A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease

We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD.The polymorphism coding for methionine (M) or valine (V) at codon 129 of the prion protein gene (PRNP M129V) plays a pivotal role in the susceptibility to Creutzfeldt-Jakob disease (CJD), influencing familial, transmitted and sporadic forms of the disease [1]. Moreover, the PRNP M129V genotype, in combination with the type of disease-associated prion protein (PrPsc) deposited in the brain, is a strong modulator of the clinical phenotype of sporadic [2-6] and genetic forms [7] and also susceptibility to variant CJD (vCJD). All vCJD cases studied to date have been methionine homozygous at this locus [8]. A recent genome wide association analysis performed pr