Potential Causal Effects of Cystatin C on Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study

<b>Background/Objectives</b>: Previous studies have shown an association between kidney function and age-related macular degeneration (AMD). This study aims to assess whether the kidney function-related parameters of serum cystatin C and creatinine levels are associated with increased risk of AMD and its subtypes. <b>Methods</b>: Genetic instruments for variants associated with serum cystatin C and creatinine levels as exposure at genome-wide significance (<i>p</i> < 5.0 × 10^-8) were obtained from the UK Biobank. Genetic data for AMD and its subtypes were obtained from the FinnGen project. A two-sample Mendelian randomization analysis was performed to evaluate the causal effects of serum cystatin C and creatinine levels on AMD and its subtypes. <b>Results</b>: Using an inverse-variance weighted approach, higher cystatin C levels are associated with an increased risk of AMD [odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.04 to 1.22, <i>p</i> = 0.004 for overall AMD; OR = 1.14, 95% CI: 1.04 to 1.25, <i>p</i> = 0.007 for dry AMD; OR = 1.14, 95% CI: 1.03 to 1.26, <i>p</i> = 0.011 for wet AMD]. However, serum creatinine levels did not significantly impact the risk of AMD or its subtypes. <b>Conclusions</b>: This study provides genetic evidence that higher cystatin C levels may be a causal risk factor for AMD and its subtypes, whereas serum creatinine was not. This result implies the need to investigate the effect of cystatin C on AMD potentially independent of kidney function.