Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

Abstract

Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.

Codon 129 polymorphism of prion protein gene in is not a risk factor for Alzheimer's disease

“…In opposition to some studies, which showed interaction between ApoE and PRNP, our data did not reveal differences in codon 129 genotypes according to the ApoE status [13][14][15][16][17][18][19][20][21] . This study of PRNP in patients with AD in the Brazilian population has, as its main limitation, the small sample.…”

“…A few studies have shown that this polymorphism may be a risk factor for AD [12][13][14] . Others, however, failed to confirm such association 5,8,[15][16][17][18][19][20][21] . A meta-analysis concluded that codon 129 homozygosity of PRNP is a risk factor for AD in a Caucasian population 19 .…”

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

“…Homozygosis at polymorphic codon 129 in the PRNP gene was shown to be strongly associated with sCJD (OR = 4.87, 95% CIs = 3.21-7.39, p = 8.49 × 10 -14 ) in agreement with a previous report for this population. 22 By sequencing analysis of the complete coding regions of the CALHM genes, we found eight single nucleotide polymorphisms (SNP) in CALHM1, 2 SNP in CALHM3, and none in CALHM2 ( Table 1). All of these SNPs were already identified in The Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation (www.ncbi.nlm.nih.gov/projects/SNP/index.html).…”

“…14 Several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms. [15][16][17][18][19][20][21][22][23] In this paper, we investigated the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a Caucasian population of Spanish origin, and explored the potential association of these genes with sporadic Creutzfeldt-Jakob disease (sCJD).…”

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.…”