Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study

Vaes, R B A; Rivadeneira, Fernando; Kerkhof, Jennifer; Hofman, Albert; Pols, Huibert A. P.; Uitterlinden, André G.; Meurs, Joyce B. J. van

doi:10.1136/ard.2008.099655

Cited by 65 publications

(42 citation statements)

References 39 publications

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“…The reduced activity of GDF5 may inhibit the process of early cartilage differentiation (Hatakeyama et al, 2004). Genetic variations in the GDF5 locus have been reported to be involved in the pathogenesis of rheumatoid arthritis and to influence human height, hip axis length and fracture risk in the elderly (Rouault et al, 2010;Vaes et al, 2009). Furthermore, association of variant T allele with other musculoskeletal phenotypes, including variation in Achilles tendon pathology, fracture risk and congenital dysplasia of the hip, has also been reported (Posthumus et al, 2010;Sanna et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Mishra¹,

Sanghi²,

Sharma³

et al. 2013

American Journal of Biochemistry and Biotechnology

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The present study investigated to identify the association of polymorphism in GDF-5 gene with osteoarthritis in North Indian population. In a case-control study, 300 cases with knee osteoarthritis and an equal number of age and gender matched healthy controls were included. Cases were diagnosed using the ACR Guidelines of Knee Osteoarthritis (KOA). Clinical symptoms were assessed with the knee specific WOMAC index and VAS for knee pain. The severity of disease was determined by radiological KL grades (Kellgren Lawren). The variant genotype of GDF-5 was found to be present at significantly higher frequency in cases than in controls, resulting in about 1.79 fold increase in risk to OA. Genotype distributions of the GDF-5 also showed significant association of variant allele with clinical score of OA patients. An association between the+104T/C GDF5 polymorphism with knee OA and clinical symptom of OA in Indian population further demonstrate a strong genetic influence of this SNP in KOA.

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Section: Discussionmentioning

confidence: 99%

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Mishra¹,

Sanghi²,

Sharma³

et al. 2013

American Journal of Biochemistry and Biotechnology

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“…The same has been observed in the BMP-signaling pathway (another key developmental pathway). Mutations in the GDF5 gene result in severe chondrodysplasia and skeletal malformations (23), and a milder variant that influences GDF5 expression levels, results in a slightly elevated risk for knee OA later in life (2,24).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Betancourt

Cailotto

Kerkhof

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

161

124

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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.

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“…These findings represent the first highly significant evidence for an OA susceptibility gene that affects diverse ethnic groups. 33 Vaes et al 34 studied the association between rs143383 and radiographic OA in hands, knees and hips, together with height, bone size parameters and fracture risk, in a population-based cohort that consisted of a total of 6365 Caucasians. The authors found the association of GDF5 with knee OA, height, bone size and fracture risk in women; however, no associations with hip OA or BMD (Bone Mineral Density) were detected, and no associations were observed in men.…”

Section: Gdf5mentioning

confidence: 99%

Recent advances in association studies of osteoarthritis susceptibility genes

Dai

Ikegawa

2010

J Hum Genet

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Osteoarthritis (OA) is a polygenic disease with a definite genetic component, and recent advances in genome research have enabled us to investigate OA susceptibility genes. Several research groups, including ours, have reported the identification of OA susceptibility genes, mainly using candidate gene association studies. However, we are now entering the era of genome-wide association studies (GWAS). Here, we review recent progress in the study of susceptibility genes for OA, focusing in particular on GWAS and large-scale replication studies.

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Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study

Cited by 65 publications

References 39 publications

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Association of Polymorphism in Growth and Differentiation Factor 5 Gene With Osteoarthritis Knee

Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Recent advances in association studies of osteoarthritis susceptibility genes

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