Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.
Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.
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DOI：
10.1093/hmg/ddr586
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发表时间：
2012-04
影响因子：
3.5
通讯作者：
S. Xiao;A. Kung;Yi Gao;K. Lau;A. Ma;Zhenlin Zhang;Jian-min Liu;W. Xia;Jin-wei He;Lin Zhao;M. Nie;W. Fu;Min-jia Zhang;Jing Sun;Johnny S. H. Kwan;G. Tso;Zhi-Jie Dai;C. Cheung;C. Bow;A. Leung;K. Tan;P. Sham
中科院分区：
文献类型：
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作者：
S. Xiao;A. Kung;Yi Gao;K. Lau;A. Ma;Zhenlin Zhang;Jian-min Liu;W. Xia;Jin-wei He;Lin Zhao;M. Nie;W. Fu;Min-jia Zhang;Jing Sun;Johnny S. H. Kwan;G. Tso;Zhi-Jie Dai;C. Cheung;C. Bow;A. Leung;K. Tan;P. Sham
我们之前在香港南方中国人群中进行的全基因组关联研究（GWAS）显示，MPP 7与骨密度（BMD）评分极端相关，MPP 7作为BMD的候选基因仅次于JAG 1。为了跟踪这一暗示性信号，我们在另外三个独立的亚洲血统样本（n= 2684）中复制了MPP 7的最高单核苷酸多态性rs 4317882。在所有可用受试者的荟萃分析中，rs 4317882的关联达到全基因组显著性（P（Meta）= 4.58 × 10（-8），n= 4204）。观察到部位异质性，对脊柱骨密度的影响大于对髋关节骨密度的影响。在斑马鱼模型中进行的进一步功能研究显示，与野生型相比，mpp 7敲除模型中的椎骨骨量较低（P= 9.64 × 10（-4），n= 21）。此外，发现MPP 7在成骨过程中在人骨源性细胞中具有组成型表达。小鼠MC 3 T3-E1细胞的免疫染色显示，Mpp 7蛋白定位于成骨细胞的质膜和胞浆内隔室。在鉴定的变体的功能的评估中，电泳迁移率变动测定证明转录因子GATA 2与rs 4317882的风险等位基因“A”而不是“G”等位基因结合。在人外周血单个核细胞中的mRNA表达研究证实，低BMD相关等位基因rs 4317882 'A'与低MPP 7表达相关（P= 9.07 × 10（-3），n= 135）。我们的数据表明MPP 7与BMD变异的遗传和功能相关。
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.