Genome-wide association study to assess the risk of variant Creutzfeldt-Jakob disease

December 07, 2008

Although measures were taken to prevent further transmission to humans after the outbreak of variant Creutzfeldt-Jakob disease (vCJD) from infected cattle in the mid-1990s, the full extent of this outbreak and that of other prion diseases* might not yet be realised. Prion diseases are controlled by genetic factors, and normal variations in DNA might influence susceptibility to prion diseases and affect the length of their silent incubation period. These are the findings of a genome-wide association study† published in an Article in the January issue of the The Lancet Neurology, written by Simon Mead and co-authors at the UK Medical Research Council Prion Unit at University College London.

The two most likely routes of infection with prions are through eating infected tissue from the central nervous systems of animals or humans or through transfusions with contaminated blood, but whether a person will succumb, and when, are under genetic control. One common SNP‡ in the gene PRNP determines which amino acid (either methionine or valine) will be at a particular position (codon 129) in the PrP protein, and this has already been shown to be associated with susceptibility to prion disease (all patients with vCJD who have been genotyped are homozygous [they inherited the same form of the gene from each parent] for methionine at codon 129 in the PrP protein), but studies done in animals suggest that many other genetic variations in the general population can affect these parameters.

To identify other common SNPs that are associated with susceptibility to prion disease, the authors genotyped samples from all of the white British patients who died from orally acquired vCJD, and compared their DNA with that from healthy blood donors and samples in the Wellcome Trust Case-Control Consortium collection, in a genome-wide association study. With the focus on the SNPs that are most strongly associated with vCJD, they then widened their search to genotype patients with other forms of prion disease: those with sporadic CJD (sCJD), those who acquired CJD through the use of cadaver-derived growth hormone (iatrogenic CJD [iCJD]), and Fore from Papua New Guinea, who did or did not acquire kuru§ despite many exposures to infected tissue, and unexposed people from the same population.

The authors' findings reinforce the strength of the association of the previously reported SNP at codon 129 of PRNP, and they also report another SNP close to PRNP that is associated, albeit less robustly, with vCJD. "Our study thus confirms the strong association of PRNP codon 129 across acquired and sporadic prion diseases as the outstanding genetic risk factor in human prion disease."

They also identified a SNP close to the gene for the beta receptor for retinoic acid that was significant in vCJD and also iCJD, but not in sCJD or kuru. In cultured cells, retinoic acid has previously been shown to regulate the expression of PRNP.

Furthermore, a region that is close to STMN2, the gene that encodes the protein SCG10 (a protein associated with neuron growth) was associated with acquired prion disease (including vCJD), kuru incubation time, and resistance to kuru. The risk genotype was not associated with sCJD but conferred an earlier age of onset. The authors went on to show that expression of this gene is significantly decreased in cultured mouse neuronal cells that are infected with prions, although no role for SCG10 in prion disease has yet been shown.

Although the authors acknowledge that the proximity of these SNPs to particular genes does not necessarily mean they have a regulatory role, "in each case these are excellent candidates for involvement in prion pathology".

"Our data lend considerable support to the hypothesis that genetic susceptibility in addition to codon 129 has contributed significantly to the outbreak of vCJD to date. Whether these effects are on the incubation period rather than susceptibility, such that further waves of BSE-associated prion disease with longer incubation periods might occur in the years unknown."

In an associated Comment, Hans Kretzschmar and Thomas Illig, respectively of the Ludwig-Maximillians University and the Helmholtz Zentrum in Munich, state that the findings of Mead and coauthors "tip the scales in favour of the genetic hypothesis [for a predisposition to prion disease and for variations in incubation time, although] the exact influence of these loci and the molecular mechanisms...will have to be investigated. A second wave of CJD with a longer incubation time might hit these shores, but we do not know whether this will be a tidal wave or just an imperceptible ripple."
Dr Simon Mead, Medical Research Council Prion Unit, UCL, London T) +44 20 7837 4888 E)

Dr Hans Kretzschmar, Ludwig-Maximilians University of Munich, Germany T) +49 89 2180 78000 E)

For full Article and Comment:

Notes for editors

*Prion diseases are transmissible fatal neurodegenerative conditions of humans and animals. Bovine spongiform encephalopathy (BSE) widely exposed the population of the UK, and many other populations to a lesser extent, to prion infection. The subsequent diagnosis of variant Creutzfeldt-Jakob disease (vCJD) in young British adults caused a major health scare for humans and animals. Although the number of confirmed deaths due to vCJD is small (about 200) compared with the millions of people who were exposed to BSE prions, estimates of subclinical infection on the basis of the screening of archived surgical specimens suggest that many thousands might be infected. The authors have previously shown that prion diseases can stay latent in infected individuals for up to 50 years.

¬¬¬†Genome-wide association studies investigate variations in genes across the human genome to identify changes (polymorphisms) that are associated with observable traits, such as health benefits or susceptibility to diseases.

‡Single nucleotide polymorphisms (or SNPs) are common variations in one nucleotide base in the DNA. SNPs occur very frequently through a person's DNA, and most have no effect; however, some SNPs are important determinants of disease susceptibility or resistance or of responsiveness to drugs and environmental factors.

§Kuru is an incurable transmissible degenerative neurological disorder of humans. It was endemic among the Fore people of Papua New Guinea and was thought to be passed on through cannibalistic funeral practices, which were outlawed in the mid 20th century.


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