Dr. Blanco has received consulting fees, speaking fees, and/or honoraria from Gebro Pharma, Bioiberica Farma, and Pfizer (less than $10,000 each).
Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies
Version of Record online: 28 MAR 2014
© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Arthritis & Rheumatology
Volume 66, Issue 4, pages 940–949, April 2014
How to Cite
Rodriguez-Fontenla, C., Calaza, M., Evangelou, E., Valdes, A. M., Arden, N., Blanco, F. J., Carr, A., Chapman, K., Deloukas, P., Doherty, M., Esko, T., Garcés Aletá, C. M., Gomez-Reino Carnota, J. J., Helgadottir, H., Hofman, A., Jonsdottir, I., Kerkhof, H. J. M., Kloppenburg, M., McCaskie, A., Ntzani, E. E., Ollier, W. E. R., Oreiro, N., Panoutsopoulou, K., Ralston, S. H., Ramos, Y. F., Riancho, J. A., Rivadeneira, F., Slagboom, P. E., Styrkarsdottir, U., Thorsteinsdottir, U., Thorleifsson, G., Tsezou, A., Uitterlinden, A. G., Wallis, G. A., Wilkinson, J. M., Zhai, G., Zhu, Y., the arcOGEN Consortium, Felson, D. T., Ioannidis, J. P. A., Loughlin, J., Metspalu, A., Meulenbelt, I., Stefansson, K., van Meurs, J. B., Zeggini, E., Spector, T. D. and Gonzalez, A. (2014), Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies. Arthritis & Rheumatology, 66: 940–949. doi: 10.1002/art.38300
- Issue online: 28 MAR 2014
- Version of Record online: 28 MAR 2014
- Accepted manuscript online: 10 DEC 2013 02:29PM EST
- Manuscript Accepted: 26 NOV 2013
- Manuscript Received: 5 MAR 2013
- European Union Seventh Framework Programme. Grant Number: Project Treat-OA; 200800
- Instituto de Salud Carlos III, Spain (ISCIII). Grant Numbers: PS09/01431, PI11/01048
- European Union
- European Regional Development Fund
- Instituto de Salud Carlos III, Spain (ISCIII predoctoral contract)
- Xunta of Galicia, Spain (Isabel Barreto Program award)
- Wellcome Trust. Grant Number: 098051
- Instituto de Salud Carlos III, Spain. Grant Number: ISCIII-FIS PI 06-0034
- NWO (NWO Investments). Grant Numbers: 175.010.2005.011, 911-03-012
- Research Institute for Diseases in the Elderly. Grant Number: RIDE 014-93-015
- The Netherlands Genomics Initiative/NWO. Grant Number: Project 050-060-810
- Erasmus Medical Center and Erasmus University, Rotterdam
- Leiden University Medical Centre
- Dutch Arthritis Association
- Pfizer Inc., Groton, Connecticut
- NWO. Grant Numbers: MW 904-61-095, 911-03-016, 917-66-344, 911-03-012
- Leiden University Medical Center
- Center of Medical System Biology
- Netherlands Consortium of Healthy Aging in the framework of the Netherlands Genomics Initiative
- Dutch Arthritis Association. Grant Number: DAA 2010_017
- European Union Seventh Framework Programme. Grant Numbers: FP7/2007-2011, 259679
- The arcOGEN Phase I study (http://www.arcogen.org.uk/) was funded by Arthritis Research UK. Grant Number: Special purpose grant 18030
- Estonian government. Grant Number: SF0180142s08
- Centre of Excellence in Genomics (EXCEGEN)
- University of Tartu (SP1GVARENG)
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.