The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation
PurposeGenome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential varia...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:151779b9018e43be8003a99816e486cd2021-12-01T02:45:21ZThe Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation1664-239210.3389/fendo.2021.730686https://doaj.org/article/151779b9018e43be8003a99816e486cd2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fendo.2021.730686/fullhttps://doaj.org/toc/1664-2392PurposeGenome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential variation in runt domain transcription factor 2 (RUNX2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding variants within RUNX2 binding sites and risk of osteoporosis in postmenopausal osteoporosis (PMOP).MethodsWe performed bioinformatics-based prediction by combining whole genome sequencing and chromatin immunoprecipitation sequencing to screen functional SNPs in the RUNX2 binding site using data from the database of Taiwan Biobank; Case-control studies with 651 postmenopausal women comprising 107 osteoporosis patients, 290 osteopenia patients, and 254 controls at Tri-Service General Hospital between 2015 and 2019 were included. The subjects were examined for bone mass density and classified into normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Furthermore, mRNA expression and luciferase reporter assay were used to provide additional evidence regarding the associations identified in the association analyses. Chi-square tests and logistic regression were mainly used for statistical assessment.ResultsThrough candidate gene approaches, 3 SNPs in the RUNX2 binding site were selected. A novel SNP rs6086746 in the PLCB4 promoter was identified to be associated with osteoporosis in Chinese populations. Patients with AA allele had higher risk of osteoporosis than those with GG+AG (adjusted OR = 6.89; 95% confidence intervals: 2.23–21.31, p = 0.001). Moreover, the AA genotype exhibited lower bone mass density (p < 0.05). Regarding mRNA expression, there were large differences in the correlation between PLCB4 and different RUNX2 alleles (Cohen’s q = 0.91). Functionally, the rs6086746 A allele reduces the RUNX2 binding affinity, thus enhancing the suppression of PLCB4 expression (p < 0.05).ConclusionsOur results provide further evidence to support the important role of the SNP rs6086746 in the etiology of osteopenia/osteoporosis, thereby enhancing the current understanding of the susceptibility to osteoporosis. We further studied the mechanism underlying osteoporosis regulation by PLCB4.Dung-Jang TsaiDung-Jang TsaiWen-Hui FangLi-Wei WuMing-Cheng TaiChung-Cheng KaoShih-Ming HuangWei-Teing ChenWei-Teing ChenPo-Jen HsiaoPo-Jen HsiaoChih-Chien ChiuWen SuChia-Chun WuSui-Lung SuSui-Lung SuFrontiers Media S.A.articleosteoporosisrunt domain transcription factor 2binding site polymorphismcase-control studyPLCB4Diseases of the endocrine glands. Clinical endocrinologyRC648-665ENFrontiers in Endocrinology, Vol 12 (2021) |
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DOAJ |
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EN |
| topic |
osteoporosis runt domain transcription factor 2 binding site polymorphism case-control study PLCB4 Diseases of the endocrine glands. Clinical endocrinology RC648-665 |
| spellingShingle |
osteoporosis runt domain transcription factor 2 binding site polymorphism case-control study PLCB4 Diseases of the endocrine glands. Clinical endocrinology RC648-665 Dung-Jang Tsai Dung-Jang Tsai Wen-Hui Fang Li-Wei Wu Ming-Cheng Tai Chung-Cheng Kao Shih-Ming Huang Wei-Teing Chen Wei-Teing Chen Po-Jen Hsiao Po-Jen Hsiao Chih-Chien Chiu Wen Su Chia-Chun Wu Sui-Lung Su Sui-Lung Su The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| description |
PurposeGenome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential variation in runt domain transcription factor 2 (RUNX2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding variants within RUNX2 binding sites and risk of osteoporosis in postmenopausal osteoporosis (PMOP).MethodsWe performed bioinformatics-based prediction by combining whole genome sequencing and chromatin immunoprecipitation sequencing to screen functional SNPs in the RUNX2 binding site using data from the database of Taiwan Biobank; Case-control studies with 651 postmenopausal women comprising 107 osteoporosis patients, 290 osteopenia patients, and 254 controls at Tri-Service General Hospital between 2015 and 2019 were included. The subjects were examined for bone mass density and classified into normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Furthermore, mRNA expression and luciferase reporter assay were used to provide additional evidence regarding the associations identified in the association analyses. Chi-square tests and logistic regression were mainly used for statistical assessment.ResultsThrough candidate gene approaches, 3 SNPs in the RUNX2 binding site were selected. A novel SNP rs6086746 in the PLCB4 promoter was identified to be associated with osteoporosis in Chinese populations. Patients with AA allele had higher risk of osteoporosis than those with GG+AG (adjusted OR = 6.89; 95% confidence intervals: 2.23–21.31, p = 0.001). Moreover, the AA genotype exhibited lower bone mass density (p < 0.05). Regarding mRNA expression, there were large differences in the correlation between PLCB4 and different RUNX2 alleles (Cohen’s q = 0.91). Functionally, the rs6086746 A allele reduces the RUNX2 binding affinity, thus enhancing the suppression of PLCB4 expression (p < 0.05).ConclusionsOur results provide further evidence to support the important role of the SNP rs6086746 in the etiology of osteopenia/osteoporosis, thereby enhancing the current understanding of the susceptibility to osteoporosis. We further studied the mechanism underlying osteoporosis regulation by PLCB4. |
| format |
article |
| author |
Dung-Jang Tsai Dung-Jang Tsai Wen-Hui Fang Li-Wei Wu Ming-Cheng Tai Chung-Cheng Kao Shih-Ming Huang Wei-Teing Chen Wei-Teing Chen Po-Jen Hsiao Po-Jen Hsiao Chih-Chien Chiu Wen Su Chia-Chun Wu Sui-Lung Su Sui-Lung Su |
| author_facet |
Dung-Jang Tsai Dung-Jang Tsai Wen-Hui Fang Li-Wei Wu Ming-Cheng Tai Chung-Cheng Kao Shih-Ming Huang Wei-Teing Chen Wei-Teing Chen Po-Jen Hsiao Po-Jen Hsiao Chih-Chien Chiu Wen Su Chia-Chun Wu Sui-Lung Su Sui-Lung Su |
| author_sort |
Dung-Jang Tsai |
| title |
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| title_short |
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| title_full |
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| title_fullStr |
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| title_full_unstemmed |
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation |
| title_sort |
polymorphism at plcb4 promoter (rs6086746) changes the binding affinity of runx2 and affects osteoporosis susceptibility: an analysis of bioinformatics-based case-control study and functional validation |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/151779b9018e43be8003a99816e486cd |
| work_keys_str_mv |
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