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dc.contributor.authorA.W., Dodd
dc.contributor.authorRodriguez-Fontenla, Cristina
dc.contributor.authorM., Calaza
dc.contributor.authorA., Carr
dc.contributor.authorGómez-Reino Carnota, Juan Jesús 
dc.contributor.authorA., Tsezou
dc.contributor.authorL.N., Reynard
dc.contributor.authorGonzález Martínez-Pedrayo, Antonio 
dc.contributor.authorJ., Loughlin
dc.date.accessioned2017-06-07T07:22:40Z
dc.date.available2017-06-07T07:22:40Z
dc.date.issued2011
dc.identifier.issn1063-4584
dc.identifier.urihttp://hdl.handle.net/20.500.11940/5735
dc.description.abstractOBJECTIVE: The common single nucleotide polymorphism (SNP) rs143383 in the 5' untranslated region (5'UTR) of growth and differentiation factor 5 (GDF5) is strongly associated with osteoarthritis (OA) and influences GDF5 allelic expression in vitro and in the joint tissues of OA patients. This effect is modulated in cis by another common SNP, also located within the 5'UTR, whilst a common SNP in the 3'UTR influences allelic expression independent of rs143383. DNA variants can be common, rare or extremely rare/unique. To therefore enhance our understanding of the allelic architecture of this very important OA susceptibility locus we sequenced the gene for potentially functional and novel rare variants. METHOD: Using the Sanger method we sequenced GDF5 in 992 OA patients and 944 controls, with DNA changes identified by sequencing software. We encompassed the protein-coding region of the two GDF5 exons, both untranslated regions and approximately 100 bp of the proximal promoter of the gene. RESULTS: We detected 13 variants. Six were extremely rare with minor allele frequencies (MAFs) of </= 0.0006. One is in a predicted transcription factor binding site in the GDF5 promoter whilst two substitute conserved amino acids. The remaining seven variants were common and are previously known variants, with MAFs ranging from 0.025 to 0.39. There was a complete absence of variants with frequencies in-between the extremely rare (n=6) and the common (n=7). CONCLUSIONS: This is the first report of the deep sequencing of an OA susceptibility locus. The absence of rare variants informs us that within the regions of the gene that we have sequenced GDF5 does not harbour any novel variants that are able to contribute, at a population level, to the OA association signal mediated by rs143383 nor does it harbour, at a population level, any novel variants that can influence OA susceptibility independent of rs143383.
dc.language.isoeng
dc.subject.meshGreece
dc.subject.meshAged
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshSpain
dc.subject.meshAged, 80 and over
dc.subject.meshCase-Control Studies
dc.subject.meshCohort Studies
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshUnited Kingdom
dc.subject.meshHigh-Throughput Nucleotide Sequencing
dc.subject.meshOsteoarthritis
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshSequence Analysis, DNA
dc.subject.meshGrowth Differentiation Factor 5
dc.titleDeep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus
dc.typeArtigoes
dc.authorsophosA.W., Dodd
dc.authorsophosC., Rodriguez-Fontenla
dc.authorsophosM., Calaza
dc.authorsophosA., Carr
dc.authorsophosJ.J., Gomez-Reino
dc.authorsophosA., Tsezou
dc.authorsophosL.N., Reynard
dc.authorsophosA., Gonzalez
dc.authorsophosJ., Loughlin
dc.identifier.doi10.1016/j.joca.2011.01.014
dc.identifier.isi289823500015
dc.identifier.pmid21281725
dc.identifier.sophos10173
dc.issue.number4
dc.journal.titleOsteoarthritis And Cartilage
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de Santiago - Complexo Hospitalario Universitario de Santiago::Reumatoloxía
dc.organizationServizo Galego de Saúde::Estrutura de Xestión Integrada (EOXI)::EOXI de Santiago::IDIS.- Instituto de investigaciones sanitarias de Santiago
dc.page.initial430
dc.page.final434
dc.rights.accessRightsopenAccess
dc.typesophosArtículo Original
dc.volume.number19


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