying mechanisms and assess potential causal relationships.