Article Text

Variant Creutzfeldt-Jakob disease is not associated with individual abilities to metabolise organophosphates
  1. O GAROFALO,
  2. EH MCFARLANE,
  3. C IYEGBE,
  4. S A WHATLEY,
  5. I C CAMPBELL
  1. Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, King's College London, London SE5 8AF, UK
  2. Hopital Neurologique, Lyon, France
  3. National CJD Surveillance Unit, Edinburgh EH4 2XV, UK
  1. Professor I C Campbell i.campbell{at}iop.kcl.ac.uk
  1. N KOPP
  1. Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, King's College London, London SE5 8AF, UK
  2. Hopital Neurologique, Lyon, France
  3. National CJD Surveillance Unit, Edinburgh EH4 2XV, UK
  1. Professor I C Campbell i.campbell{at}iop.kcl.ac.uk
  1. R G WILL
  1. Institute of Psychiatry, Department of Neuroscience, De Crespigny Park, King's College London, London SE5 8AF, UK
  2. Hopital Neurologique, Lyon, France
  3. National CJD Surveillance Unit, Edinburgh EH4 2XV, UK
  1. Professor I C Campbell i.campbell{at}iop.kcl.ac.uk

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Since its identification as a distinct form of human prion disease, it has been demonstrated that vCJD is related to bovine spongiform encephalopathy (BSE),1 thus providing evidence for transmission of the disease from cattle to humans. Despite widespread beef consumption, however, the number of cases of vCJD has been low and moreover, there is no history of unusual exposure to beef or its products among affected persons,1 These findings may arise from a combination of factors, including the existence of environmental factors that may affect susceptibility, the long incubation period for vCJD, uneven exposure to infected beef, and variations in individual genetic susceptibility to the transmission process. Of the known genetic factors, it has been established that polymorphisms of codon 129 of the prion protein gene confer individual susceptibility to vCJD.1 However, this polymorphism is common in the normal population, suggesting that other genes contribute to genetic susceptibility to vCJD.

This study aimed to establish whether polymorphisms in the paraoxonase (PON) family of genes are associated with incidence of vCJD and was based on the hypothesis that exposure to OPs, widely used as insecticides in the United Kingdom, was causally related to the BSE epidemic.2 PON1 and PON2 have a major role in the detoxification of many organophosphate pesticides: PON1 allelic variants confer fast or slow abilities to detoxify these xenobiotics.3 PON1 is also known to protect against accumulation of potentially harmful oxidised lipids: this scavenging role of PON1 has been used to provide a rationale for the association of both PON1 and PON2 polymorphic variants with predisposition to heart disease.4

The rationale for our study is also supported by the finding that, in cultured cells, the organophosphate pesticide phosmet, widely used at high doses in the United Kingdom to eradicate warble fly, upregulates cell surface levels of normal prion protein in human neuronal cells5; high levels of PrP expression are themselves known to be associated with increased ease of transmission of prion diseases.1 Although it has been shown that vCJD does not seem to be associated with exposure to organophosphates present in head lice treatments,6 our study aimed to establish whether persons affected by vCJD are more genetically susceptible to organophosphate exposure than the normal population.

Using the polymerase chain reaction and restriction analysis, we genotyped 26 patients with vCJD, 19 patients with sporadic CJD, and 10 neurological controls for both codon 54 and 192 of PON1 and codon 311 of PON2 polymorphisms.3-4 In addition, we genotyped 93, 117, and 95 normal persons, respectively for codon 54 and 192 of PON1 and codon 311 of PON2 polymorphisms.

All patients were clinically diagnosed and neuropathologically confirmed. None of the patients with vCJD that we studied belonged to the cluster recently found in Leicestershire.7

Statistical analysis of the data was performed using the Pearson's χ2 test (p<0.05).

The distribution of PON1 and PON2 genotypes and allele frequencies in patients and controls is shown in table 1. All genotype frequencies did not deviate significantly from the predicted Hardy-Weinberg equilibrium (data not shown). The frequencies of alleles L(Leu) and M(Met) at codon 54 of PON1 were respectively 0.672 and 0.328 in the control population (n=93), 0.654 and 0.346 in vCJD, 0.684 and 0.316 in sporadic CJD, and 0.700 and 0.300 in neurological controls. The frequencies for alleles A(Gln) and B(Arg) at codon 192 of PON1 were respectively 0.726 and 0.274 (n=117) in the controls, 0.731 and 0.269 in vCJD, 0.737 and 0.263 in sporadic CJD, and 0.700 and 0.300 in neurological controls. Finally, the frequencies for alleles S(Ser) and C(Cys) at codon 311 of PON 2 were respectively 0.774 and 0.226 in controls (n=95), 0.769 and 0.231 in vCJD, 0.763 and 0.237 in sporadic CJD, and 0.700 and 0.300 in neurological controls. There was no significant association between any of the PON polymorphisms studied and vCJD, sporadic CJD, or the other neurological disorders (table 1). Our data show that PON polymorphic variants are not associated with vCJD. These data, together with the data of Churchill et al,6indicate that exposure to organophosphates is unlikely to contribute to the incidence of vCJD.

Table 1

Distribution of PON1 and PON2 genotypes and allele frequencies in cases and controls*

Acknowledgments

We thank Dr Maureen Marks for statistical help and advice.

References

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