Osteoporosis is known to be highly heritable. However, to date, the findings from more than 20 genome-wide association studies (GWASs) have explained less than 6% of genetic risks. Studies suggest that the missing heritability data may be because of joint effects among genes. To identify novel heritability for osteoporosis, we performed a system-level study on bone mineral density (BMD) by weighted gene coexpression network analysis (WGCNA), using the largest GWAS data set for BMD in the field, Genetic Factors for Osteoporosis Consortium (GEFOS-2), and a transcriptomic gene expression data set generated from transiliac bone biopsies in women. A weighted gene coexpression network was generated for 1574 genes with GWAS nominal evidence of association (p 0.05) based on dissimilarity measurement on the expression data. Twelve distinct gene modules were identified, and four modules showed nominally significant associations with BMD (p 0.05), but only one module, the yellow module, demonstrated a good correlation between module membership (MM) and gene significance (GS), suggesting that the yellow module serves an important biological role in bone regulation. Interestingly, through characterization of module content and topology, the yellow module was found to be significantly enriched with contractile fiber part (GO:044449), which is widely recognized as having a close relationship between muscle and bone. Furthermore, detailed submodule analyses of important candidate genes (HOMER1, SPTBN1) by all edges within the yellow module implied significant enrichment of functional connections between bone and cytoskeletal protein binding. Our study yielded novel information from system genetics analyses of GWAS data jointly with transcriptomic data. The findings highlighted a module and several genes in the model as playing important roles in the regulation of bone mass in females, which may yield novel insights into the genetic basis of osteoporosis.

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TIMP-1 is a valuable single biomarker for the evaluation of significant fibrosis in CHB patients.

PurposeWe have found that expression of γδT cells is increased in pathological mucosa of chronic rhinosinusitis with nasal polyps (CRSwNP) compared with normal nasal mucosa. This increase is correlated with the infiltration of eosinophils in CRSwNP. Here, we investigated the expression of γδT cells, inflammation and tissue remodeling factors as well as their probable relationships in different types of chronic rhinosinusitis (CRS) in China.MethodsA total of 76 surgical tissue samples that included 43 CRSwNP samples (15 eosinophilic and 28 non-eosinophilic), 17 CRS samples without nasal polyps (CRSsNP), and 16 controls were obtained. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of Vγ1+ γδT cells, Vγ4+ γδT cells, eosinophil cationic protein (ECP), interleukin (IL)-8, transforming growth factor (TGF)-β2, metalloproteinase (MMP)-7, tissue inhibitor of metalloproteinase (TIMP)-4 and hypoxia-inducible factor (HIF)-1α. Enzyme linked immunosorbent assay (ELISA) was used to measure the protein level of ECP and MMP-7 in CRSwNP. The eosinophils were counted and the level of edema was analyzed with HE staining.ResultsThe mRNA expression levels of the Vγ1 subset, ECP and MMP-7 were significantly increased in CRSwNP with histological characteristics of eosinophilic infiltration and edema. The expression of the Vγ1 gene in CRSwNP correlated positively with the expression of both ECP and MMP-7. No significant decreases in the mRNA expression levels of TGF-β2, TIMP-4 or HIF-1α were observed in the CRSwNP samples. The expression levels of Vγ1 gene, ECP and MMP-7 were significantly increased in eosinophilic CRSwNP compared to non-eosinophilic CRSwNP.ConclusionsOur results suggest the associations between Vγ1+ γδT cells, ECP and MMP-7 in CRSwNP, indicating that Vγ1+ γδT cells can induce the eosinophilic inflammation, which has a further effect on the formation of edema.

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