Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis

Daniel S. Evans, Frederic Cailotto, Neeta Parimi, Ana M. Valdes, Martha C. Castaño-Betancourt, Youfang Liu, Robert C. Kaplan, Martin Bidlingmaier, Ramachandran S. Vasan, Alexander Teumer, Gregory J. Tranah, Michael C. Nevitt, Steven R. Cummings, Eric S. Orwoll, Elizabeth Barrett-Connor, Jordan B. Renner, Joanne M. Jordan, Michael Doherty, Sally A. Doherty, Andre G. UitterlindenJoyce B J Van Meurs, Tim D. Spector, Rik J. Lories, Nancy E. Lane

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1861-1867
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume74
Issue number10
DOIs
StatePublished - Oct 1 2015

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Hip Osteoarthritis
Genome-Wide Association Study
Genes
Single Nucleotide Polymorphism
Osteoporotic Fractures
Polymorphism
Genome
Chondrocytes
Meta-Analysis
Nucleotides
Alleles
HapMap Project
Chondrogenesis
Hip Replacement Arthroplasties
Linkage Disequilibrium
Osteogenesis
Hypertrophy
Cartilage
Population
Proteins

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

Cite this

Evans, D. S., Cailotto, F., Parimi, N., Valdes, A. M., Castaño-Betancourt, M. C., Liu, Y., ... Lane, N. E. (2015). Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. Annals of the Rheumatic Diseases, 74(10), 1861-1867. https://doi.org/10.1136/annrheumdis-2013-205020

Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. / Evans, Daniel S.; Cailotto, Frederic; Parimi, Neeta; Valdes, Ana M.; Castaño-Betancourt, Martha C.; Liu, Youfang; Kaplan, Robert C.; Bidlingmaier, Martin; Vasan, Ramachandran S.; Teumer, Alexander; Tranah, Gregory J.; Nevitt, Michael C.; Cummings, Steven R.; Orwoll, Eric S.; Barrett-Connor, Elizabeth; Renner, Jordan B.; Jordan, Joanne M.; Doherty, Michael; Doherty, Sally A.; Uitterlinden, Andre G.; Van Meurs, Joyce B J; Spector, Tim D.; Lories, Rik J.; Lane, Nancy E.

In: Annals of the Rheumatic Diseases, Vol. 74, No. 10, 01.10.2015, p. 1861-1867.

Research output: Contribution to journalArticle

Evans, DS, Cailotto, F, Parimi, N, Valdes, AM, Castaño-Betancourt, MC, Liu, Y, Kaplan, RC, Bidlingmaier, M, Vasan, RS, Teumer, A, Tranah, GJ, Nevitt, MC, Cummings, SR, Orwoll, ES, Barrett-Connor, E, Renner, JB, Jordan, JM, Doherty, M, Doherty, SA, Uitterlinden, AG, Van Meurs, JBJ, Spector, TD, Lories, RJ & Lane, NE 2015, 'Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis', Annals of the Rheumatic Diseases, vol. 74, no. 10, pp. 1861-1867. https://doi.org/10.1136/annrheumdis-2013-205020
Evans, Daniel S. ; Cailotto, Frederic ; Parimi, Neeta ; Valdes, Ana M. ; Castaño-Betancourt, Martha C. ; Liu, Youfang ; Kaplan, Robert C. ; Bidlingmaier, Martin ; Vasan, Ramachandran S. ; Teumer, Alexander ; Tranah, Gregory J. ; Nevitt, Michael C. ; Cummings, Steven R. ; Orwoll, Eric S. ; Barrett-Connor, Elizabeth ; Renner, Jordan B. ; Jordan, Joanne M. ; Doherty, Michael ; Doherty, Sally A. ; Uitterlinden, Andre G. ; Van Meurs, Joyce B J ; Spector, Tim D. ; Lories, Rik J. ; Lane, Nancy E. / Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis. In: Annals of the Rheumatic Diseases. 2015 ; Vol. 74, No. 10. pp. 1861-1867.
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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.",
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T1 - Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis

AU - Evans, Daniel S.

AU - Cailotto, Frederic

AU - Parimi, Neeta

AU - Valdes, Ana M.

AU - Castaño-Betancourt, Martha C.

AU - Liu, Youfang

AU - Kaplan, Robert C.

AU - Bidlingmaier, Martin

AU - Vasan, Ramachandran S.

AU - Teumer, Alexander

AU - Tranah, Gregory J.

AU - Nevitt, Michael C.

AU - Cummings, Steven R.

AU - Orwoll, Eric S.

AU - Barrett-Connor, Elizabeth

AU - Renner, Jordan B.

AU - Jordan, Joanne M.

AU - Doherty, Michael

AU - Doherty, Sally A.

AU - Uitterlinden, Andre G.

AU - Van Meurs, Joyce B J

AU - Spector, Tim D.

AU - Lories, Rik J.

AU - Lane, Nancy E.

PY - 2015/10/1

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N2 - 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.

AB - 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.

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