title: Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease.
abstract: Sporadic Alzheimer's disease (AD) appears to be the consequence of the interaction between combinations of genes and environmental factors (for example virus infections). To test this hypothesis, we are examining human genes relevant to herpes simplex virus type 1 (HSV-1) infection via genetic association studies in AD case-control samples. Recently, we found that a variant in TAP2, a major target used by HSV-1 to evade immune surveillance, is associated with AD. The present work analyses another gene involved in the host cell response to HSV-1, EIF2AK2 (eukaryotic translation initiation factor 2-alpha kinase 2; coding for PKR); PKR mediates the virus-induced shut-off of translation, and levels of activated PKR are high in the brains of AD patients. An EIF2AK2 SNP (rs2254958) located in the 5'-UTR region within an exonic splicing enhancer was found to be associated with AD. More specifically: the C allele was more commonly found in the patients and, compared to non-CC genotypes, the CC homozygotes showed earlier (around 3.3 years) onset of AD, especially in the absence of the APOE4 allele. These results further support the hypothesis that variants of human genes participating in HSV-1 infection modulate the susceptibility and/or clinical manifestations of AD.
authors.affiliation: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (C.S.I.C.-U.A.M.), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Bullido
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-García
authors.forename: Raquel
authors.initials: R
authors.lastname: Tenorio
authors.forename: Isabel
authors.initials: I
authors.lastname: Sastre
authors.forename: David G
authors.initials: DG
authors.lastname: Muñoz
authors.forename: Ana
authors.initials: A
authors.lastname: Frank
authors.forename: Fernando
authors.initials: F
authors.lastname: Valdivieso
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D015995:Prevalence; D012330:RNA, Double-Stranded / Q000235:genetics*; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013030:Spain / Q000453:epidemiology; D019892:eIF-2 Kinase / Q000235:genetics*
chemical_list: D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase