den Hollander Wouter, 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
Department of Medical Statistics and Bioinformatics, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Internal Medicine, Genetic Laboratory, Erasmus Medical Center, Rotterdam, The Netherlands.
Ann Rheum Dis. 2017 Dec;76(12):2046-2053. doi: 10.1136/annrheumdis-2017-211214. Epub 2017 Aug 30.
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.
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.
We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10) 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=0.83, P=1.810). This variant is high linkage disequilibrium with a coding variant in , 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<510).
Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of , which may increase the burden of hand OA by decreased inhibition of cartilage calcification.
骨关节炎（OA）是最常见的关节炎形式，也是老年人残疾的主要原因。在所有关节中，手部OA的遗传易感性最强；然而，仅发现了少数手部OA的遗传风险位点。我们的目的是鉴定与手部OA相关的新基因并研究其潜在机制。
我们对12784名个体（发现队列：8743人，复制队列：4011人）的手部OA定量指标进行了全基因组关联研究。通过分析人类关节软骨RNA测序数据集（n = 96）中的基因和等位基因特异性表达，对全基因组显著信号进行后续研究。
我们在发现队列中发现了两个显著相关的位点：位于基质Gla蛋白（MGP）基因附近的12号染色体（p = 3.5×10）和位于CCDC91基因附近的12号染色体（p = 6.1×10）。MGP基因附近的DNA变异在另外三项研究中得到验证，这导致MGP变异与手部OA之间存在高度显著的关联（rs4764133，β = 0.83，P = 1.8×10）。该变异与软骨钙化的维生素K依赖性抑制剂中的一个编码变异处于高度连锁不平衡状态。使用来自人类原发性软骨组织（n = 96）的RNA测序数据，我们观察到手部OA风险等位基因的MGP RNA表达与参考等位基因的MGP RNA表达相比显著降低（40.7%，p < 5×10）。
我们的结果表明，MGP变异与手部OA风险增加之间的关联是由于其表达降低所致，这可能通过减少对软骨钙化的抑制作用而增加手部OA的负担。
