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Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Castaño-Betancourt, Martha C ; Evans, Dan S ; Ramos, Yolande F M ; Boer, Cindy G ; Metrustry, Sarah ; Liu, Youfang ; den Hollander, Wouter ; van Rooij, Jeroen ; Kraus, Virginia B ; Yau, Michelle S ; Mitchell, Braxton D ; Muir, Kenneth ; Hofman, Albert ; Doherty, Michael ; Doherty, Sally ; Zhang, Weiya ; Kraaij, Robert ; Rivadeneira, Fernando ; Barrett-Connor, Elizabeth ; Maciewicz, Rose A ; Arden, Nigel ; Nelissen, Rob G H H ; Kloppenburg, Margreet ; Jordan, Joanne M ; Nevitt, Michael C ; Slagboom, Eline P ; Hart, Deborah J ; Lafeber, Floris ; Styrkarsdottir, Unnur ; Zeggini, Eleftheria ; Evangelou, Evangelos ; Spector, Tim D ; Uitterlinden, Andre G ; Lane, Nancy E ; Meulenbelt, Ingrid ; Valdes, Ana M ; van Meurs, Joyce B J Barsh, Gregory S.

PLoS genetics, 2016-10, Vol.12 (10), p.e1006260-e1006260 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis
Autor: Castaño-Betancourt, Martha C ; Evans, Dan S ; Ramos, Yolande F M ; Boer, Cindy G ; Metrustry, Sarah ; Liu, Youfang ; den Hollander, Wouter ; van Rooij, Jeroen ; Kraus, Virginia B ; Yau, Michelle S ; Mitchell, Braxton D ; Muir, Kenneth ; Hofman, Albert ; Doherty, Michael ; Doherty, Sally ; Zhang, Weiya ; Kraaij, Robert ; Rivadeneira, Fernando ; Barrett-Connor, Elizabeth ; Maciewicz, Rose A ; Arden, Nigel ; Nelissen, Rob G H H ; Kloppenburg, Margreet ; Jordan, Joanne M ; Nevitt, Michael C ; Slagboom, Eline P ; Hart, Deborah J ; Lafeber, Floris ; Styrkarsdottir, Unnur ; Zeggini, Eleftheria ; Evangelou, Evangelos ; Spector, Tim D ; Uitterlinden, Andre G ; Lane, Nancy E ; Meulenbelt, Ingrid ; Valdes, Ana M ; van Meurs, Joyce B J
Barsh, Gregory S.
Assuntos: Aged ; Aged, 80 and over ; Arthritis ; Bioinformatics ; Biology and Life Sciences ; Cartilage ; Cartilage - pathology ; Class Ia Phosphatidylinositol 3-Kinase ; Colleges & universities ; Epidemiology ; Female ; Gene expression ; Gene loci ; Genetic aspects ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genomes ; Hip Joint - physiopathology ; Humans ; Internal medicine ; Male ; Medical statistics ; Medicine ; Medicine and Health Sciences ; Middle Aged ; Osteoarthritis ; Osteoarthritis, Hip - genetics ; Osteoarthritis, Hip - pathology ; Phosphatidylinositol 3-Kinases - genetics ; Physiological aspects ; Polymorphism, Single Nucleotide ; Public health ; Receptor, Fibroblast Growth Factor, Type 3 - genetics ; Regulatory Sequences, Nucleic Acid - genetics ; Rheumatology ; Transforming Growth Factor alpha - genetics ; Transforming growth factors ; Trehalase - genetics
É parte de: PLoS genetics, 2016-10, Vol.12 (10), p.e1006260-e1006260
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
Conceptualization: MCCB JBJvM. Data curation: MCCB CGB JBJvM. Formal analysis: MCCB DSE YFMR CGB SM YL JvR MSY AMV. Funding acquisition: JBJvM. Investigation: MCCB DSE YFMR CGB YL WdH JvR VBK MSY BDM KM AH MD SD WZ RK FR EBC RAM NA RGHHN MK JMJ MCN EPS DJH FL US EZ EE TDS AGU NEL IM AMV JBJvM. Methodology: MCCB CGB IM JBJvM. Project administration: JBJvM. Supervision: JBJvM AMV NEL IM AGU. Validation: DSE YFMR SM YL WdH VBK MSY BDM KM MD SD WZ EBC RAM NA RGHHN MK JMJ MCN EPS DJH FL. Visualization: MCCB CGB JBJvM. Writing – original draft: MCCB CGB JBJvM. Writing – review & editing: MCCB DSE YFMR CGB SM YL WdH JvR VBK MSY BDM KM AH MD SD WZ RK FR EBC RAM NA RGHHN MK JMJ MCN EPS DJH FL US EZ EE TDS AGU NEL IM AMV JBJvM.
These authors jointly supervised this work.
The collection of GOAL samples was funded by Astra Zeneca UK. Dr R. Maciewicz has ownership of stocks or shares in AstraZeneca and has paid employment in AstraZeneca. Dr J. Jordan was funded for genotyping by Algynomics, Inc. and had, but no longer has, stock options in Algynomics. Dr. U. Styrkarsdottir is an employee of deCODE, a biotechnology company that provides genetic testing services. The set-up of the GARP study was partially funded by Pfzer. The GoGo study was funded by GlaxoSmithKline. The rest of the authors have declared that they have no competing interests.
Descrição: Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.
Editor: United States: Public Library of Science
Idioma: Inglês

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Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

United States: Public Library of Science

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