Sporadic - but not variant - Creutzfeldt-Jakob disease is associated with polymorphisms upstream of PRNP Exon 1

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 s train as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic. The etiology of classical (sporadic) CJD, which ha s 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. Ho wever, a quantitative-trait-locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independ ent of its coding sequence or that of the nearby prion-like doppel gene (Pr nd). 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 t he PRNP 3' untranslated region. These have been characterized in 61 Centre d'Etude du Polymorphisme Humain (CEPH) families, demonstrating extensive li nkage disequilibrium around PRNP and the existence of 11 major European PRN P haplotypes. Haplotype frequencies estimated in healthy U.K. control indiv iduals were very similar to those deduced in the CEPH families. A common ha plotype was overrepresented in patients with sporadic CJD (sCJD). Through u se 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 addit ion to the strong susceptibility conferred by codon 129 (P=2 x 10(-8)). How ever, although our sample size was necessarily small, no association was fo und between these polymorphisms and vCJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms. In addition, there was no eviden ce of a PRNP founder effect in the first reported geographical cluster of v CJD.