TY - JOUR
T1 - Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand
AU - Den Hollander, Wouter
AU - Boer, Cindy G.
AU - Hart, Deborah J.
AU - Yau, Michelle S.
AU - Ramos, Yolande F.M.
AU - Metrustry, Sarah
AU - Broer, Linda
AU - Deelen, Joris
AU - Cupples, L. Adrienne
AU - Rivadeneira, Fernando
AU - Kloppenburg, Margreet
AU - Peters, Marjolein
AU - Spector, Tim D.
AU - Hofman, Albert
AU - Slagboom, P. Eline
AU - Nelissen, Rob G.H.H.
AU - Uitterlinden, André G.
AU - Felson, David T.
AU - Valdes, Ana M.
AU - Meulenbelt, Ingrid
AU - Van Meurs, Joyce J.B.
N1 - Publisher Copyright:
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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, Beta meta =0.83, P meta =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.
AB - 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, Beta meta =0.83, P meta =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.
KW - functional study
KW - genetics
KW - genome-wide association study
KW - hand osteoarthritis
KW - Matrix-Gla protein
UR - http://www.scopus.com/inward/record.url?scp=85037588097&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2017-211214
DO - 10.1136/annrheumdis-2017-211214
M3 - Article
C2 - 28855172
AN - SCOPUS:85037588097
SN - 0003-4967
VL - 76
SP - 2046
EP - 2053
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 12
ER -