Mendelian randomization and genetic analyses reveal causal roles of immune cells and inflammatory proteins in keratoconus.

Immunity and inflammation are implicated in the progression of keratoconus (KC), but the causal relationships between inflammatory immune phenotypes and the disease remain unclear. We conducted a comprehensive Mendelian randomization (MR) analysis using GWAS data to investigate the causal effects of inflammatory and immune factors on KC. Multiple sensitivity analyses were performed to validate our findings, with significant results confirmed through meta-analyses using independent GWAS datasets. The Steiger test, LD score regression, and multivariate MR were applied to assess independent effects. Analysis of inflammatory proteins revealed that IL-12B (P = 8.26 × 10^-5) and IL-13 (P = 0.012) were associated with an increased risk of KC, whereas IL-17 A (P = 0.049) was inversely associated with KC risk. After FDR adjustment, the results for IL-12B (P = 0.007) remained significant. Twenty-two protective and eleven risk immune cells were identified. Meta-analysis supports CD20 on IgD- CD24- B cells and Central Memory CD8 + T cells %CD8 + T cells as protective factors against KC. Multivariable MR revealed independent heritability for seven inflammatory proteins and three immune cells. These findings highlight the critical role of immune and inflammatory factors in KC pathogenesis, suggesting possible targets for future investigation in KC prevention and treatment.