Search for genetic influence on vCJD continues
8 December 2008
Scientists at the Medical Research Council Prion Unit, University College London, searching for variations in DNA that might influence a person’s risk of developing variant Creutzfeldt-Jakob disease (vCJD),following exposure to BSE prions, have published the findings of their genome-wide association study in Lancet Neurology.
Past research has shown that genes influence susceptibility to prion diseases. They are also key in determining how long prion infection incubates before disease develops – which in humans can exceed 50 years. MRC Prion Unit scientists demonstrated some years ago that a common variation in the human prion protein gene (PRNP) plays a major role in susceptibility and indeed all individuals that have developed vCJD have the same PRNP genotype, encoding the amino acid methionine at position 129 on both their PRNP genes.
The study sought to identify other genes that might influence vCJD development. The researchers scrutinised DNA samples from people who had died from vCJD in the UK. They compared hundreds of thousands of genetic markers known as single nucleotide polymorphisms (SNP’s) to those carried by healthy blood donors and to samples held in the Wellcome Trust Case-Control Consortium collection.
With a focus on the SNPs most strongly associated with vCJD the authors then widened their search to the DNA of patients with other forms of prion disease. This included samples from people with sporadic CJD (arises spontaneously), those with disease acquired through the use of cadaver-derived growth hormone (hospital-acquired CJD) and the Fore people of Papua New Guinea including people who did not develop kuru (another type of prion disease) despite being exposed to infected sources.
The authors’ findings reinforce the strength of the influence of the SNP that determines variations in the PRNP gene. They also identified another SNP close to the PRNP gene that is associated, albeit less robustly, with vCJD. The variation was found close to a gene that determines the structure of a receptor for retinoic acid, a form of vitamin A made by the body that has previously been shown to regulate expression of the PRNP gene. The SNP is through to be significant in vCJD and hospital-acquired CJD but not when the condition arises spontaneously.
A second SNP was also identified in relation to vCJD in a region close to a gene called STMN2 that codes for a protein involved in brain cell growth. This SNP variation was also associated with kuru age of onset and resistance to kuru, and determined age of onset of sporadic CJD.
Although the authors acknowledge that the proximity of these SNPs to particular genes does not necessarily mean that the genes have a causal role in prion diseases, Professor John Collinge explains:
“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 SNP variation in the PRNP gene 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 ahead, is unknown.”
Original research paper: Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study is published in Lancet Neurology.
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