Genetic susceptibility to vCJD and other prion diseases

13 January 2009

Prion diseases are progressive neurodenegerative conditions that can be transmitted in a manner akin to infectious diseases, although the ‘infectious agent’ is not a living organism but rather a prion protein (PrP) that stimulates the autocatalytic misfolding of other PrPs in the host. Such diseases can affect both animals and humans, for example scrapie in sheep, and kuru in humans. Perhaps best known is bovine spongiform encephalopathy (BSE) in cattle, and epidemic of which in the UK and other countries exposed much of the human population to abnormal PrPs via the consumption of animal products. Subsequently, a new form of prion disease, variant Creutzfeldt-Jakob disease (vCJD), was identified in young adults and found to be caused by BSE-like prions.

It is not known how many millions of individuals were exposed to the BSE prions, but a very low number of cases of vCJD have been diagnosed to date, less than two hundred. However, since the incubation period for the disease can be extremely long, it is not known how many more cases may yet appear, and there is significant interest in the genetic basis of susceptibility and resistance to infection. The best known genetic variant involved is a common single nucleotide polymorphism (SNP) in the PRNP gene that encodes the human form of PrP. All patients with clinical vCJD who have been genotyped are homozygous for methionine at position 129 in the PRNP gene; however, since around a third of the UK population share this genotype, there are presumed to be other genetic factors involved in susceptibility.

A paper in the journal Lancet Neurology reports the findings from a genome-wide association (GWA) study that compared samples from 119 vCJD patients with several hundred controls from the Wellcome Trust Case-Control Consortium (see previous news). The researchers also compared the strongest SNP associations with several hundred samples from patients with other forms of prion disease, including iatrogenic CJD (iCJD), sporadic CJD (sCJD), and kuru [Mead S et al. (2009) Lancet Neurol. 8(1):57-66]. Several variants within the PRNP gene locus were found to be strongly associated with prion disease risk; the previously identified codon 129 showed the greatest contribution to disease risk, but a new SNP from the region was also found to be involved. Another variant upstream of the RARB (retinoic acid receptor beta) gene showed weaker association with vCJD and also with iCJD. Yet another variant in a region upstream of the STMN2 gene was associated with prion disease more generally, including resistance to vCJD and kuru, and age of onset of sCJD. The STMN2 gene encodes a protein called SCG10, which regulates microtubule stability in neuronal cells.

The researchers conclude that their study confirms the primary importance of the PRNP codon 129 SNP as the outstanding genetic risk factor in human prion disease. The new associations identified were less robust, but still significant taking into account the inherent limitations of a study with so few case samples. They therefore propose that the genes closest to the three candidate SNPs (PRNP, STMN2 and RARB) warrant further investigation as potentially being involved in prion pathology, and postulate that susceptibility conferred by these variants may also contribute to vCJD cases

Comment: This research presents the first GWA to look for associations with susceptibility to prion disease in humans, although the small number of cases of vCJD at the present time has limited the strength and reliability of the findings. However, the results may nevertheless lead to further useful investigations. Better understanding of the genetic factors involved in susceptibility to BSE infection in humans may not only allow estimation of the probable scale of public health problem likely to emerge in coming years as a result of sub-clinical vCJD infections becoming symptomatic, but also contribute towards elucidation of the mechanisms by which the disease becomes established and progresses – and hence towards efforts to devise a therapy.

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