Macular telangiectasia type 2 genetic risk variants associated with clinical characteristics in the Slovenian cohort

PURPOSE: Early diagnosis of macular telangiectasia type 2 (MacTel) remains challenging, and the contribution of genetic variation to its clinical heterogeneity is unclear. This study investigated associations between MacTel risk variants and clinical characteristics in a Slovenian cohort. METHODS: In this case-control study, including 65 patients with MacTel and 73 healthy controls, participants underwent a complete ophthalmological examination and multimodal imaging. Clinical parameters included best-corrected visual acuity (BCVA), retinal thickness, area of ellipsoid zone (EZ) break, retinal pigment epithelium (RPE) hyperplasia and neovascularization (NV). Ten MacTel risk variants were genotyped using TaqMan assays. A polygenic risk score (PRS) was calculated, and phenotype-phenotype and genotype-phenotype associations were evaluated using correlation and regression analyses. Two variants showed nominal differences in minor allele frequency between groups: rs36259 (CERS4) and rs146953046 (PHGDH), with the latter associated with higher odds of MacTel (OR = 3.51, p = 0.040). The rs11077850-C allele (SNHG16) showed nominal associations with better BCVA (logMAR) (ρ = -0.33, p = 0.0066), a smaller area of EZ break (ρ = -0.27, p = 0.032) and lower odds of progressed disease (OR = 0.30, p = 0.011). These associations were attenuated after FDR correction. A PRS constructed from five MacTel risk variants, combined with age moderately discriminated patients from controls (AUC = 0.68). CONCLUSION: MacTel risk variants are associated with clinically relevant functional and structural retinal changes. Integrating genetic information with multimodal imaging may support risk stratification and earlier recognition in selected patients.