Large‐scale analysis of association between <i>GDF5</i> and <i>FRZB</i> variants and osteoarthritis of the hip, knee, and hand

Εvangelou, Εvangelos; Chapman, Kay; Meulenbelt, Ingrid; Karassa, Fotini B.; Loughlin, John; Carr, Andrew; Doherty, Michael; Doherty, Sally; Gómez-Reino, Juan J.; González, Antonio; Halldórsson, Bjarni V.; Hauksson, Valdimar B.; Hofman, Albert; Hart, Deborah; Ikegawa, Shiro; Ingvarsson, Þorvaldur; Jiang, Qing; Jónsdóttir, Ingileif; Jónsson, Helgi; Kerkhof, Hanneke J. M.; Kloppenburg, Margreet; Lane, Nancy E.; Li, Jia; Lories, Rik; Meurs, Joyce B. J. van; Näkki, Annu; Nevitt, Michael C.; Rodriguez‐Lopez, Julio A.; Shi, Dongquan; Slagboom, P. Eline; Stefánsson, Kāri; Tsezou, Aspasia; Wallis, Gillian A.; Watson, Christopher M.; Spector, Tim D.; Uitterlinden, André G.; Valdes, Ana M.; Ioannidis, John P. A.

doi:10.1002/art.24524

Cited by 188 publications

(156 citation statements)

References 48 publications

(68 reference statements)

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“…What is interesting in this respect is the fact that genes that are mainly active in skeletal development, such as FRZB and GDF5, are identified as OA susceptibility genes (5,6). These genes are involved in the orchestration of growth plate chondrocytes that results in formation of cartilage and eventually bone during endochondral ossification (7).…”

mentioning

confidence: 99%

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

Waarsing

Kloppenburg

Slagboom

et al. 2011

Arthritis & Rheumatism

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Objective. The identified osteoarthritis (OA) susceptibility genes are mainly active in skeletal development and could thus affect joint geometry. Because nonoptimal joint geometry is a risk factor for the development of OA, we investigated if and how the path that leads from nonoptimal joint geometry to OA of the hip is influenced by these genes.Methods. The shape of the hips of subjects in the Genetics, Osteoarthritis and Progression Study, consisting of sibling pairs with symptomatic OA at multiple joint locations, was quantified by applying a statistical shape model to radiographs. Shape aspects (modes) were correlated to OA characteristics. We then tested for the association of shape modes with OA susceptibility single-nucleotide polymorphisms (SNPs) of GDF5, FRZB, and DIO2.Results. Four of 23 shape modes (mode 1, mode 17, mode 18, and mode 21) were strongly associated with OA characteristics. We observed a significant interaction between carrier status of DIO2 rs12885300 and hip OA characteristics for mode 1 (P ‫؍‬ 0.005). This indicates that this specific aspect of hip shape correlates with OA characteristics only in carriers of the susceptibility allele.Conclusion. Our results suggest that it is more likely that the rs12885300 SNP of DIO2 increases the vulnerability of cartilage to nonoptimal bone shapes rather than directly influencing the formation of these shapes.The genetic predisposition for osteoarthritis (OA) (1) may reflect the result of multiple interacting genes with small effects (2). The identification of such genes should be considered essential to obtain a better understanding of OA and the underlying biologic events preceding its onset (3). One path leading to OA in which genes might play a role starts with the causal effect of hip morphology on the development of OA and may explain part of the heritability of hip OA. The life-long biomechanical stress caused by a nonoptimal shape of the bones in the joint leads to recurrent damage of cartilage, which eventually triggers the onset of OA (4).What is interesting in this respect is the fact that genes that are mainly active in skeletal development, such as FRZB and GDF5, are identified as OA susceptibility genes (5,6). These genes are involved in the orchestration of growth plate chondrocytes that results in formation of cartilage and eventually bone during endochondral ossification (7). A recent large-scale metaanalysis (6) did not provide evidence for the relatively rare FRZB OA risk alleles, indicating that these variants do not confer susceptibility to common OA. It is, however, generally known that meta-analyses have little power to detect relatively rare variants with a modest effect that confer risk in a specific subset of OA cases. Furthermore, functional studies in Frzb-knockout mice showed increased cortical bone thickness and density, resulting in stiffer bones upon mechanical loading, which may increase OA susceptibility and stresses developmental aspects (8).

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confidence: 99%

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

Waarsing

Kloppenburg

Slagboom

et al. 2011

Arthritis & Rheumatism

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“…35 The associations reported in the original paper were marginal. 36 When multiple testing is considered, only a negative association has been reported in replication studies, even in the European Caucasians.…”

Section: Gdf5mentioning

confidence: 97%

“…In a large-scale meta-analysis using 3500-5800 cases and 5200-10 800 controls, collected by 14 research groups in the Western Europe and East Asia, Evangelou et al 35 examined the association of OA with three SNPs in previously reported genes, rs143383 in GDF5 together with rs7775 and rs288326 in FRZB. A significant association for rs143383 with knee OA without significant betweenstudy heterogeneity, were identified (P¼9.4Â10 À7 ).…”

Section: Gdf5mentioning

confidence: 99%

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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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“…31,32 Polymorphisms in FRZB have been associated with hip osteoarthritis although the effect is not consistent over different groups. 33,34 Frzb − / − mice show increased susceptibility to cartilage damage in induced models of osteoarthritis. 35 We could associate this observation with increased Wnt signaling and destructive enzyme expression within the articular cartilage but also with abnormalities in bone.…”

Section: Progress In Genetics Identifies a Key Role For Developmentalmentioning

confidence: 99%

Osteoarthritis, a disease bridging development and regeneration

Lories

Luyten²

2012

BoneKEy Reports

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The osteoarthritic diseases are common disorders characterized by progressive destruction of the articular cartilage in the joints, and associated with remodeling of the subchondral bone, synovitis and the formation of bone outgrowths at the joint margins, osteophytes. From the clinical perspective, osteoarthritis leads to joint pain and loss of function. Osteoarthritis is the leading cause of progressive disability. New data from genetic, translational and basic research have demonstrated that pathways with essential roles in joint and bone development also contribute to the postnatal homeostasis of the articular cartilage and are involved in osteoarthritis, making these potential therapeutic targets. Other systems of interest are the tissue-destructive enzymes that break down the extracellular matrix of the cartilage as well as mediators of inflammation that contribute to synovitis. However, the perspective of a durable treatment over years to decades highlights the need for a personalized medicine approach encompassing a global view on the disease and its management, thereby including nonpharmaceutical approaches such as physiotherapy and advanced surgical methods. Integration of novel strategies based on their efficacy and safety with the identification of individuals at risk and optimal individual rehabilitation management remains a major challenge for the medical community in particular, as the incidence of osteoarthritis is likely to further increase with the overall aging of the population.

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Large‐scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand

Cited by 188 publications

References 48 publications

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis

Recent advances in association studies of osteoarthritis susceptibility genes

Osteoarthritis, a disease bridging development and regeneration

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