Association Of Mitochondrial Dna Variants With Keratoconus: A Genotype-Phenotype Association Study

Mitochondrial DNA (mtDNA) variants have been linked to the pathogenesis of keratoconus. This study analyzed mtDNA variants in keratoconus and their relationship with patient phenotype. 

Keratoconus corneas show higher levels of mitochondrial DNA (mtDNA) damage compared with normal corneas . Recent reports have also suggested the potential role of mtDNA variations in the pathogenesis of keratoconus

Peripheral blood samples from 335 keratoconus cases and 658 matched controls were subjected to whole genome sequencing. Bi-allele SNPs were tested by mitochondria‑wide single‑variant association analysis using Fisher’s exact association analysis. Two independent replicate cohorts were used for validation. Whole-mitochondrial association analysis of 2,051 biallelic SNPs identified 18 variants that reached significance. Eight variants were significant in the replicate cohorts.

Three protective variants, rs200999343 in RNR2, rs200786872 in CYB, and rs386829037 in ATP8, showed strong linkage and two harmful SNPs (rs386828968 and rs2068690114) showed a strong linkage (R²=1). ATP8, COX3, ND3, ND5, and T1 were significantly associated with keratoconus (p<0.05). Compared with patients with early symptom onset, those in the middle age group carried significantly more coding region and tRNA region variants (p<0.05). Patients carrying m.9968C>T had a lower onset age of symptoms (p=0.017). Higher posterior radius of curvature was found in samples carrying m.5802T>C and m.4721A>G (p=0.022). Longer eye axis was found in patients carrying m.5417G>A.