title: A functional polymorphism in the parkin gene promoter affects the age of onset of Parkinson's disease.
abstract: Mutations in the parkin gene are the major cause of autosomal recessive early-onset forms of Parkinson's disease (PD). As reduced parkin expression might also affect the clinical course of idiopathic PD we investigated the effect of a low expressing allele in the parkin promoter region on the age at disease onset (AAO). Patients with PD (n=175) fulfilling standard diagnostic criteria were recruited by experienced neurologists at two movement disorders clinics in Sydney and Brisbane, Australia. DNA was extracted from whole blood and the -258 T/G polymorphism genotyped using PCR/RFLP. AAO effects were analysed using univariate ANOVA, binomial logistic regression modelling and Kaplan-Meier survival analysis. Subjects with the GG genotype (n=10, mean AAO=46.2+/-11.5 (S.D.) years) had a significantly lower mean AAO compared to the common TT genotype (n=104, mean AAO=56.1+/-12.7, p=0.02). There was no difference in mean AAO between the TT and TG individuals (n=61, mean AAO=55.3+/-11.6). Stratifying the sample by median AAO (55 years) revealed that the GG genotype was over-represented in the early-onset group (n=9, OR=18.6, 95% CI=1.41-245.3, p=0.03). We speculate that reduced expression of normal parkin protein may result in an early manifestation of PD symptoms.
authors.affiliation: Prince of Wales Medical Research Institute, University of New South Wales, and Department of Neurology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Sutherland
authors.forename: George
authors.initials: G
authors.lastname: Mellick
authors.forename: Carolyn
authors.initials: C
authors.lastname: Sue
authors.forename: Daniel K Y
authors.initials: DK
authors.lastname: Chan
authors.forename: Dominic
authors.initials: D
authors.lastname: Rowe
authors.forename: Peter
authors.initials: P
authors.lastname: Silburn
authors.forename: Glenda
authors.initials: G
authors.lastname: Halliday
mesh_terms: D017668:Age of Onset; D000368:Aged; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein