Significant association of a M129V independent polymorphism in the 5\prime UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study

Background: A single nucleotide polymorphism (SNP) in the coding
region of the prion protein gene (PRNP) at codon 129 has been
repeatedly shown to be an associated factor to sporadic
Creutzfeldt-Jakob disease (sCJD), but additional major predisposing
DNA variants for sCJD are still unknown. Several previous studies
focused on the characterisation of polymorphisms in PRNP and the
prion-like doppel gene (PRND), generating contradictory results on
relatively small sample sets. Thus, extensive studies are required
for validation of the polymorphisms in PRNP and PRND.Methods: We
evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593
German sCJD patients and 748 German healthy controls. Genotyping
was performed using MALDI-TOF mass spectrometry.Results: In
addition to PRNP 129, we detected a significant association between
sCJD and allele frequencies of six further PRNP SNPs. No
significant association of PRND T174M with sCJD was shown. We
observed strong linkage disequilibrium within eight adjacent PRNP
SNPs, including PRNP 129. However, the association of sCJD with
PRNP 1368 and PRNP 34296 appeared to be independent on the genotype
of PRNP 129. We additionally identified the most common haplotypes
of PRNP to be over-represented or under-represented in our cohort
of patients with sCJD.Conclusion: Our study evaluated previous
findings of the association of SNPs in the PRNP and PRND genes in
the largest cohorts for association study in sCJD to date, and
extends previous findings by defining for the first time the
haplotypes associated with sCJD in a large population of the German
CJD surveillance study.