title: Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset: gene and smoking status interaction.
abstract: BACKGROUND
  Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5-CHRNA3-CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies.
  
  
  OBJECTIVE
  Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers.
  
  
  METHODS
  We performed a genetic association study in a sample of 677 Italian PD patients, ages 34-76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO.
  
  
  RESULTS
  We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO (p = 0.04). The rs588765 ND risk allele 'C' was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the 'CC' genotype presented delayed AAO compared to carriers of the 'CT' or 'TT' genotypes.
  
  
  CONCLUSIONS
  Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required.
authors.affiliation: Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Ein Karem, 91120 Jerusalem, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Greenbaum
authors.forename: Amihai
authors.initials: A
authors.lastname: Rigbi
authors.forename: Nurit
authors.initials: N
authors.lastname: Lipshtat
authors.forename: Roberto
authors.initials: R
authors.lastname: Cilia
authors.forename: Silvana
authors.initials: S
authors.lastname: Tesei
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Ruth
authors.initials: R
authors.lastname: Djaldetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
mesh_terms: D017668:Age of Onset; D000368:Aged; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012306:Risk; D012907:Smoking / Q000009:adverse effects*; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic