title: Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis.
abstract: OBJECTIVE
  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.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Cailotto
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.affiliation: Department of Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam/Leiden, The Netherlands.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Castaño-Betancourt
authors.affiliation: Departments of Medicine and Orthopedics, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Youfang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Kaplan
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA Laboratory of Tissue Homeostasis and Disease, Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium Department of Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam/Leiden, The Netherlands Departments of Medicine and Orthopedics, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Albert Einstein College of Medicine, Bronx, New York, USA Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA Institute of Functional Genomics, Ernst Moritz Arndt University, University of Greifswald, Greifswald, Germany Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA School of Medicine, Oregon Health & Science University, Portland, Oregon, USA Division of Epidemiology, Departments of Family and Preventive Medicine and Medicine, University of California San Diego, La Jolla, California, USA Departments of Medicine and Radiology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands Department of Twin Research and Genetic Epidemiology Unit, King's College London, London, UK Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium University of California at Davis, Sacramento, California, USA.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts, USA Institute of Functional Genomics, Ernst Moritz Arndt University, University of Greifswald, Greifswald, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Teumer
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nevitt
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.affiliation: School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orwoll
authors.affiliation: Division of Epidemiology, Departments of Family and Preventive Medicine and Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Barrett-Connor
authors.affiliation: Departments of Medicine and Radiology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jordan B
authors.initials: JB
authors.lastname: Renner
authors.affiliation: Departments of Medicine and Orthopedics, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Jordan
authors.affiliation: Department of Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: Department of Academic Rheumatology, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Doherty
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Rotterdam/Leiden, The Netherlands Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Department of Twin Research and Genetic Epidemiology Unit, King's College London, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Laboratory of Tissue Homeostasis and Disease, Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium Division of Rheumatology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Lories
authors.affiliation: University of California at Davis, Sacramento, California, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics* / Q000503:physiopathology; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3
keywords: Chondrocytes; Epidemiology; Gene Polymorphism; Osteoarthritis