Association of the PRNP regulatory region polymorphisms with the occurrence of sporadic Creutzfeldt-Jakob disease

The prion protein (PrP) plays a central role in the pathogenesis of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies (TSEs). Mutations in the coding region of the prion protein (PRNP) gene are linked to inherited forms of TSEs whereas aetiology of sporadic CJD (sCJD) remains obscure. It remains unclear whether the primary DNA sequence at non-coding region of PRNP gene influences development of the sCJD. Several recent reports showed non-coding region polymorphisms associated with sCJD but other could not support those findings. To test the hypothesis that there is a relationship between SNPs polymorphisms of PRNP non-coding regions and susceptibility to sCJD, we compared the primary structure of the regulatory region of the PRNP in 45 Dutch sCJD patients and in 135 healthy controls. We found a significant linkage of +310 C allele (OR 0.27, 95% CI 0.09-0.77; P = 0.009) and +310G/C genotype (OR 0.33, 95% CI 0.11-0.98; P = 0.048) with sCJD. No differences in frequencies of genotypes and allele of -101C/G and +258 G/A polymorphisms were found between sCJD patients and controls. We found two haplotypes protecting from sCJD (C-V in block 1 and G-C in block 2) and one susceptible haplotype for sCJD (G-G in block 2). Our findings support the hypothesis that polymorphism in the regulatory region of the PRNP gene may play an important role in the pathogenesis of sCJD.