title: PARK2 variability in Polish Parkinson's disease patients--interaction with mitochondrial haplogroups.
abstract: OBJECTIVE
  A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability.
  
  
  METHODS
  104 early-onset PD patients (EOPD, age at onset ≤ 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay.
  
  
  RESULTS
  PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P). In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038).
  
  
  CONCLUSIONS
  Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients.
authors.affiliation: Department of Neurodegenerative Disorders, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. kasiawal@libero.it
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gaweda-Walerych
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Safranow
authors.forename: Barbara
authors.initials: B
authors.lastname: Jasinska-Myga
authors.forename: Monika
authors.initials: M
authors.lastname: Bialecka
authors.forename: Gabriela
authors.initials: G
authors.lastname: Klodowska-Duda
authors.forename: Monika
authors.initials: M
authors.lastname: Rudzinska
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Czyzewski
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cobb
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Slawek
authors.forename: Maria
authors.initials: M
authors.lastname: Styczynska
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Opala
authors.forename: Marek
authors.initials: M
authors.lastname: Drozdzik
authors.forename: Kenya
authors.initials: K
authors.lastname: Nishioka
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Cezary
authors.initials: C
authors.lastname: Zekanowski
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006238:Haploidy; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein