DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study
Background: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that can result in limb pain, disability, or mortality. Notably, diabetes mellitus (DM) stands out as one of the most significant risk factors for the development of PAD. Compared to individuals with PAD but n...
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Ubiquity Press
2024-12-01
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| Series: | Global Heart |
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| Online Access: | https://account.globalheartjournal.com/index.php/up-j-gh/article/view/1373 |
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| author | Qiaoqiao Li Fuli Cao Xueping Gao Yuan Xu Bo Li Tianyang Hu |
| author_facet | Qiaoqiao Li Fuli Cao Xueping Gao Yuan Xu Bo Li Tianyang Hu |
| author_sort | Qiaoqiao Li |
| collection | DOAJ |
| description | Background: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that can result in limb pain, disability, or mortality. Notably, diabetes mellitus (DM) stands out as one of the most significant risk factors for the development of PAD. Compared to individuals with PAD but no DM, those with concurrent DM and PAD (DM-PAD, diabetes mellitus–peripheral artery disease) face a seven-fold higher risk of critical limb ischemia and a five-fold higher risk of amputation. However, the pathogenic factors and effective therapeutic targets for DM-PAD still remain elusive. Method: To identify candidate hub genes and develop insights into the pathogenesis of DM-PAD, we employed a comprehensive approach encompassing two-sample Mendelian Randomization (two-sample MR), summary data-based Mendelian randomization (SMR), and Bayesian colocalization (COLOC) methods. These methodologies facilitated the integration of summary-level data derived from genome-wide association studies of DM-PAD with expression quantitative trait locus (eQTLs) studies conducted on blood samples. Result: DENND5B, C4A, and CYP21A2 were found to have passed two-sample MR and SMR analyses, indicating their status as hub genes associated with DM-PAD through mechanisms involving not linkage but rather causality. The COLOC analysis provided strong evidence suggesting that DENND5B and the DM-PAD trait were influenced by the common causal variant rs1150948. Conclusion: Our study has pinpointed several crucial genes (DENND5B, C4A, and CYP21A2), notably the DENND5B gene, as potential regulators in the pathogenesis of DM-PAD. These discoveries hold promises for shedding light on the underlying mechanisms and novel targets of the disease in future research. |
| format | Article |
| id | doaj-art-59d28b5d40bd4242bcc08f1229f810f6 |
| institution | Kabale University |
| issn | 2211-8179 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Ubiquity Press |
| record_format | Article |
| series | Global Heart |
| spelling | doaj-art-59d28b5d40bd4242bcc08f1229f810f62025-01-08T07:57:07ZengUbiquity PressGlobal Heart2211-81792024-12-01191919110.5334/gh.13731354DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization StudyQiaoqiao Li0Fuli Cao1Xueping Gao2Yuan Xu3Bo Li4Tianyang Hu5Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, Chongqing, 400010Department of Geriatrics and Special Service Medicine, First Affiliated Hospital of Army Medical University (Southwest Hospital), Chongqing, 400038Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, 200000Chongqing University Jiangjin Hospital, Chongqing University, Chongqing, 402260Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010Background: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that can result in limb pain, disability, or mortality. Notably, diabetes mellitus (DM) stands out as one of the most significant risk factors for the development of PAD. Compared to individuals with PAD but no DM, those with concurrent DM and PAD (DM-PAD, diabetes mellitus–peripheral artery disease) face a seven-fold higher risk of critical limb ischemia and a five-fold higher risk of amputation. However, the pathogenic factors and effective therapeutic targets for DM-PAD still remain elusive. Method: To identify candidate hub genes and develop insights into the pathogenesis of DM-PAD, we employed a comprehensive approach encompassing two-sample Mendelian Randomization (two-sample MR), summary data-based Mendelian randomization (SMR), and Bayesian colocalization (COLOC) methods. These methodologies facilitated the integration of summary-level data derived from genome-wide association studies of DM-PAD with expression quantitative trait locus (eQTLs) studies conducted on blood samples. Result: DENND5B, C4A, and CYP21A2 were found to have passed two-sample MR and SMR analyses, indicating their status as hub genes associated with DM-PAD through mechanisms involving not linkage but rather causality. The COLOC analysis provided strong evidence suggesting that DENND5B and the DM-PAD trait were influenced by the common causal variant rs1150948. Conclusion: Our study has pinpointed several crucial genes (DENND5B, C4A, and CYP21A2), notably the DENND5B gene, as potential regulators in the pathogenesis of DM-PAD. These discoveries hold promises for shedding light on the underlying mechanisms and novel targets of the disease in future research.https://account.globalheartjournal.com/index.php/up-j-gh/article/view/1373diabetes combined peripheral artery diseasesummary-data-based mendelian randomizationmultivariable mendelian randomization |
| spellingShingle | Qiaoqiao Li Fuli Cao Xueping Gao Yuan Xu Bo Li Tianyang Hu DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study Global Heart diabetes combined peripheral artery disease summary-data-based mendelian randomization multivariable mendelian randomization |
| title | DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study |
| title_full | DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study |
| title_fullStr | DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study |
| title_full_unstemmed | DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study |
| title_short | DENND5B Gene Expression as a Trigger for the Development of Diabetes Mellitus–Peripheral Artery Disease: Insights from a Univariate and Multivariate Mendelian Randomization Study |
| title_sort | dennd5b gene expression as a trigger for the development of diabetes mellitus peripheral artery disease insights from a univariate and multivariate mendelian randomization study |
| topic | diabetes combined peripheral artery disease summary-data-based mendelian randomization multivariable mendelian randomization |
| url | https://account.globalheartjournal.com/index.php/up-j-gh/article/view/1373 |
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