Sporadic—but Not Variant—Creutzfeldt-Jakob Disease Is Associated with Polymorphisms Upstream of PRNP Exon 1

Abstract

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.

Association between thePRNP1368 polymorphism and the occurrence of sporadic Creutzfeldt-Jakob disease

“…PRNP T1368C polymorphism was found to be associated with sCJD in UK (p = 0.003) and among 129Met/Met homozygotes in German study (p = 0.049). 12,15 However, no differences in genotype and allele frequencies between sCJD patients and controls were found in Korean populations. 16 This discrepancy may be related to the differencies in the ethnic background of the investigated populations or to different demographic structure.…”

“…These results in part confirm the previous study undertaken in British population by Mead et al who found decreased frequency of TC-AG genotype in sCJD compared with controls (5.4 vs. 22.3%). 12 Haplotype-based association analysis revealed that the distribution of C-G haplotype was significantly different between sCJD patients and controls. Our results are in contrast to the results reported by Jeong et al who showed no association of C-G containing haplotype (ht6) with CJD in Korean population.…”

“…1). Fifty-six polymorphic sites located within 25 kb region flanking PRNP gene were found by Mead et al 12 An association between -101, +310, as well as +385 SNPs and sCJD was reported by McCormack and colleagues. 13 A single nucleotide polymorphism 1368 upstream of PRNP exon 1 has been shown to be associated with sporadic CJD in British population.…”

“…However, no difference in age at onset of disease or in disease duration between the three genotypes at SNP 1368 was noticed. 12 The purpose of the current study was to investigate the allele, genotype, and haplotype frequencies of 1368 PRNP polymorphic position and codon 129 polymorphism among the Dutch sCJD patients and controls to determine if SNP 1368 modulates susceptibility to sCJD in the Dutch population.…”

Analyses of the mitochondrial mutations in the Chinese patients with sporadic Creutzfeldt–Jakob disease

“…4 Codons 127 and 219 of PRNP also harbour amino-acid (AA) polymorphisms that confer resistance to Kuru 5 or sCJD. 6 Recently, other candidate genes have been identified as risk factors for sCJD, such as an SNP upstream of PRNP exon 1 (SNP 1368), 7 c.592C4T(p.T174M) in prion-like doppel gene (PRND), 8 APOE e4 allele, 9 polymorphisms at CALHM1 gene, 10 and BACE1 gene. 11 Identification of the potential genetic risk factors for sCJD seems to be one of the important pathways for understanding of the pathogenic mechanisms and human susceptibility to the disease.…”