OBJECTIVE:To determine genome-wide methylation profiles of bone from patients with hip osteoarthritis (OA) and those with osteoporotic (OP) hip fractures. METHODS:Trabecular bone pieces were obtained from the central part of the femoral head of 27 patients with hip fractures and 26 patients with hip OA. DNA was isolated, and methylation was explored with Illumina methylation arrays. RNA was extracted, pooled, and deep-sequenced to obtain the whole transcriptome. Differentially methylated regions were identified, and connections between genes with differentially methylated regions were explored by pathway and text-mining analyses. RESULTS:After quality control, methylation of 23,367 CpG sites (13,463 genes) was analyzed. There was a genome-wide inverse relationship between methylation and gene expression in both patient groups. Comparison of OP and OA bones revealed 241 CpG sites, located in 228 genes, with significant differences in methylation (false discovery rate<0.05). Of them, 217 were less methylated in OP than in OA. The absolute methylation differences were >5% in 128 CpG sites and >10% in 45 CpG sites. The differentially methylated genes were enriched for association with bone traits in the genome-wide association study catalog. Pathway analysis and text-mining analysis with Gene Relationships Across Implicated Loci software revealed enrichment in genes participating in glycoprotein metabolism or cell differentiation, and particularly in the homeobox superfamily of transcription factors. CONCLUSION:Genome-wide methylation profiling of bone samples revealed differentially methylated regions in OP and OA. These regions were enriched in genes associated with cell differentiation and skeletal embryogenesis, such as those in the homeobox superfamily, suggesting the existence of a developmental component in the predisposition to these disorders.

译文

目的:确定髋骨关节炎(OA)和骨质疏松(OP)髋部骨折患者的骨骼全基因组甲基化分布。
方法:从27例髋部骨折患者和26例髋部OA患者的股骨头中部获得小梁骨碎片。分离DNA,并用Illumina甲基化阵列探索甲基化。提取RNA,合并,并进行深度测序以获得完整的转录组。鉴定差异甲基化区域,并通过途径和文本挖掘分析探索具有差异甲基化区域的基因之间的联系。
结果:质量控制后,分析了23,367个CpG位点(13,463个基因)的甲基化。在两个患者组中,甲基化和基因表达之间存在全基因组范围的负相关。 OP和OA骨骼的比较显示241个CpG位点,位于228个基因中,甲基化差异显着(假发现率<0.05)。其中,OP中的甲基化程度比OA中少217。在128个CpG位点中,绝对甲基化差异> 5%,在45个CpG位点中> 10%。在全基因组关联研究目录中,丰富了差异甲基化基因与骨骼特征的关联。涉及所有基因座软件的基因关系的途径分析和文本挖掘分析表明,参与糖蛋白代谢或细胞分化的基因,尤其是转录因子的同源异型超家族中的基因富集。
结论:骨骼样品的全基因组甲基化分布图显示了OP和OA中甲基化区域的差异。这些区域富含与细胞分化和骨骼胚胎发生相关的基因,例如同源异型盒超家族中的那些基因,表明在这些疾病的易感性中存在发育成分。

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