Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis - Université de Lorraine Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2012

Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis

J. Hart
  • Fonction : Auteur
A. Hofman
  • Fonction : Auteur
F. Luyten
  • Fonction : Auteur
A. Maciewicz
  • Fonction : Auteur
M. Mangino
  • Fonction : Auteur
S. Metrustry
  • Fonction : Auteur
K. Muir
  • Fonction : Auteur
J. Peters
  • Fonction : Auteur
F. Rivadeneira
  • Fonction : Auteur
M. Wheeler
  • Fonction : Auteur
W. Zhang
N. Arden
  • Fonction : Auteur
T. Spector
  • Fonction : Auteur
A. Uitterlinden
  • Fonction : Auteur
M. Doherty
  • Fonction : Auteur
A. Valdes
  • Fonction : Auteur
J. Meurs
  • Fonction : Auteur

Résumé

Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in os-teoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10 −10). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10 −11. The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10 −4). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondro-genesis in vitro. Dot1l knockdown reduces proteoglycan and colla-gen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage ho-meostasis. DOT1L may represent a therapeutic target for OA.

Dates et versions

hal-01704478 , version 1 (15-02-2018)

Identifiants

Citer

M. Castano Betancourt, F. Cailotto, H. Kerkhof, F. Cornelis, A. Doherty, et al.. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (21), pp.8218-8223. ⟨10.1073/pnas.1119899109⟩. ⟨hal-01704478⟩
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