title: Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.
abstract: 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 osteoarthritis (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 chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen 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 homeostasis. DOT1L may represent a therapeutic target for OA.
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Castaño Betancourt
authors.forename: Frederic
authors.initials: F
authors.lastname: Cailotto
authors.forename: Hanneke J
authors.initials: HJ
authors.lastname: Kerkhof
authors.forename: Frederique M F
authors.initials: FM
authors.lastname: Cornelis
authors.forename: Sally A
authors.initials: SA
authors.lastname: Doherty
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Hart
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Frank P
authors.initials: FP
authors.lastname: Luyten
authors.forename: Rose A
authors.initials: RA
authors.lastname: Maciewicz
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Sarah
authors.initials: S
authors.lastname: Metrustry
authors.forename: Kenneth
authors.initials: K
authors.lastname: Muir
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: Maggie
authors.initials: M
authors.lastname: Wheeler
authors.forename: Weiya
authors.initials: W
authors.lastname: Zhang
authors.forename: Nigel
authors.initials: N
authors.lastname: Arden
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.forename: Rik J U
authors.initials: RJ
authors.lastname: Lories
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
mesh_terms: D000367:Age Factors; D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology / Q000502:physiology; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D020219:Chondrogenesis / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D015207:Osteoarthritis, Hip / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C473477:DOT1L protein, human; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase