Genetic variants of TP53 and EPHX1 in Leber's hereditary optic neuropathy and their relationship to age at onset.

Purpose: To determine whether genetic polymorphisms of the genes for oxidative stress and apoptosis cause the clinical variability in patients with Leber's hereditary optic neuropathy (LHON).

Methods: Eighty-seven unrelated Japanese LHON patients carrying the 11778 mitochondrial mutation were studied at the Keio University Hospital. Their mean age (+/-SD) was 25.0 +/- 13.0 years with a range 3 to 65 years. Eleven polymorphisms in nine genes were studied: seven genes related to oxidative stress (SOD2, GSTT1, GSTM1, EPHX1, NQO1, p22 PHOX, and NOS3), and two genes related to apoptosis (TP53 and CD95). Each genetic polymorphism was analyzed in relation to the age at onset and the final visual acuity.

Results: Among the oxidative stress-related polymorphisms, a significant association between Tyr113His in the EPHX1 gene and the age at onset of the disease was identified (P = 0.026). LHON patients who were homozygous for His113 developed the disease earlier than those without this genotype (21.9 vs. 27.9 years). Among the apoptosis-related polymorphisms, a significant association between Arg72Pro in the TP53 gene and the age at onset was identified (P = 0.007). LHON patients who were homozygous for Arg72 developed the disease earlier than those without this genotype (20.5 vs. 28.1 years). In addition, LHON patients with both genotypes developed the disease significantly earlier (17.5 years, P = 0.011). No associations were found between the final visual acuity and the genetic polymorphisms examined.

Conclusion: Nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age at onset of LHON.