Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt–Jakob disease

Abstract

The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05 -8.09; P ¼ 0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.

Polymorphisms at codons 56 and 174 of the prion-like protein gene (PRND) are not associated with sporadic Creutzfeldt-Jakob disease

“…In the French population, the distributions of PRND genotype and allele frequencies in sporadic CJD patients did not significantly differ from those of controls. The genotype frequency of the T174 M PRND polymorphism in the normal Korean population differs significantly from that previously reported for the British (v 2 = 17.3604, P =0.0002), French (v 2 =20.1895, P<0.0001), German (v 2 =6.072, P =0.048), and Dutch populations (v 2 =9.947, P =0.007) (Mead et al 2000;Peoc'h et al 2000;Schroder et al 2001;Croes et al 2004). These results suggest that there is a difference in the genotype frequency of this polymorphism between Europeans and Asians.…”

“…The major PRND polymorphism in these studies was substitution from threonine (Thr) to methionine (Met) at codon 174 (T174 M). This polymorphism in British, French, and Dutch populations was not associated with sporadic CJD or variant CJD (Peoc'h et al 2000;Mead et al 2000;Croes et al 2004). In the Spanish population, the polymorphism was not associated with sporadic Alzheimer's disease (AD) (Infante et al 2002).…”

“…The genotype frequencies of PRNP polymorphisms in Asian populations, including Koreans, are considerably different from those in Europeans Jeong et al 2004). Although the polymorphisms of the PRND have been studied in several European countries (Mead et al 2000;Peoc'h et al 2000;Schroder et al 2001;Infante et al 2002;Croes et al 2004;Golanska et al 2004), there have been no reports of PRND from other parts of the world.…”

“…The PrP-like protein gene (PRND) is located 27 kb downstream of the human PRNP. Its open reading frame (ORF) has been shown to contain polymorphic codons, but studies on a correlation between the PRND polymorphisms and neurodegenerative disorders in various populations have shown contradictory results (Peoc'h et al 2000;Mead et al 2000;Schroder et al 2001;Infante et al 2002;Croes et al 2004;Golanska et al 2004). Therefore, the role of the PRND in CJD and other diseases still remains unexplained.…”

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

“…It is especially interesting that our results are not concordant with an earlier Dutch study performed on 46 sCJD and 248 controls by Croes et al who found no association between SNP 1368 and sCJD. 17 The differences between both studies may be due to the relatively small sample sizes. Therefore, further studies on larger population should be undertaken to avoid random fluctuations.…”