Skip to main content
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 BJ;
- Spector, Tim D;
- Lories, Rik J;
- Lane, Nancy E
- et al.
Published Web Location
https://ard.bmj.com/content/74/10/1861No data is associated with this publication.
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.