Matrix–Mechanical Genetic Susceptibility and Reduced Inflammatory and Immediate-Early Programs in Keratoconus

Purpose. To determine which proposed keratoconus (KC) mechanisms carry its genetic susceptibility and how it relates to corneal structure, and which describe its corneal tissue. Methods. Six mechanism modules and two attribution sets (transforming growth factor-β [TGF-β] and canonical type-2 atopy) were tested for enrichment in three independent European KC genome-wide association studies (GWAS) and in GWAS of central corneal thickness (CCT) and corneal resistance factor (CRF), with colocalization at matrix loci. Tissue expression was pooled across nine arms from eight studies with control-source meta-regression; activator protein-1 (AP-1)/immediate-early regulatory activity was scored in 107 donors, spatial expression in 21, and serum responses in human and rabbit stromal cells. Results. Extracellular matrix (ECM) was the only module enriched in all three KC sources ( P ≤ 5.46 × 10⁻⁴) and for CCT, CRF, and thickness-independent CRF ( P ≤ 2.07 × 10⁻⁵). COL5A1 shared causal variants with CCT in all three sources (posterior probability 0.985–0.991), and FNDC3B and COL1A1 with CRF or its thickness-independent component (0.961–0.986). Pooled, KC corneas had lower general and corneal-local inflammatory and stress/immediate-early expression (log₂ fold-change −0.97, −0.98, −0.82; P ≤ 0.049). In whole-cornea and stromal tissue, ECM expression reversed between postmortem-donor and pathological controls (log₂ fold-change +0.36, −2.34), whereas inflammatory and TGF-β programs were lower against both. AP-1/immediate-early regulatory activity was lower in four donor cohorts (Hedges' g −1.50) and stress/immediate-early expression in two spatial cohorts; serum raised immediate-early readouts in human and rabbit cells. Conclusions. KC combines matrix–mechanical genetic susceptibility with a low-inflammatory, low-immediate-early corneal state whose matrix expression direction depends on the control source. Because this susceptibility is genetically shared with corneal thickness and resistance, interventions on the inherited disease are judged by corneal structure and mechanics.