title: Gene-environment interactions in Leber hereditary optic neuropathy.
abstract: Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.
authors.affiliation: Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK.
authors.forename: Matthew Anthony
authors.initials: MA
authors.lastname: Kirkman
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.forename: Alex
authors.initials: A
authors.lastname: Korsten
authors.forename: Miriam
authors.initials: M
authors.lastname: Leonhardt
authors.forename: Konstantin
authors.initials: K
authors.lastname: Dimitriadis
authors.forename: Ireneaus F
authors.initials: IF
authors.lastname: De Coo
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Patrick Francis
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking / Q000009:adverse effects / Q000453:epidemiology; D004272:DNA, Mitochondrial / Q000235:genetics; D004739:England / Q000453:epidemiology; D004812:Epidemiologic Methods; D005260:Female; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D029242:Optic Atrophy, Hereditary, Leber / Q000150:complications* / Q000453:epidemiology / Q000235:genetics; D019683:Penetrance; D017354:Point Mutation; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology; D014786:Vision Disorders / Q000453:epidemiology / Q000209:etiology*; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial