Dataset Information

Three functional polymorphisms in CCDC170 were associated with osteoporosis phenotype.

ABSTRACT: MicroRNAs (miRNAs) play essential roles in regulating bone formation and homeostasis. Genomic variations within miRNA target sites may therefore be important sources of genetic differences in osteoporosis risk. The function of CCDC170 in bone biology is still unclear. To verify the function of CCDC170, we knocked down CCDC170 in cells and mice and searched for miRNA recognition sites within CCDC170 using the TargetScan, miRNASNP, and miRBase databases. In this study, our results demonstrated that CCDC170 plays an important role in the positive regulation of bone formation. MiR-153-3p, miR-374b-3p, miR-4274, miR-572 and miR-2964a-5p inhibited CCDC170 expression in an allele-specific manner by binding GWAS lead SNPs rs6932603, rs3757322 and rs3734806. These findings may improve our understanding of the association between CCDC170, miRNAs, GWAS lead SNPs, and osteoporosis pathogenesis and may provide a potential therapeutic target for osteoporosis therapy.

SUBMITTER: Liu X

PROVIDER: S-EPMC8061906 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Three functional polymorphisms in CCDC170 were associated with osteoporosis phenotype.

Liu Xinhong X Li Yu-Gang YG Tan Fang F Liu Jia J Yi Ruokun R Zhao Xin X

Biology open 20210416 4

MicroRNAs (miRNAs) play essential roles in regulating bone formation and homeostasis. Genomic variations within miRNA target sites may therefore be important sources of genetic differences in osteoporosis risk. The function of CCDC170 in bone biology is still unclear. To verify the function of CCDC170, we knocked down CCDC170 in cells and mice and searched for miRNA recognition sites within CCDC170 using the TargetScan, miRNASNP, and miRBase databases. In this study, our results demonstrated tha ...[more]

PMID: 33785515

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Project description:Determining molecular markers for osteoporosis may be valuable for improving the quality of life of affected elderly patients by aiding in early detection and disease management. In the present study, the association between single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) and tumour necrosis factor superfamily number 11 (TNFSF11) genes and the susceptibility of developing osteoporosis was investigated in a Thai female cohort. The study group consisted of 105 Thai postmenopausal patients diagnosed with osteoporosis and 132 healthy Thai postmenopausal female volunteers. DNA extracted from blood samples was used to genotype the VDR and TNFSF11 genes using polymerase chain reaction-restriction fragment length polymorphism and sequencing analysis. For VDR, the frequencies of the genotypes TT, CT and CC for the TaqI SNP (rs731236) were 87.88, 11.36 and 0.76%, respectively, in the control group, while in the osteoporosis cohort were 92.38, 5.71 and 1.91%, respectively. For the FokI SNP (rs2228570), the frequencies of the genotypes CC, CT and TT were 31.06, 55.30 and 13.64%, respectively, in the control group, and in the osteoporosis group were 29.52, 43.81 and 26.67%, respectively. For BsmI SNP (rs1544410), the frequencies of the genotypes GG, GA and AA were 78.03, 18.94 and 3.03%, respectively, in control group, and in the osteoporosis group were 80.95, 18.10 and 0.95%, respectively. The significant risk of osteoporosis associated with the FokI SNP was determined. The odds ratio (95% confidence interval) was 2.30 (1.14-4.69; P=0.01) among patients with osteoporosis with TT as the susceptibility genotype. For TNFSF11, the frequencies of the genotypes TT, CT and CC for the -290C>T SNP (rs9525641) in the control group were 36.36, 50.76 and 12.88%, respectively, while in the osteoporosis group were 31.43, 56.19 and 12.38%, respectively. For the -643C>T SNP (rs9533156), the frequencies of the genotypes TT, CT and CC in the control group were 35.61, 48.48 and 15.91%, respectively, while in the osteoporosis group were 32.38, 55.24 and 12.38%, respectively. For the -693G>C SNP (rs9533155), the frequencies of the genotypes CC, CG, and GG in the control group were 39.39, 46.97 and 13.64%, respectively, and in the osteoporosis group were 36.19, 53.33 and 10.48%, respectively. No significant associations of the TNFSF11 SNPs with osteoporosis were determined; however, it was notable that the GCT haplotype of TNFSF11 may be a protective haplotype for osteoporosis. Therefore, it was concluded that the SNP FokI of VDR may be a potential molecular biomarker for the development of osteoporosis in Thai females.

Project description:Over the past decade, the role of the gut microbiota in many disease states has gained a great deal of attention. Mounting evidence from case-control and observational studies has linked changes in the gut microbiota to the pathophysiology of osteoporosis (OP). Nonetheless, the results of these studies contain discrepancies, leaving the literature without a consensus on osteoporosis-associated microbial signatures. Here, we conducted a comprehensive meta-analysis combining and reexamining five publicly available 16S rRNA partial sequence data sets to identify gut bacteria consistently associated with osteoporosis across different cohorts. After adjusting for the batch effect associated with technical variation and heterogeneity of studies, we observed a significant shift in the microbiota composition in the osteoporosis group. An increase in the relative abundance of opportunistic pathogens Clostridium sensu stricto, Bacteroides, and Intestinibacter was observed in the OP group. Moreover, short-chain-fatty-acid (SCFA) producers, including members of the genera Collinsella, Megasphaera, Agathobaculum, Mediterraneibacter, Clostridium XIV, and Dorea, were depleted in the OP group relative to the healthy control (HC) group. Lactic acid-producing bacteria, including Limosilactobacillus, were significantly increased in the OP group. The random forest algorithm further confirmed that these bacteria differentiate the two groups. Furthermore, functional prediction revealed depletion of the SCFA biosynthesis pathway (glycolysis, tricarboxylic acid [TCA] cycle, and Wood-Ljungdahl pathway) and amino acid biosynthesis pathway (methionine, histidine, and arginine) in the OP group relative to the HC group. This study uncovered OP-associated compositional and functional microbial alterations, providing robust insight into OP pathogenesis and aiding the possible development of a therapeutic intervention to manage the disease. IMPORTANCE Osteoporosis is the most common metabolic bone disease associated with aging. Mounting evidence has linked changes in the gut microbiota to the pathophysiology of osteoporosis. However, which microbes are associated with dysbiosis and their impact on bone density and inflammation remain largely unknown due to inconsistent results in the literature. Here, we present a meta-analysis with a standard workflow, robust statistical approaches, and machine learning algorithms to identify notable microbial compositional changes influencing osteoporosis.

Dataset Information

Three functional polymorphisms in CCDC170 were associated with osteoporosis phenotype.

Publications

Three functional polymorphisms in CCDC170 were associated with osteoporosis phenotype.

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