Department of Medicine, The University of Hong Kong, Hong Kong, China.
Hum Mol Genet. 2012 Apr 1;21(7):1648-57. doi: 10.1093/hmg/ddr586. Epub 2011 Dec 13.
Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.
我们之前在一个香港南方汉族人群中进行的全基因组关联研究（GWAS），该人群具有极端的骨矿物质密度（BMD）评分，结果提示 MPP7 与 BMD 候选基因 JAG1 并列第二。为了跟进这个提示信号，我们在另外三个亚洲血统的独立样本（n=2684）中复制了 MPP7 的顶级单核苷酸多态性 rs4317882。rs4317882 在所有可用受试者的荟萃分析中达到了全基因组显著水平（P(meta)=4.58×10(-8)，n=4204）。观察到了位点异质性，对脊柱 BMD 的影响大于对髋部 BMD 的影响。在斑马鱼模型中的进一步功能研究表明，与野生型相比，mpp7 敲低模型的椎骨骨量较低（P=9.64×10(-4)，n=21）。此外，在成骨过程中发现 MPP7 在人源性骨细胞中具有组成性表达。对鼠 MC3T3-E1 细胞的免疫染色显示，Mpp7 蛋白定位于成骨细胞的质膜和细胞内区室。在对鉴定出的变异体功能的评估中，电泳迁移率变动分析显示转录因子 GATA2 与风险等位基因 'A' 而不是 rs4317882 的 'G' 等位基因结合。在人外周血单核细胞中的 mRNA 表达研究证实，rs4317882 与低 BMD 相关的等位基因 'A' 与 MPP7 表达较低相关（P=9.07×10(-3)，n=135）。我们的数据表明 MPP7 与 BMD 变异存在遗传和功能关联。
