Tang Hui, Zhu Xiao-Wei, Wu Long-Fei, Mo Xing-Bo, Deng Fei-Yan, Lei Shu-Feng
Center for Genetic Epidemiology and Genomics, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu 215123, China.
Center for Genetic Epidemiology and Genomics, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu 215123, China;Zhangjiagang Center for Disease Control and Prevention, Zhangjiagang, Jiangsu 215600, China.
Chin Med Sci J. 2019 Jun 30;34(2):147-156. doi: 10.24920/003466.
Objective This study aimed to verify the association between osteoprotegerin gene () and its variants with osteoporosis (OP) by performing integrative analysis.Methods We used the KGG software to perform gene-based association analysis, which integrated all publicly available single-nucleotide polymorphism (SNP)-based values and obtained an overall value for the . The significant SNPs were screened for expression quantitative trait loci (eQTLs). Meta-analysis was used to combine the associations between the variants of and bone mineral density (BMD) reported in the literatures. Then we performed dual-luciferase reporter gene systems for the functional verification of the variants of .Results In the gene-based association analysis, the over all value of was 6.24×10 for BMD at femoral neck (FN) and 7.37×10 for BMD at lumbar spine (LS), indicating the importance of for OP. The publicly available eQTL database identified 5 eQTLs which exert cis-regulation effects on at FN and LS. Literature searching found that rs2073617 (known as T950C) was the hot spot SNP. There were 13 relevant studies on rs2073617 besides the GEFOS-2 study identified from the PubMed. Significant differences among TT, TC and CC genotypes at FN (= 0.047) and LS (= 0.025) were shown by meta-analysis, demonstrating the associations between T950C polymorphism and BMD. Luciferase gene expression was significantly higher at the presence of allele C than allele T in the 293T cells (=-9.47, <0.01). Conclusion The integrative analysis further confirmed the importance of in OP and the correlation of T950C polymorphism with BMD of OP. The strategy can be used as a reference for functional interpretation of other disease-related genes.
目的 本研究旨在通过综合分析验证骨保护素基因（）及其变体与骨质疏松症（OP）之间的关联。方法 我们使用KGG软件进行基于基因的关联分析，该分析整合了所有公开可用的基于单核苷酸多态性（SNP）的 值，并获得该基因的总体 值。筛选出显著的SNP用于表达数量性状位点（eQTL）分析。采用荟萃分析来综合文献中报道的该基因变体与骨密度（BMD）之间的关联。然后我们进行双荧光素酶报告基因系统以对该基因变体进行功能验证。结果 在基于基因的关联分析中，股骨颈（FN）处BMD的该基因总体 值为6.24×10 ，腰椎（LS）处BMD的该基因总体 值为7.37×10 ，表明该基因对OP的重要性。公开可用的eQTL数据库确定了5个对FN和LS处的该基因发挥顺式调节作用的eQTL。文献检索发现rs2073617（又称T950C）是热点SNP。除了从PubMed中识别出的GEFOS - 2研究外，还有13项关于rs2073617的相关研究。荟萃分析显示FN（= 0.047）和LS（= 0.025）处TT、TC和CC基因型之间存在显著差异，证明了T950C多态性与BMD之间的关联。在293T细胞中，存在等位基因C时荧光素酶基因表达显著高于等位基因T（= -9.47，<0.01）。结论 综合分析进一步证实了该基因在OP中的重要性以及T950C多态性与OP的BMD之间的相关性。该策略可作为其他疾病相关基因功能解释的参考。
