title: Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene.
abstract: Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Valcárcel-Ocete
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, United States of America.
authors.forename: Gorka
authors.initials: G
authors.lastname: Alkorta-Aranburu
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Iriondo
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Asier
authors.initials: A
authors.lastname: Fullaondo
authors.affiliation: Genetics Unit, Basurto University Hospital, Bilbao, Spain.
authors.forename: María
authors.initials: M
authors.lastname: García-Barcina
authors.affiliation: Neurology Service, Basurto University Hospital, Bilbao, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-García
authors.affiliation: Department of Neurology, Cruces University Hospital, Barakaldo, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lezcano-García
authors.affiliation: Department of Neurology, Cruces University Hospital, Barakaldo, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Losada-Domingo
authors.affiliation: Department of Neurology, Galdakao-Usansolo Hospital, Galdakao, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ruiz-Ojeda
authors.affiliation: Department of Neurology, Alava University Hospital, Txagorritxu, Vitoria-Gasteiz, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Álvarez de Arcaya
authors.affiliation: Department of Neurology, Alava University Hospital, Santiago Apóstol, Vitoria-Gasteiz, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Pérez-Ramos
authors.affiliation: Department of Neurology, Leiden University Medical Centre (LUMC), Leiden, The Netherlands.
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.affiliation: Danish Dementia Research Centre, Neurogenetics Clinic, University Hospital of Copenhagen- Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jørgen E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Huntington-Zentrum (NRW) Bochum, St. Josef-Hospital, Bochum, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Saft
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Aguirre
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D005091:Exons / Q000235:genetics; D005260:Female; D060045:Genes, Modifier / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics; D055815:Young Adult