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Abstract：
Epidemiological evidence suggests existing comorbidity between postmenopausal osteoporosis (OP) and cardiovascular disease (CVD), but identification of possible shared genes is lacking. The skeletal global transcriptomes were analyzed in trans-iliac bone biopsies (n = 84) from clinically well-characterized postmenopausal women (50 to 86 years) without clinical CVD using microchips and RNA sequencing. One thousand transcripts highly correlated with areal bone mineral density (aBMD) were further analyzed using bioinformatics, and common genes overlapping with CVD and associated biological mechanisms, pathways and functions were identified. Fifty genes (45 mRNAs, 5 miRNAs) were discovered with established roles in oxidative stress, inflammatory response, endothelial function, fibrosis, dyslipidemia and osteoblastogenesis/calcification. These pleiotropic genes with possible CVD comorbidity functions were also present in transcriptomes of microvascular endothelial cells and cardiomyocytes and were differentially expressed between healthy and osteoporotic women with fragility fractures. The results were supported by a genetic pleiotropy-informed conditional False Discovery Rate approach identifying any overlap in single nucleotide polymorphisms (SNPs) within several genes encoding aBMD- and CVD-associated transcripts. The study provides transcriptional and genomic evidence for genes of importance for both BMD regulation and CVD risk in a large collection of postmenopausal bone biopsies. Most of the transcripts identified in the CVD risk categories have no previously recognized roles in OP pathogenesis and provide novel avenues for exploring the mechanistic basis for the biological association between CVD and OP.
摘要：
流行病学证据表明，绝经后骨质疏松症（OP）和心血管疾病（CVD）之间存在共病，但是缺乏可能的共享基因的识别。使用微芯片和RNA测序，在临床特征明确的绝经后妇女（50至86岁）的经髂骨活检（n=84）中分析了骨骼整体转录组，而没有临床CVD。使用生物信息学进一步分析了与区域骨矿物质密度（aBMD）高度相关的一千个转录本，以及与CVD和相关生物学机制重叠的常见基因，确定了途径和功能。50个基因（45个mRNA，5个miRNA)被发现在氧化应激中具有既定的作用，炎症反应，内皮功能，纤维化，血脂异常和成骨/钙化。这些具有可能的CVD共病功能的多效性基因也存在于微血管内皮细胞和心肌细胞的转录组中，并且在患有脆性骨折的健康和骨质疏松女性之间差异表达。结果得到了遗传多效性通知的条件错误发现率方法的支持，该方法可识别编码aBMD和CVD相关转录本的几个基因中单核苷酸多态性（SNP）的任何重叠。该研究为大量绝经后骨活检中BMD调节和CVD风险的重要基因提供了转录和基因组证据。在CVD风险类别中鉴定的大多数转录本在OP发病机理中没有先前公认的作用，并且为探索CVD和OP之间的生物学关联的机理基础提供了新的途径。
