title: Genetic variants of TP53 and EPHX1 in Leber's hereditary optic neuropathy and their relationship to age at onset.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  Nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age at onset of LHON.
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Karin
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Funayama
authors.forename: Hisao
authors.initials: H
authors.lastname: Ohde
authors.forename: Yoko
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Mashima
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017209:Apoptosis; D002648:Child; D002675:Child, Preschool; D004272:DNA, Mitochondrial / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D009252:NADPH Dehydrogenase / Q000235:genetics; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D013482:Superoxide Dismutase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D004272:DNA, Mitochondrial; D004851:Epoxide Hydrolases; D005982:Glutathione Transferase; D026901:Membrane Transport Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D010750:Phosphoproteins; D013482:Superoxide Dismutase; D016159:Tumor Suppressor Protein p53; D000099156:Superoxide Dismutase 2; C496314:NOS3 protein, human; C086986:CYBA protein, human; C447479:NQO1 protein, human