Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.
Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.
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全基因组的关联和功能研究确定了基质gla蛋白在手的骨关节炎中的作用。
DOI：
10.1136/annrheumdis-2017-211214
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发表时间：
2017-12
影响因子：
27.4
通讯作者：
van Meurs JJB
中科院分区：
文献类型：
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作者：
den Hollander W;Boer CG;Hart DJ;Yau MS;Ramos YFM;Metrustry S;Broer L;Deelen J;Cupples LA;Rivadeneira F;Kloppenburg M;Peters M;Spector TD;Hofman A;Slagboom PE;Nelissen RGHH;Uitterlinden AG;Felson DT;Valdes AM;Meulenbelt I;van Meurs JJB
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 的遗传倾向最强。然而，仅发现了少数手部 OA 的遗传风险位点。我们的目的是识别与手部 OA 相关的新基因并检查其潜在机制。我们对 12 784 名个体进行了手部 OA 定量测量的全基因组关联研究（发现：8743 例，重复：4011 例）。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，追踪全基因组的显着信号。我们在发现集中发现了两个显着相关的位点：在基质 Gla 蛋白 (MGP) 基因附近的 chr12 (p=3.5 × 10−10) 和在 CCDC91 基因附近的 chr12 (p=6.1×10−9)。 MGP 基因附近的 DNA 变异在另外三项研究中得到了验证，这导致 MGP 变异与手部 OA 之间存在高度显着的关联（rs4764133，Betameta=0.83，Pmeta=1.8*10−15）。该变体与 MGP（一种维生素 K 依赖性软骨钙化抑制剂）的编码变体存在高度连锁不平衡。使用来自人类原发软骨组织（n=96）的RNA测序数据，我们观察到手OA风险等位基因的MGP RNA表达显着低于参考等位基因的MGP RNA表达（40.7%，p<5*10−16）。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 MGP 表达较低引起的，这可能通过减少对软骨钙化的抑制来增加手部 OA 的负担。
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 × 10−10) 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). 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.
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影响因子：
27.4
作者：
Neogi T;Felson DT;Sarno R;Booth SL
通讯作者：
Booth SL
影响因子：
3.7
作者：
Nakajima M;Takahashi A;Kou I;Rodriguez-Fontenla C;Gomez-Reino JJ;Furuichi T;Dai J;Sudo A;Uchida A;Fukui N;Kubo M;Kamatani N;Tsunoda T;Malizos KN;Tsezou A;Gonzalez A;Nakamura Y;Ikegawa S
通讯作者：
Ikegawa S
DOI：
10.1097/01.blo.0000144971.12731.a2
发表时间：
2004-10-01
影响因子：
4.2
作者：
Felson, DT
通讯作者：
Felson, DT
一项全基因组关联研究确定了7q22染色体上的骨关节炎易感性基因座。
影响因子：
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作者：
Kerkhof, Hanneke J. M.;Lories, Rik J.;Meulenbelt, Ingrid;Jonsdottir, Ingileif;Valdes, Ana M.;Arp, Pascal;Ingvarsson, Thorvaldur;Jhamai, Mila;Jonsson, Helgi;Stolk, Lisette;Thorleifsson, Gudmar;Zhai, Guangju;Zhang, Feng;Zhu, Yanyan;van der Breggen, Ruud;Carr, Andrew;Doherty, Michael;Doherty, Sally;Felson, David T.;Gonzalez, Antonio;Halldorsson, Bjarni V.;Hart, Deborah J.;Hauksson, Valdimar B.;Hofman, Albert;Ioannidis, John P. A.;Kloppenburg, Margreet;Lane, Nancy E.;Loughlin, John;Luyten, Frank P.;Nevitt, Michael C.;Parimi, Neeta;Pols, Huibert A. P.;Rivadeneira, Fernando;Slagboom, Eline P.;Styrkarsdottir, Unnur;Tsezou, Aspasia;van de Putte, Tom;Zmuda, Joseph;Spector, Tim D.;Stefansson, Kari;Uitterlinden, Andre G.;van Meurs, Joyce B. J.
通讯作者：
van Meurs, Joyce B. J.
影响因子：
--
作者：
Gee, Fiona;Clubbs, Clare F.;Loughlin, John
通讯作者：
Loughlin, John