Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension
Abstract Background Pulmonary arterial hypertension (PAH) is a severe and progressive cardiovascular disease. While potential links between clonal hematopoiesis (CH) and cardiovascular diseases have been identified, the causal relationship between CH and PAH remains unclear. This study aims to inves...
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BMC
2025-01-01
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| Series: | BMC Cardiovascular Disorders |
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| Online Access: | https://doi.org/10.1186/s12872-025-04475-4 |
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| author | Jia-Yong Qiu Shen-Shen Huang Chao Liu Dong Ding Yan-Hong Xu Yi-Min Mao Ya-Dong Yuan |
| author_facet | Jia-Yong Qiu Shen-Shen Huang Chao Liu Dong Ding Yan-Hong Xu Yi-Min Mao Ya-Dong Yuan |
| author_sort | Jia-Yong Qiu |
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| description | Abstract Background Pulmonary arterial hypertension (PAH) is a severe and progressive cardiovascular disease. While potential links between clonal hematopoiesis (CH) and cardiovascular diseases have been identified, the causal relationship between CH and PAH remains unclear. This study aims to investigate the causal effect of CH on the risk of PAH using a two-sample Mendelian randomization (MR) approach. Methods We utilized genetic variants associated with CH as instrumental variables, identified from two large genome-wide association studies (GWAS) involving 359,088 participants in the discovery cohort and 184,121 participants in the validation cohort, all of European descent. We obtained GWAS summary statistics for PAH. The inverse-variance weighted (IVW) method was employed as the primary analysis, complemented by sensitivity analyses to assess the robustness of our findings. A bidirectional MR analysis was conducted to estimate the causation between CH and PAH. Results Our results indicate a causal effect of CH on the risk of PAH in the discovery cohort, with TET2 showing an IVW odds ratio (OR) of 1.200 (95% CI: 1.001–1.438, P = 0.049). Sensitivity analysis did not reveal significant pleiotropy or heterogeneity. In the validation cohort, we found that TET2 remains a risk factor for PAH (OR = 2.3E + 08, 95% CI 17.007-3.1E + 15, P = 0.022). Additionally, no causal relationship was found between other CH genes, such as DNMT3A and PAH (P > 0.05). The reverse MR analysis provided no evidence of causal effects of PAH on CH. Conclusion These findings showed that individuals with CH due to TET2 mutations may have a higher risk of developing PAH, suggesting that the CH patients may be tested for TET2 gene mutations. |
| format | Article |
| id | doaj-art-4a05f1562e514d07bf24356714c3151f |
| institution | Kabale University |
| issn | 1471-2261 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cardiovascular Disorders |
| spelling | doaj-art-4a05f1562e514d07bf24356714c3151f2025-01-26T12:14:24ZengBMCBMC Cardiovascular Disorders1471-22612025-01-012511810.1186/s12872-025-04475-4Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertensionJia-Yong Qiu0Shen-Shen Huang1Chao Liu2Dong Ding3Yan-Hong Xu4Yi-Min Mao5Ya-Dong Yuan6Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and TechnologyDepartment of Cardiology, Guangdong Provincial People’s Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical UniversityInstitute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, National Infrastructures for Translational Medicine, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and TechnologyDepartment of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical UniversityAbstract Background Pulmonary arterial hypertension (PAH) is a severe and progressive cardiovascular disease. While potential links between clonal hematopoiesis (CH) and cardiovascular diseases have been identified, the causal relationship between CH and PAH remains unclear. This study aims to investigate the causal effect of CH on the risk of PAH using a two-sample Mendelian randomization (MR) approach. Methods We utilized genetic variants associated with CH as instrumental variables, identified from two large genome-wide association studies (GWAS) involving 359,088 participants in the discovery cohort and 184,121 participants in the validation cohort, all of European descent. We obtained GWAS summary statistics for PAH. The inverse-variance weighted (IVW) method was employed as the primary analysis, complemented by sensitivity analyses to assess the robustness of our findings. A bidirectional MR analysis was conducted to estimate the causation between CH and PAH. Results Our results indicate a causal effect of CH on the risk of PAH in the discovery cohort, with TET2 showing an IVW odds ratio (OR) of 1.200 (95% CI: 1.001–1.438, P = 0.049). Sensitivity analysis did not reveal significant pleiotropy or heterogeneity. In the validation cohort, we found that TET2 remains a risk factor for PAH (OR = 2.3E + 08, 95% CI 17.007-3.1E + 15, P = 0.022). Additionally, no causal relationship was found between other CH genes, such as DNMT3A and PAH (P > 0.05). The reverse MR analysis provided no evidence of causal effects of PAH on CH. Conclusion These findings showed that individuals with CH due to TET2 mutations may have a higher risk of developing PAH, suggesting that the CH patients may be tested for TET2 gene mutations.https://doi.org/10.1186/s12872-025-04475-4Pulmonary arterial hypertensionClonal hematopoiesisMendelian randomizationTET2Inflammation |
| spellingShingle | Jia-Yong Qiu Shen-Shen Huang Chao Liu Dong Ding Yan-Hong Xu Yi-Min Mao Ya-Dong Yuan Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension BMC Cardiovascular Disorders Pulmonary arterial hypertension Clonal hematopoiesis Mendelian randomization TET2 Inflammation |
| title | Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| title_full | Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| title_fullStr | Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| title_full_unstemmed | Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| title_short | Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| title_sort | genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension |
| topic | Pulmonary arterial hypertension Clonal hematopoiesis Mendelian randomization TET2 Inflammation |
| url | https://doi.org/10.1186/s12872-025-04475-4 |
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