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Paraoxonase 1 promoter and coding region polymorphisms in Parkinson’s disease
  1. S N Kelada1,
  2. P Costa-Mallen1,
  3. H Checkoway1,2,
  4. H A Viernes1,
  5. F M Farin1,
  6. T Smith-Weller1,
  7. G M Franklin1,
  8. L G Costa1,6,
  9. W T Longstreth, Jr2,5,
  10. C E Furlong3,4,
  11. G P Jarvik3,4,
  12. P D Swanson5
  1. 1Department of Environmental Health, University of Washington, Seattle, USA
  2. 2Department of Epidemiology, University of Washington
  3. 3Department of Genome Sciences, University of Washington
  4. 4Department of Medicine, Division of Medical Genetics, University of Washington
  5. 5Department of Neurology, University of Washington
  6. 6Department of Pharmacology and Physiology, University of Roma La Sapienza, Rome, Italy
  1. Correspondence to:
 Dr L G Costa, Department of Environmental Health, University of Washington, 4225 Roosevelt Way, NE, Suite 100, Seattle, WA 98195–6099, USA; 
 lgcosta{at}u.washington.edu

https://doi.org/10.1136/jnnp.74.4.546

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    Parkinson’s disease (PD) is thought to be caused by a combination of genetic and environmental factors. Epidemiological studies have found associations of PD with pesticide exposure, or suspected pathways of pesticide exposure, such as rural residence and well water consumption. Many organophosphorous insecticides (for example, chlorpyrifos and diazinon) are bioactivated to potent cholinesterase inhibitors by the cytochromes P450, and the resulting toxic oxon forms are hydrolysed by paraoxonase (PON1). Genetic variants of detoxifying enzymes or pesticide metabolising enzymes, such as paraoxonase, may confer a predisposition to PD and thus are considered candidate genes for association studies.

    Multiple polymorphisms have been identified in the PON1 gene. The coding region contains two common polymorphisms, at amino acid codons 55 and 192. The glutamine (Q) to arginine (R) substitution at codon 192 causes substrate dependent differences in the kinetics of hydrolysis: compared with the PON1 192Q isoform, PON1 192R has higher activity towards paraoxon and chlorpyrifos oxon, but lower activity towards diazoxon, soman, and sarin. The leucine (L) to methionine (M) substitution at codon 55 does not affect the catalytic efficiency of substrate hydrolysis by the enzyme, but the PON1 55M allele is correlated with decreased mRNA and protein levels, because of linkage disequilibrium with a single nucleotide polymorphism (SNP) at position -108 of the promoter region of the gene. Five SNPs have been identified …

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