Evaluation of Candidate Genes Related to Neuronal Apoptosis in Late-Onset Alzheimer's Disease

Article type: Research Article

Authors: Moreno-Grau, Sonia^{a; b} | Barneda, Bruna^{b; c; d} | Carriba, Paulina^{b; c; d} | Marín, Juan^e | Sotolongo-Grau, Oscar^a | Hernández, Isabel^a | Rosende-Roca, Maitée^a | Mauleón, Ana^a | Vargas, Liliana^a | Espinosa, Ana^a | Alegret, Montserrat^a | Rodriguez, Octavio^a | Ortega, Gemma^a | Fernández, Maria Victoria^a | López-Arrieta, Jesús^f | Tárraga, Lluís^a | Boada, Mercè^a | Antúnez, Carmen^e | López, Joaquin^{b; c; d} | Ruiz, Agustín^{a; *} | Comella, Joan Xavier^{b; c; d}

Affiliations: [a] Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain | [b] Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Passeig Vall d'Hebron, Barcelona, Spain | [c] Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra (Edifici M), Bellaterra, Spain | [d] Centro de Investigación Biomádica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain | [e] Dementia Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain | [f] Memory Unit, University Hospital La Paz-Cantoblanco, Madrid, Spain

Correspondence: [*] Correspondence to: Agustín Ruiz, Fundació ACE. Barcelona Alzheimer Treatment & Research Center, C/Marquès de Sentmenat, 57, 08029 Barcelona, Spain. Tel.: +34 93 444 73 18; Fax: +34 93 410 17 01; E-mail: [email protected].

Abstract: The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780; OR = 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer's disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer's disease and human leukocyte antigen.

Keywords: Alzheimer's disease, apoptosis, death receptors, FASLG, genetics, genome-wide association study, meta-analysis, TNF

DOI: 10.3233/JAD-142721

Journal: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 621-629, 2015