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Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension

BMC Cardiovascular Disorders volume 25, Article number: 38 (2025) Cite this article

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.

Peer Review reports

Introduction

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease with a complex pathogenesis, leading to high levels of disability and mortality [1]. Recent research indicates that the incidence of PAH among adults in developed countries ranges from approximately 5 to 10 cases per million, while the prevalence is estimated at 15 to 50 cases per million [2, 3]. This ratio may be higher in certain high-risk populations, such as those with genetic disorders or chronic infectious diseases in specific regions [4, 5]. PAH severely impacts patients’ quality of life and can lead to heart failure and premature death, making it crucial to understand its pathological mechanisms and to conduct clinical research. Despite advancements in targeted therapies and interventional treatments in recent years, early diagnosis and effective treatment of PAH remain challenging. Therefore, elucidating the pathogenesis of PAH and exploring potential therapeutic targets are critical for improving patient outcomes.

Clonal hematopoiesis (CH) has gained attention in recent years, particularly regarding its potential role in cardiovascular diseases [6, 7]. CH refers to the proliferation of a single clone of blood cells resulting from mutations in hematopoietic stem cells (HSCs). It is often age-related and considered a precursor to various hematological disorders [8, 9]. CH is associated with an altered inflammatory state, characterized by enhanced expression of IL-6 and IL-1β, pro-inflammatory T-cell polarization, and increased neutrophil extracellular traps, which elevate the risk of cardiovascular diseases [7]. The most commonly mutated driver genes associated with CH include DNA methyltransferases-3 Alpha (DNMT3A) and TET methylcytosine dioxygenase 2 (TET2). Current observational studies have identified a potential link between CH and cardiovascular diseases, particularly in coronary artery disease (CAD) and chronic thromboembolic pulmonary hypertension (CTEPH) [6, 10]. Two prospective cohorts found that carriers of CH had a 1.9 times higher risk of CAD and a 4.0 times higher risk of myocardial infarction compared to non-carriers [6]. In our preliminary study involving DNA sequencing of peripheral blood from 499 CTEPH patients, we found that 9.4% (47/499) carried CH-related gene mutations, with DNMT3A and TET2 being the most frequently observed [10]. Similarly, gene driver mutations associated with CH have also been identified in the PAH population. Qazazi et al. [11] discovered that 14.6% of PAH patients exhibited CH-related gene mutations, with DNMT3A as the most commonly mutated gene. The DNMT3A mutation causes pro-inflammatory T-cell polarization and activation of the inflammasome complex in all hematopoietic lineages [12]. Furthermore, recent targeted analyses from a PAH biobank have shown an increased burden of TET2 gene mutations in PAH patients [13]. This suggests that PAH may share susceptibility to CH, similar to that seen in CTEPH. TET2 mutation increases circulating levels of IL-1 through induction of the NLRP3 inflammasome, IL-6, and IL-8 [6, 14, 15]. Additionally, Potus et al. [16] found that mutations in CH-related genes (such as TET2) could promote the pathogenesis of PAH and have pro-inflammatory effects, providing further evidence for the correlation between CH and PAH. In summary, CH may serve as a risk factor that promotes the development of PAH through inflammatory mechanisms. While potential links between CH and cardiovascular diseases have been identified, the causal relationship between CH and PAH remains unclear.

Mendelian randomization (MR) is an observational study design that uses genetic variations as instrumental variables (IVs) to minimize confounding bias and effectively infer causal relationships [17]. Successful applications of MR have been reported in cardiovascular diseases, including investigations into causal relationships involving novel biomarkers and therapeutic targets [18, 19]. This study aims to explore the causal relationship between CH and PAH using MR methodology. Our findings highlight the potential genetic mechanisms underlying the CH-PAH relationship and aim to improve understanding of the role of CH in the pathogenesis of PAH, providing new insights and rationale for the prevention and treatment of this condition.

Methods

Study design

The study employed a two-sample MR approach, using genetic variants (single nucleotide polymorphisms, SNPs) as IVs to assess the causal relationship between the exposure factor, CH, and PAH [20]. The two-sample MR approach is the most commonly used methods, which greatly improves statistical power by integrating data from multiple sources [20]. As illustrated in Fig. 1, the following assumptions were made: (1) Assumption 1, IVs were significantly associated with CH; (2) Assumption 2, IVs were independent of other confounding factors; and (3) Assumption 3, the exposure factor was the sole pathway through which SNPs influence the outcome [20]. Furthermore, we considered PAH as the exposure factor and CH as the outcome variable, utilizing reverse MR analysis to evaluate the impact of PAH on CH. This report adhered to the guidelines set forth by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) for MR. The study followed ethical principles for medical research, with all data sourced from publicly accessible databases. Additionally, the Ethics Committee of the Second Hospital of Hebei Medical University approved the study for exemption, given that it used publicly available and anonymized data (Clinical trial number: not applicable).

Fig. 1
figure 1

Overview of present Mendelian randomization study

Full size image

Data sources and selection of instrumental variables

We obtained genetic variants associated with CH from public databases, which will serve as IVs. Summary statistics for CH were developed from a large genome-wide association studies (GWAS) published in Nature, which included data from 359,088 European participants as a discovery cohort (https://www.ebi.ac.uk/gwas/) [21]. The study revealed a strong association between specific gene mutations, such as DNMT3A, TET2, and additional sex combs like-1(ASXL1), etc., and the occurrence of CH [7]. To validate our primary findings, we further utilized another GWAS from a large CH study published in Nature Genetics as a validation cohort [22]. This cohort comprised 10,203 cases and 173,918 controls from European participants (https://zenodo.org/records/5893861). The mutated driver genes of CH were determined by whole-exome sequencing data from two cohorts.

We applied strict criteria for selecting SNPs as IVs for CH: these SNPs must be significantly associated with CH (P < 5 × 10− 8) and have no direct association with PAH. Additionally, we required the linkage disequilibrium level to be low (R² < 0.001, with a clustering distance of 10,000 kb) and the F-statistic to be sufficiently large (F > 10) [23]. We also reviewed each IV and its proxies in the iCPAGdb [24] (interactive Cross-Phenotype Analysis of GWAS database; https://github.com/tbalmat/iCPAGdb) to assess potential associations with confounders. The iCPAGdb provides information on pairwise trait signals and shared signals from trait associations with linkage disequilibrium proxy SNPs. The outcomes include Fisher’s exact test adjusted for a 5% false discovery rate and Bonferroni’s correction, among others.

The summary statistics for PAH were obtained from an international GWAS study and meta-analysis (PAH meta, https://www.ebi.ac.uk/gwas/), which included 11,744 individuals of European ancestry, comprising 2,085 patients [25]. PAH was defined as a mean pulmonary artery pressure of ≥ 25 mmHg, pulmonary artery wedge pressure ≤ 15 mm Hg, and pulmonary vascular resistance > 3 Wood units at rest.

To further validate the causal relationship between CH and PAH, we considered PAH as the exposure variable and CH as the outcome variable, conducting a reverse MR analysis. To obtain a sufficient number of SNPs as IVs, we applied the following selection criteria: the SNPs must be significantly associated with PAH (P < 5 × 10− 7) [26], while all other criteria remain unchanged.

Statistical analysis

We employed three different methods to assess the causal effect of CH or PAH on various outcomes: Inverse Variance Weighted (IVW), Weighted Median, and Mendelian Randomization Egger (MR-Egger). For our primary analysis, we used IVW to combine the beta values and standard errors of the causal estimate of CH with the risk of PAH [27]. If the number of instrumental variable SNPs is fewer than three, we will apply the Wald ratio method [28].

To evaluate the stability of the results, we used Cochran’s Q test to quantify heterogeneity [29]. The MR-Egger method assessed potential horizontal pleiotropy, where a non-zero intercept indicates its presence [30]. Additionally, we conducted a leave-one-out analysis to determine if any single SNP significantly impacts the MR analysis, allowing us to exclude the influence of potential outliers on our results. All data analyses were performed using R version 4.3.3. The results were presented as beta-values with corresponding 95% confidence intervals (CI). A P-value of less than 0.05 indicated statistical significance.

Results

Selection of genetic instrumental variables

As previously mentioned, we identified five driver genes associated with CH in the discovery cohort: DNMT3A, TET2, Janus kinase 2 (JAK2), ASXL1, and Tumor suppressor p53 (TP53). Of these, three genes-DNMT3A, TET2, and ASXL1- had a total of 33 SNPs that met our inclusion criteria (see Table S1).

In the validation cohort, two of these genes, DNMT3A and TET2, had 10 SNPs that also met the inclusion criteria (see Table S2). We used these SNPs in two-sample MR analyses to assess the impact of CH on the risk of PAH. Additionally, we reviewed all instrumental variables related to cross-phenotype associations using the iCPAGdb database and found no confounding factors.

The causal effect of CH on PAH

The forest plot illustrating the MR analysis results for the three genes related to PAH is shown in Fig. 2. The IVW analysis indicated that TET2 is a significant risk factor for PAH (OR = 1.200, 95% CI 1.001–1.438, P = 0.049), suggesting a positive correlation. In contrast, no significant causal relationship was observed for DNMT3A (OR = 1.011, 95% CI 0.870–1.175, P = 0.883), or ASXL1 (OR = 1.042, 95% CI 0.822–1.3215, P = 0.733) in relation to PAH (see Table S3). The weighted median analysis further indicated that both DNMT3A (OR = 1.068, 95% CI 0.846–1.320, P = 0.541) and TET2 (OR = 1.225, 95% CI 0.981–1.528, P = 0.073) are not significant risk factors for PAH. Additionally, MR Egger analysis revealed that neither DNMT3A (OR = 1.134, 95% CI 0.798–1.610, P = 0.491) nor TET2 (OR = 1.211, 95% CI 0.660–2.219, P = 0.581) are risk factors for PAH. The scatterplot demonstrates a causal relationship between CH and PAH (see Figure S1A-1B).

Fig. 2
figure 2

The genetic associations between clonal hematopoiesis and risk of pulmonary arterial hypertension

Full size image

Furthermore, our results were validated in a separate cohort, where TET2 remained a significant risk factor for PAH (OR = 2.3E + 08, 95% CI 17.007-3.1E + 15, P = 0.022), while DNMT3A was not found to be a significant risk factor (OR = 0.214, 95% CI 0.000-103.152, P = 0.625) (see Table S4).

The leave-one-out analysis, which involved conducting MR analyses on the remaining SNPs after excluding each SNP one at a time, produced consistent results and demonstrated the robustness of our findings (see Figure S1C-1D). Cochran’s Q test indicated no heterogeneity associated with TET2 across both in the discovery cohort (P = 0.942) and validation cohort (P = 0.347) (see Table S5). Additionally, the MR-Egger analysis showed no evidence of horizontal pleiotropy for the TET2 results in both in the discovery cohort (P = 0.979) and validation cohort (P = 0.476) (see Table S6).

The causal effect of PAH on CH

In our reverse MR analysis, we selected independent SNPs as IVs for PAH. We utilized the IVW method to assess whether there is a causal effect of PAH on CH. We identified five SNPs that met our inclusion criteria (see Table S7). The IVW analysis showed that PAH is not a risk factor for DNMT3A (OR = 0.998, 95% CI 0.995–1.002, P = 0.318), and TET2 (OR = 0.999, 95% CI 0.997–1.002, P = 0.662) (see Table S8).

Cochran’s Q statistic indicated that no heterogeneity was present (P > 0.05). Additionally, the MR-Egger analysis did not provide any evidence of horizontal pleiotropy (P > 0.05). Detailed information can be found in the supplementary materials (Table S9-S10).

Discussion

Our study is the first to investigate the potential causal relationship between CH and PAH using MR. The results reveal an association between CH with TET2 mutations, indicating a strong positive correlation with the occurrence of PAH. However, no correlation was found between DNMT3A and ASXL1 mutations and PAH. This study emphasizes the significance of genetic factors in understanding the etiology of PAH. Gaining insight into this relationship may enhance our understanding of PAH’s pathophysiology and identify potential therapeutic targets for treatment.

Our findings indicated a potential causal relationship between TET2 and PAH by IVW method. Although weighted median and MR-Egger showed that there was no statistical difference between TET2 and PAH, but both methods supported IVW (all Beta-values > 0, Tables S3 and S4). TET2 serves as a critical regulatory factor in DNA demethylation and belongs to the TET family of proteins. Mutations in TET2 have been established as key contributors to various hematological malignancies, with functional dysregulation leading to abnormal proliferation of blood cells [31]. Bick et al. [32] analyzed whole genome sequences from 97,691 participants and identified donor-specific TET2 risk variants in individuals of African ancestry. These variants disrupt TET2 enhancers in HSCs, resulting in decreased TET2 expression and increased self-renewal, which contribute to clonal hematopoiesis. Recent evidence also suggests that TET2 plays a role in regulating signaling pathways related to the initiation and resolution of inflammation. This implicates TET2 in inflammatory diseases such as atherosclerosis and rheumatoid arthritis [33].

In the context of PAH, TET2 mutations may influence the development of the condition through epigenetic regulation, affecting signaling pathways associated with inflammatory responses. Research has shown that TET2 mutations are linked to elevated circulating levels of inflammatory cytokines, such as IL-6 and IL-1β, in PAH patients [16]. Additionally, the study using Tet2−/− mouse models demonstrated a significant increase in circulating cytokine levels, including IL-1β, accompanied by heightened DNA methylation. This results in the spontaneous development of PAH [16]. Moreover, the application of the anti-IL-1β antibody (canakinumab) to inhibit IL-1β has been found to reverse PAH in Tet2 mutation mouse models [16]. These findings indicate that the complete or partial loss of TET2 function can lead to vascular remodeling as a result of increased inflammation, highlighting TET2 as a detrimental gene mutation associated with PAH. This research supports our conclusion that mutations in the TET2 gene are a risk factor for PAH. However, given the differences between mouse and human biology, further research is necessary to explore the role of TET2 in PAH patients.

In addition to TET2, DNMT3A is one of the most common driver genes in CH, and these two genes exhibit antagonistic biochemical activities. DNMT3A plays a crucial role in DNA methylation by catalyzing the addition of methyl groups to DNA, which forms 5-methylcytosine. In contrast, TET2 functions to remove these methyl groups by oxidizing them to 5-hydroxymethylcytosine [34, 35]. DNMT3A mutations lead to mild hypomethylation of the genome, whereas TET2 mutations result in hypermethylation [36, 37]. Moreover, CH associated with DNMT3A and TET2 mutations promotes the activation of the NLRP3 inflammasome in macrophages, which in turn leads to increased release of downstream inflammatory cytokines such as IL-1β [38]. In peripheral blood mononuclear cells from PAH patients, reduced expression of DNMT3A has been observed. In Dnmt3a−/− mouse models, there is an increase in pulmonary macrophages and elevated plasma levels of IL-13, which results in spontaneous PAH. Furthermore, administering IL-1β antibodies has been shown to alleviate PAH in these models [11]. ASXL1 ranks as the third most frequently mutated gene in CH, increasing the risk (2.0 times) of incident of CAD [6]. Although DNMT3A, ASXL1, and other genes did not demonstrate the causal effect on PAH in our study, their associations and potential relevance warrant further investigation.

Previous studies have highlighted the significance of CH in the risk of cardiovascular disease, and our research further supports the connection between CH and PAH. The presence of CH is associated with a pro-inflammatory state that may worsen pulmonary vascular remodeling and increase susceptibility to PAH. Studies suggest that CH encourages the differentiation of HSCs into immune cells with inflammatory phenotypes [39]. These inflammatory cells may infiltrate the lungs, leading to PAH, or embed within the endothelium, contributing to atherosclerosis and CAD [39]. In addition, Kimishima et al. [40] found that CH with JAK2 mutations promotes the upregulation of ALK1 in pulmonary neutrophils, leading to PAH. Further use of ALK 1/2 inhibitors completely prevents chronic hypoxia-induced PAH in JAK2 mediated CH without causing hematological toxicity [40]. Our study revealed that individuals carrying TET2 mutations have a 20% increased risk of developing PAH, suggesting that the CH patients should be screened for TET2 gene, and patients with these mutations should be monitored for the potential development of PAH. Furthermore, the presence of CH in peripheral blood cells doubles the risk of CAD [6]. Potus et al. [16] identified TET2 as a novel gene associated with harmful mutations in the largest cohort of PAH patients with TET2 mutations linked to idiopathic PAH showing a relative risk of 10.79 [16]. Additionally, TET2 mutations have been validated in Japanese PAH patients, corroborating these findings [41]. The collective evidence from these studies, along with our results, highlight that individuals carrying TET2 mutations face significantly elevated risks of developing PAH. This highlights the urgent need for further exploration of the underlying mechanisms and potential therapeutic interventions for this high-risk population.

DNMT3A and TET2 mutations contribute to approximately 50% of the CH mutations in patients with atherosclerosis [42]. These mutations increase the risk of CAD, with hazard ratios of 1.7 for DNMT3A and 1.9 for TET2 [6]. Moreover, individuals with TET2 mutations and CH may face an even higher risk of heart failure, accompanied by elevated levels of inflammatory factors [43]. Tet2 restrains inflammatory gene expression in macrophages [44]. Studies with Tet2 knockout mice have shown that several chemokine and cytokine genes that contribute to atherosclerosis are significantly upregulated [6]. Inhibition of the IL-1β -NLRP3 inflammasome has been shown to improve heart failure outcomes [43]. Research by Zhang et al. revealed that Tet2 selectively represses the expression of interleukin-6 (IL-6) during inflammation resolution by recruiting Hdac2 in dendritic cells and macrophages [15]. Interestingly, the presence of a variant in the IL-6 receptor gene (IL6R p.Asp358Ala), which targets IL-6 inhibition, reduces the risk of cardiovascular disease in carriers of DNMT3A and TET2 mutations by approximately 50% [45]. This underscores the potential of IL-6 signaling inhibition in lowering the risk of cardiovascular disease among individuals with CH. A randomized controlled trial using the anti-IL-1β antibody canakinumab demonstrated a reduction in adverse cardiovascular events in patients who had experienced myocardial infarction, with notable benefits observed in TET2-CH carriers [46]. Additionally, recent findings by Avagyan et al. [47] proposed that the interaction between CH and inflammation creates a continuous cycle, suggesting that blocking inflammation may be a feasible therapeutic approach for high-risk CH patients. In summary, these studies indicate that targeting CH driver genes or related inflammatory molecules may represent a promising therapeutic avenue for combating cardiovascular diseases.

Strengths and limitations

The strength of our research lies in the use of two-sample and bidirectional MR, which effectively mitigates confounding factors and reverse causation that often affect observational studies. By leveraging genetic variants associated with CH as IVs, we were able to draw robust causal inferences regarding their impact on the risk of PAH. Furthermore, the use of a large sample size from two cohorts enhances our statistical power, allowing for more precise estimates and bolstering the reliability of our conclusions. Overall, the methodological rigor employed in this study underscores the importance of CH with TET2 mutations as a potential risk factor for PAH.

This study does have some limitations. Firstly, while we utilized MR to minimize confounding biases, there remain potential confounding factors that we cannot completely control. Secondly, although our discovery and validation cohorts obtained similar results, it is important to recognize that there is heterogeneity between the two cohorts, including demographic factors and genetic diversity within the cohort. The generalizability of our findings may be limited due to the demographic structure of the cohorts, as genetic diversity can influence the prevalence and effects of CH across different ethnic groups. Lastly, while our study includes a validation cohort, the limited number of SNPs and borderline statistical significance may impact the robustness of our findings in relation to multiple testing. Therefore, further studies are needed to corroborate these findings and explore their potential therapeutic implications.

Conclusion

These findings showed that individuals with CH of TET2 mutations may have an increased risk of developing PAH. This finding provided new insights into the pathogenesis of PAH, suggesting that the CH patients may be tested for TET2 gene mutations. Additionally, patients with TET2 mutations should be aware of their potential risk for PAH. With advancements in technology and ongoing research, we look forward to exploring the role of CH in cardiovascular diseases more deeply, both in vivo and in vitro, and developing new strategies for the prevention and treatment of PAH.

Data availability

The raw data of this article will be made available publicly accessible databases (https://www.ebi.ac.uk/gwas/).

Abbreviations

ASXL1:

additional sex combs like-1

CAD:

coronary artery disease

CH:

Clonal hematopoiesis

CI:

confidence intervals

CTEPH:

chronic thromboembolic pulmonary hypertension

DNMT3A:

DNA methyltransferases-3 Alpha

GWAS:

genome-wide association studies

HSCs:

hematopoietic stem cells

IVs:

instrumental variables

IVW:

Inverse Variance Weighted

MR:

Mendelian randomization

PAH:

Pulmonary arterial hypertension

SNPs:

single nucleotide polymorphisms

STROBE:

Strengthening the Reporting of Observational Studies in Epidemiology

TET2:

TET methylcytosine dioxygenase 2

WM:

Weighted Median

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Acknowledgements

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Funding

This work was supported by grants from Key R&D Program Project of Hebei Province (21377701D) and Nature Science Foundation of Henan Province (182300410365).

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Author notes

  1. Jia-Yong Qiu and Shen-Shen Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei, China

    Jia-Yong Qiu, Yan-Hong Xu & Ya-Dong Yuan

  2. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, College of Clinical Medicine of Henan, University of Science and Technology, 24 Jinhua Road, Luoyang, China

    Jia-Yong Qiu, Shen-Shen Huang & Yi-Min Mao

  3. Department of Cardiology, Guangdong Provincial People’s Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China

    Chao Liu

  4. Institute 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 College, Beijing, China

    Dong Ding

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Contributions

JQ and SH designed and wrote the article. JQ and CL out the feasibility analysis of the article; JQ and DD management and collated the literature; SH and JQ analyzed the data; YX added some methods and results, and revised the manuscript. YM and YY obtained funding; YY is for the control and proofreading the quality, and the article responsible for the article, reading and collated reading. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yi-Min Mao or Ya-Dong Yuan.

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The study received exemption approval from the Ethics Committee of the Second Hospital of Hebei Medical University (Clinical trial number: not applicable).

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Qiu, JY., Huang, SS., Liu, C. et al. Genetic evidence for the causal effect of clonal hematopoiesis on pulmonary arterial hypertension. BMC Cardiovasc Disord 25, 38 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12872-025-04475-4

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Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

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