A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.
A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22.
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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。
DOI：
10.1002/art.27184
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发表时间：
2010-02
影响因子：
--
通讯作者：
van Meurs, Joyce B. J.
中科院分区：
文献类型：
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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.
为了确定与骨关节炎（OA）（最常见的关节疾病形式）相关的基因，我们进行了一项全基因组关联研究（GWAS），在该研究中，我们在1341例OA病例和3496例荷兰白人对照中检测了500，510个单核苷酸多态性（SNP）。在14，938例OA病例和约39，000例对照中分析了与至少两种OA表型相关的SNP。染色体7 q22上rs3815148的C等位基因（MAF 23%，GPR 22基因上游172 kb）与1.14倍的风险增加相关。（95%CI：1.09-1.19），膝关节和/或手部OA（p=8×10−8），膝关节OA进展风险增加30%（95%CI：1.03-1.64，p=0.03）。该SNP与rs3757713（位于GPR 22上游68 kb）几乎完全连锁不平衡，rs3757713与淋巴母细胞系中的GPR 22表达水平相关（p=4×10−12）。GPR 22编码具有未知配体的G蛋白偶联受体（孤儿受体）。免疫组化实验显示，GPR 22在正常小鼠关节软骨或滑膜中不存在。然而，在小鼠膝关节的关节软骨的上层中发现GPR 22阳性软骨细胞，所述小鼠膝关节通过体内木瓜蛋白酶处理或在存在白细胞介素-1驱动的炎症的情况下受到攻击。在不稳定性诱导的OA的骨赘中也发现了GRP 22阳性的软骨细胞样细胞。此外，GPR 22还存在于参与运动功能的大脑区域中。我们的研究结果揭示了染色体7 q22上的一种新的常见变异影响OA患病率和进展的易感性。
To identify genes involved in osteoarthritis (OA), the most prevalent form of joint disease, we performed a genome-wide association study (GWAS) in which we tested 500,510 Single Nucelotide Polymorphisms (SNPs) in 1341 OA cases and 3496 Dutch Caucasian controls. SNPs associated with at least two OA-phenotypes were analysed in 14,938 OA cases and approximately 39,000 controls. The C-allele of rs3815148 on chromosome 7q22 (MAF 23%, 172 kb upstream of the GPR22 gene) was consistently associated with a 1.14-fold increased risk (95%CI: 1.09–1.19) for knee- and/or hand-OA (p=8×10−8), and also with a 30% increased risk for knee-OA progression (95%CI: 1.03–1.64, p=0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (located 68 kb upstream of GPR22) which is associated with GPR22 expression levels in lymphoblast cell lines (p=4×10−12). GPR22 encodes an G-protein coupled receptor with unkown ligand (orphan receptor). Immunohistochemistry experiments showed absence of GPR22 in normal mouse articular cartilage or synovium. However, GPR22 positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged by in vivo papain treatment or in the presence of interleukin-1 driven inflammation. GRP22 positive chondrocyte-like cells were also found in osteophytes in instability-induced OA. In addition, GPR22 is also present in areas of the brain involved in locomotor function. Our findings reveal a novel common variant on chromosome 7q22 to influence susceptibility for prevalence and progression of OA.
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影响因子：
--
作者：
Evangelou, Evangelos;Chapman, Kay;Meulenbelt, Ingrid;Karassa, Fotini B.;Loughlin, John;Carr, Andrew;Doherty, Michael;Doherty, Sally;Gomez-Reino, Juan J.;Gonzalez, Antonio;Halldorsson, Bjarni V.;Hauksson, Valdimar B.;Hofman, Albert;Hart, Deborah J.;Ikegawa, Shiro;Ingvarsson, Thorvaldur;Jiang, Qing;Jonsdottir, Ingileif;Jonsson, Helgi;Kerkhof, Hanneke J. M.;Kloppenburg, Margreet;Lane, Nancy E.;Li, Jia;Lories, Rik J.;van Meurs, Joyce B. J.;Nakki, Annu;Nevitt, Michael C.;Rodriguez-Lopez, Julio;Shi, Dongquan;Slagboom, Eline;Stefansson, Kari;Tsezou, Aspasia;Wallis, Gillian A.;Watson, Christopher M.;Spector, Tim D.;Uitterlinden, Andre G.;Valdes, Ana M.;Ioannidis, John P. A.
通讯作者：
Ioannidis, John P. A.
影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.
影响因子：
--
作者：
ALTMAN, R;ALARCON, G;WOLFE, F
通讯作者：
WOLFE, F
影响因子：
3.5
作者：
Meulenbelt, Ingrid;Min, Josine L.;Slagboom, P. Eline
通讯作者：
Slagboom, P. Eline
影响因子：
3.5
作者：
Chapman, Kay;Takahashi, Atsushi;Ikegawa, Shiro
通讯作者：
Ikegawa, Shiro