Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand
Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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BMJ Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/48020/ |
| _version_ | 1848797673571745792 |
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| author | Hollander, Wouter den Boer, Cindy G. Hart, Deborah J. Yau, Michelle S. Ramos, Yolande F.M. Metrustry, Sarah Broer, Linda Deelen, Joris Cupples, L. Adrienne Rivadeneira, Fernando Kloppenburg, Margreet Peters, Marjolein Spector, Tim D. Hofman, Albert Slagboom, P. Eline Nelissen, Rob G.H.H. Uitterlinden, André G. Felson, David T. Valdes, Ana M. Meulenbelt, Ingrid van Meurs, Joyce J.B. |
| author_facet | Hollander, Wouter den Boer, Cindy G. Hart, Deborah J. Yau, Michelle S. Ramos, Yolande F.M. Metrustry, Sarah Broer, Linda Deelen, Joris Cupples, L. Adrienne Rivadeneira, Fernando Kloppenburg, Margreet Peters, Marjolein Spector, Tim D. Hofman, Albert Slagboom, P. Eline Nelissen, Rob G.H.H. Uitterlinden, André G. Felson, David T. Valdes, Ana M. Meulenbelt, Ingrid van Meurs, Joyce J.B. |
| author_sort | Hollander, Wouter den |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism.
Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage.
Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶).
Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification. |
| first_indexed | 2025-11-14T20:07:37Z |
| format | Article |
| id | nottingham-48020 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T20:07:37Z |
| publishDate | 2017 |
| publisher | BMJ Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-480202024-08-15T15:24:09Z https://eprints.nottingham.ac.uk/48020/ Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand Hollander, Wouter den Boer, Cindy G. Hart, Deborah J. Yau, Michelle S. Ramos, Yolande F.M. Metrustry, Sarah Broer, Linda Deelen, Joris Cupples, L. Adrienne Rivadeneira, Fernando Kloppenburg, Margreet Peters, Marjolein Spector, Tim D. Hofman, Albert Slagboom, P. Eline Nelissen, Rob G.H.H. Uitterlinden, André G. Felson, David T. Valdes, Ana M. Meulenbelt, Ingrid van Meurs, Joyce J.B. Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification. BMJ Publishing Group 2017-09-19 Article PeerReviewed Hollander, Wouter den, Boer, Cindy G., Hart, Deborah J., Yau, Michelle S., Ramos, Yolande F.M., Metrustry, Sarah, Broer, Linda, Deelen, Joris, Cupples, L. Adrienne, Rivadeneira, Fernando, Kloppenburg, Margreet, Peters, Marjolein, Spector, Tim D., Hofman, Albert, Slagboom, P. Eline, Nelissen, Rob G.H.H., Uitterlinden, André G., Felson, David T., Valdes, Ana M., Meulenbelt, Ingrid and van Meurs, Joyce J.B. (2017) Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand. Annals of the Rheumatic Diseases . ISSN 1468-2060 http://ard.bmj.com/content/early/2017/09/19/annrheumdis-2017-211214 doi:10.1136/annrheumdis-2017-211214 doi:10.1136/annrheumdis-2017-211214 |
| spellingShingle | Hollander, Wouter den Boer, Cindy G. Hart, Deborah J. Yau, Michelle S. Ramos, Yolande F.M. Metrustry, Sarah Broer, Linda Deelen, Joris Cupples, L. Adrienne Rivadeneira, Fernando Kloppenburg, Margreet Peters, Marjolein Spector, Tim D. Hofman, Albert Slagboom, P. Eline Nelissen, Rob G.H.H. Uitterlinden, André G. Felson, David T. Valdes, Ana M. Meulenbelt, Ingrid van Meurs, Joyce J.B. Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title | Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title_full | Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title_fullStr | Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title_full_unstemmed | Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title_short | Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand |
| title_sort | genome-wide association and functional studies identify a role for matrix gla protein in osteoarthritis of the hand |
| url | https://eprints.nottingham.ac.uk/48020/ https://eprints.nottingham.ac.uk/48020/ https://eprints.nottingham.ac.uk/48020/ |