title: ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.
abstract: BACKGROUND
  A higher prevalence of individuals affected by Parkinsonism was found in Valcamonica, Italy. This may be related to ferro-alloy smelters in the area, releasing manganese (Mn) in the air, soil and water for about a century. There exists individual susceptibility for Mn neurotoxicity.
  
  
  OBJECTIVE
  To analyse how polymorphism in genes regulating Mn metabolism and toxicity can modify neurophysiological effects of Mn exposure.
  
  
  METHODS
  Elderly (N=255) and adolescents (N=311) from Northern Italy were examined for neuromotor and olfactory functions. Exposure to Mn was assessed in blood and urine by atomic absorption spectroscopy and in soil by a portable instrument based on X-Ray fluorescence technology. Polymorphisms in the Parkinson-related gene ATPase type 13A2 (ATP13A2, also called PARK9: rs3738815, rs2076602, rs4920608, rs2871776 and rs2076600), and in the secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 gene (SPCA1: rs218498, rs3773814 and rs2669858) were analysed by TaqMan probes.
  
  
  RESULTS
  For both adolescents and elderly, negative correlations between Mn in soil and motor coordination (R(s)=-0.20, p<0.001; R(s)=-0.13, p=0.05, respectively) were demonstrated. Also among adolescents, negative correlations were seen between Mn in soil with odor identification (R(s)=-0.17, p<0.01). No associations were seen for Mn in blood or urine. ATP13A2 polymorphisms rs4920608 and rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in elderly (p for interaction=0.029, p=0.041, respectively), also after adjustments for age and gender. The rs2871776 altered a binding site for transcription factor insulinoma-associated 1.
  
  
  CONCLUSIONS
  ATP13A2 variation may be a risk marker for neurotoxic effects of Mn in humans.
authors.affiliation: Division of Occupational and Environmental Medicine, Lund University, SE-22185 Lund, Sweden.
authors.forename: Gerda
authors.initials: G
authors.lastname: Rentschler
authors.forename: Loredana
authors.initials: L
authors.lastname: Covolo
authors.forename: Amelia Ahmadi
authors.initials: AA
authors.lastname: Haddad
authors.forename: Roberto G
authors.initials: RG
authors.lastname: Lucchini
authors.forename: Silvia
authors.initials: S
authors.lastname: Zoni
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D002648:Child; D003430:Cross-Sectional Studies; D004781:Environmental Exposure / Q000009:adverse effects*; D004784:Environmental Monitoring; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007501:Iron / Q000009:adverse effects* / Q000097:blood / Q000652:urine; D007558:Italy; D016014:Linear Models; D008297:Male; D008345:Manganese / Q000009:adverse effects* / Q000097:blood / Q000652:urine; D020149:Manganese Poisoning / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D000857:Olfaction Disorders / Q000139:chemically induced / Q000503:physiopathology; D010302:Parkinson Disease, Secondary / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology / Q000652:urine; D010641:Phenotype; D016133:Polymerase Chain Reaction; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D012111:Residence Characteristics; D018570:Risk Assessment; D012307:Risk Factors; D012903:Smell / Q000187:drug effects / Q000235:genetics; D012987:Soil / Q000737:chemistry; D012989:Soil Pollutants / Q000009:adverse effects* / Q000097:blood / Q000652:urine; D013052:Spectrometry, X-Ray Emission; D013054:Spectrophotometry, Atomic
chemical_list: C514983:ATP13A2 protein, human; D012987:Soil; D012989:Soil Pollutants; C083456:ferro-manganese alloy; D008345:Manganese; D007501:Iron; D006180:Proton-Translocating ATPases