Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases
Por:
Calero, O, Bullido, MJ, Clarimon, J, Frank-Garcia, A, Martinez-Martin, P, Lleo, A, Rey, MJ, Rabano, A, Blesa, R, Gomez-Isla, T, Valdivieso, F, de Pedro-Cuesta, J, Ferrer, I, Calero, M
Publicada:
20 jul 2011
Resumen:
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 epsilon 4 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 epsilon 4 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.
Filiaciones:
Calero, O:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Salud Carlos III CNM ISCIII, Unidad Encefalopatias Espongiformes, Ctr Nacl Microbiol, Madrid, Spain
Bullido, MJ:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid, Spain
Inst Sanit Res Hosp la Paz IdIPaz, Madrid, Spain
Clarimon, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Frank-Garcia, A:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Sanit Res Hosp la Paz IdIPaz, Madrid, Spain
Hosp Univ La Paz UAM, Neurol Serv, Madrid, Spain
Martinez-Martin, P:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Alzheimer Ctr Reina Sofia Fdn, Alzheimer Dis Res Unit, CIEN Fdn, Carlos III Inst Hlth, Madrid, Spain
Lleo, A:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Rey, MJ:
Banco Tejidos Neurol Univ Barcelona Hosp Clin, Barcelona, Spain
Rabano, A:
Alzheimer Ctr Reina Sofia Fdn, Banco Tejidos Fdn CIEN, CIEN Fdn, Carlos III Inst Hlth, Madrid, Spain
Blesa, R:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Gomez-Isla, T:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, E-08193 Barcelona, Spain
Valdivieso, F:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid, Spain
Inst Sanit Res Hosp la Paz IdIPaz, Madrid, Spain
de Pedro-Cuesta, J:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Salud Carlos III CNM ISCIII, Area Epidemiol Aplicada, Ctr Nacl Epidemiol, Madrid, Spain
Ferrer, I:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Univ Barcelona, Fac Med, Inst Neuropathol INP, IDIBELL Hosp Univ Bellvitge, Barcelona 08907, Spain
Calero, M:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
Inst Salud Carlos III CNM ISCIII, Unidad Encefalopatias Espongiformes, Ctr Nacl Microbiol, Madrid, Spain
Gold, Green Published
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