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Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis
  1. Daniel S Evans1,
  2. Frederic Cailotto2,
  3. Neeta Parimi1,
  4. Ana M Valdes3,
  5. Martha C Castaño-Betancourt4,5,
  6. Youfang Liu6,
  7. Robert C Kaplan7,
  8. Martin Bidlingmaier8,
  9. Ramachandran S Vasan,
  10. Alexander Teumer9,10,
  11. Gregory J Tranah1,11,
  12. Michael C Nevitt11,
  13. Steven R Cummings1,
  14. Eric S Orwoll12,
  15. Elizabeth Barrett-Connor13,
  16. Jordan B Renner14,
  17. Joanne M Jordan6,
  18. Michael Doherty3,
  19. Sally A Doherty3,
  20. Andre G Uitterlinden4,5,15,
  21. Joyce B J van Meurs4,
  22. Tim D Spector16,
  23. Rik J Lories2,17,
  24. Nancy E Lane18
  1. 1California Pacific Medical Center Research Institute, San Francisco, California, USA
  2. 2Laboratory of Tissue Homeostasis and Disease, Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium
  3. 3Department of Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK
  4. 4Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  5. 5The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam/Leiden, The Netherlands
  6. 6Departments of Medicine and Orthopedics, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  7. 7Albert Einstein College of Medicine, Bronx, New York, USA
  8. 8Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
  9. 9Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA
  10. 10Institute of Functional Genomics, Ernst Moritz Arndt University, University of Greifswald, Greifswald, Germany
  11. 11Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
  12. 12School of Medicine, Oregon Health & Science University, Portland, Oregon, USA
  13. 13Division of Epidemiology, Departments of Family and Preventive Medicine and Medicine, University of California San Diego, La Jolla, California, USA
  14. 14Departments of Medicine and Radiology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  15. 15Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  16. 16Department of Twin Research and Genetic Epidemiology Unit, King's College London, London, UK
  17. 17Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium
  18. 18University of California at Davis, Sacramento, California, USA
  1. Correspondence to Professor Nancy E Lane, Center for Musculoskeletal Health, University of California at Davis School of Medicine, 4625 Second Avenue, Suite 1002, Sacramento, CA 95817, USA; nancy.lane{at}ucdmc.ucdavis.edu

Abstract

Objectives To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.

Methods The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10−8) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.

Results The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10−8). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10−6). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10−13), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.

Conclusions Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

  • Osteoarthritis
  • Gene Polymorphism
  • Epidemiology
  • Chondrocytes

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