Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study

Autor: Shin S-Y., Steffan D. Bos, Margreet Kloppenburg, Andres Metspalu, Ashok Rai, Karen E. Chapman, Tõnu Esko, J M Willkinson, Panagiotis Deloukas, Gudmar Thorleifsson, Nigel K Arden, Ingileif Jonsdottir, Andrew Carr, Kalliope Panoutsopoulou, Fernando Rivadeneira, Michelle Ricketts, F O'Neill, Sarah Metrustry, Massimo Mangino, Ollier Wer., Sarah E. Hunt, N Koller, Sally Doherty, M C Lopes, John Loughlin, Raine Eva., Andrew McCaskie, Bridget Watkins, Lorraine Southam, Gillian A. Wallis, Battley P-K., Vijay K. Yadav, U Stykarsdottir, N Aslam, Evangelos Evangelou, van Meurs Jbj., K Walker, Donald Salter, Mike R. Reed, K. Stefansson, I Carluke, E Arden, K Sherburn, Stuart Ralston, Tim D. Spector, Suzannah Bumpstead, Madhushika Ratnayake, Hannah Blackburn, K S Elliott, H Jonnson, Guangju Zhai, Michael Doherty, M. Wheeler, Thorvaldur Ingvarsson, Ingrid Meulenbelt, J Joseph, Fraser Birrell, D Swift, A.G. Uitterlinden, K Dixon, Ioannidis Jpa., Hanneke J. M. Kerkhof, Aaron G. Day-Williams, E Paling, Simon C. Potter, Ana M. Valdes, P E Slagboom, Richard Keen, Sheryl Mitchell, C Beazley, Eleftheria Zeggini, A Hoffman, Vesna Boraska, Jeanine J. Houwing-Duistermaat, Allan Gordon, N W Rayner
Rok vydání: 2012
Předmět:
Zdroj: Lancet
Zeggini, E, Panoutsopoulou, K, Southam, L, Rayner, N W, Day-Williams, A G, Lopes, M C, Boraska, V, Esko, T, Evangelou, E, Hofman, A, Houwing-Duistermaat, J J, Ingvarsson, T, Jonsdottir, I, Jonsson, H, Kerkhof, H J M, Kloppenburg, M, Bos, S D, Mangino, M, Metrustry, S, Slagboom, P E, Thorleifsson, G, Raine, E V A, Ratnayake, M, Ricketts, M, Beazley, C, Blackburn, H, Bumpstead, S, Elliott, K S, Hunt, S E, Potter, S C, Shin, S-Y, Yadav, V K, Zhai, G, Sherburn, K, Dixon, K, Arden, E, Aslam, N, Battley, P-K, Carluke, I, Doherty, S, Gordon, A, Joseph, J, Keen, R, Koller, N C, Mitchell, S, O'Neill, F, Paling, E, Reed, M R & Salter, D & Ralston, S H 2012, ' Identification of new susceptibility loci for osteoarthritis (arcOGEN) : a genome-wide association study ', The Lancet, vol. 380, no. 9844, pp. 815-823 . https://doi.org/10.1016/S0140-6736(12)60681-3
The Lancet; Vol 380
ISSN: 0140-6736
DOI: 10.1016/s0140-6736(12)60681-3
Popis: BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.
Databáze: OpenAIRE
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