title: The impact of single-nucleotide polymorphisms (SNPs) in OGG1 and XPC on the age at onset of Huntington disease.
abstract: The age at onset of Huntington disease (HD) shows a strong, negative correlation with the number of CAG repeats within the huntingtin (HTT) gene. However, this does not account for all the inter-individual variability seen among patients. In order to assess whether single-nucleotide polymorphisms (SNPs) in the OGG1 and XPC genes, both implicated in responses to oxidative stress, are associated with the age of onset of HD, 9 SNPs have been genotyped in 299 individuals with HD and 582 controls. After correction for multiple testing, two OGG1/XPC haplotypes were found to be associated with younger age at onset independently of the number of CAG repeats within the HTT gene. Both haplotypes contain XPC coding variants that would be expected to impact on protein function and/or variants in the 3'UTR that could result in altered protein levels via allele-specific mIR binding. One haplotype also contains the OGG1-326Cys (rs1052133) allele that has been associated with a lower 8-oxoG repair activity and is particularly sensitive to the cellular redox status. These results highlight the potential role of oxidative stress in determining the age at onset of HD.
authors.affiliation: Institut Curie, Centre de Recherche, 91405 Orsay, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Berger
authors.forename: Laurence
authors.initials: L
authors.lastname: Vaslin
authors.forename: Lisa
authors.initials: L
authors.lastname: Belin
authors.forename: Bernard
authors.initials: B
authors.lastname: Asselain
authors.forename: Sylvie
authors.initials: S
authors.lastname: Forlani
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Janet
authors.initials: J
authors.lastname: Hall
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics* / Q000502:physiology; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C086984:XPC protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: Age at onset; Huntington disease; OGG1; XPC