title: Influence of single nucleotide polymorphisms in COMT, MAO-A and BDNF genes on dyskinesias and levodopa use in Parkinson's disease.
abstract: BACKGROUND
  Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence.
  
  
  OBJECTIVE
  We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID.
  
  
  METHODS
  We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course.
  
  
  RESULTS
  Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 ± 445 vs. 508 ± 316 mg; p = 0.0056, mean LED: 601 ± 335 vs. 398 ± 260 mg; p = 0.025).
  
  
  CONCLUSIONS
  Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation.
authors.affiliation: Department of Medicine (Neuroscience), Monash University (Alfred Hospital), Melbourne, Vic., Australia.
authors.forename: Perdita
authors.initials: P
authors.lastname: Cheshire
authors.forename: Kelly
authors.initials: K
authors.lastname: Bertram
authors.forename: Helen
authors.initials: H
authors.lastname: Ling
authors.forename: Sean S
authors.initials: SS
authors.lastname: O'Sullivan
authors.forename: Glenda
authors.initials: G
authors.lastname: Halliday
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.forename: Tom
authors.initials: T
authors.lastname: Foltynie
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015331:Cohort Studies; D004409:Dyskinesia, Drug-Induced / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D013997:Time Factors
chemical_list: D000978:Antiparkinson Agents; D019208:Brain-Derived Neurotrophic Factor; D007980:Levodopa; C579455:BDNF protein, human; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase