Sporadic--but not variant--Creutzfeldt-Jakob disease is associated with polymorphisms upstream of PRNP exon 1
| Autor: | Simon Mead, John Collinge, Sukhvir P. Mahal, Elizabeth M. C. Fisher, Martin Farrall, Tracy Campbell, John Beck |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Adult
Amyloid Linkage disequilibrium Prions Bovine spongiform encephalopathy animal diseases Locus (genetics) Biology Polymorphism Single Nucleotide Creutzfeldt-Jakob Syndrome Linkage Disequilibrium Prion Proteins PRNP 03 medical and health sciences Exon 0302 clinical medicine Gene Frequency mental disorders medicine Genetics Humans Coding region Genetic Predisposition to Disease Genetics(clinical) Age of Onset Protein Precursors Promoter Regions Genetic 3' Untranslated Regions Genetics (clinical) Aged 030304 developmental biology 0303 health sciences Haplotype Articles Exons Middle Aged medicine.disease Virology Founder Effect United Kingdom 3. Good health nervous system diseases Haplotypes Case-Control Studies 030217 neurology & neurosurgery Founder effect |
| Popis: | Human prion diseases have inherited, sporadic, and acquired etiologies. The appearance of the novel acquired prion disease, variant Creutzfeldt-Jakob disease (vCJD), and the demonstration that it is caused by the same prion strain as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic. The etiology of classical (sporadic) CJD, which has a worldwide incidence, remains obscure. A common human prion-protein-gene (PRNP) polymorphism (encoding either methionine or valine at codon 129) is a strong susceptibility factor for sporadic and acquired prion disease. However, a quantitative-trait-locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independent of its coding sequence or that of the nearby prion-like doppel gene (Prnd). We have analyzed the PRNP locus for such tightly linked susceptibility factors. Fifty-six polymorphic sites have been identified within 25 kb of the PRNP open reading frame, including sites within the PRNP promoter and the PRNP 3' untranslated region. These have been characterized in 61 Centre d'Etude du Polymorphisme Humain (CEPH) families, demonstrating extensive linkage disequilibrium around PRNP and the existence of 11 major European PRNP haplotypes. Haplotype frequencies estimated in healthy U.K. control individuals were very similar to those deduced in the CEPH families. A common haplotype was overrepresented in patients with sporadic CJD (sCJD). Through use of a log-linear modeling approach to simultaneously model Hardy-Weinberg and linkage disequilibria, a significant independent association was found between sCJD and a polymorphism upstream of PRNP exon 1 (P=.005), in addition to the strong susceptibility conferred by codon 129 (P=2x10(-8)). However, although our sample size was necessarily small, no association was found between these polymorphisms and vCJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms. In addition, there was no evidence of a PRNP founder effect in the first reported geographical cluster of vCJD. |
| Databáze: | OpenAIRE |
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