CBLN2 rs2217560 was Associated with Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus.
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SUBMITTER: Huang C
PROVIDER: S-EPMC6302654 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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<i>CBLN2</i> rs2217560 was Associated with Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus.
Huang Can C Yang Jun J Li Meng-Tao MT Wang Qian Q Zhao Jiu-Liang JL Yang Xiao-Xi XX Tian Zhuang Z Liu Yong-Tai YT Guo Xiao-Xiao XX Wang Hui H Lai Jin-Zhi JZ Xing Yan-Jiang YJ Zeng Xiao-Feng XF
Chinese medical journal 20181201 24
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Project description:BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that involves multi-organ damage. Pulmonary arterial hypertension (PAH) is one of the life-threatening complications of SLE. The underlying cause of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been fully comprehended. Besides the mechanisms implicated in the development of PAH, such as damage to the endothelial cells, the aberrant activation of the immune system also plays a substantial role in the pathogenesis of SLE-PAH.MethodsIn this study, peripheral blood samples from 100 patients with SLE-PAH and 95 patients of SLE without PAH (SLE-nonPAH) were obtained for RNA sequencing and comprehensive transcriptomic analysis. Pathway enrichment analysis was performed based on differentially expressed genes (DEGs) between SLE-PAH and SLE-nonPAH to elucidate the mechanisms potentially driving the development of PAH in SLE patients. Utilizing consensus non-negative matrix factorization (cNMF), we also conducted a detailed analysis to identify distinct subgroups within the SLE-PAH population. Meanwhile, the protein-protein interaction (PPI) analysis was performed and hub genes among the SLE-PAH subgroups were detected. Common transcription factors (TFs) of detected hub genes were also discovered to serve as potential therapeutic targets.ResultsInflammatory signaling pathways, notably those involving interferon and TNFα, were found to play an important role in the SLE-PAH. Utilizing cNMF method, three unique subgroups of SLE-PAH patients were delineated, each characterized by a distinct level of inflammatory activity. Specifically, the high inflammation subgroup, marked by the activity of Interleukin-6 (IL-6), exhibited a milder form of PAH. In contrast, the subgroup with moderate inflammation displayed the most pronounced PAH symptoms. Further disease enrichment analysis revealed that, beyond the dysregulated inflammatory pathways, patients with the most severe PAH exhibited distinct pathogenic transcriptomic profiles that disrupted vascular smooth muscle homeostasis, a critical component of vascular health. In the most severely affected subgroup, 13 hub genes were identified. Additionally, two transcription factors commonly associated with these genes, KLF1 and GATA1, were discovered, which may serve as potential therapeutic targets.ConclusionOur investigation establishes inflammation as a key driver in the development of SLE-PAH. Patients who presented with concurrent dysregulations in inflammatory responses along with PAH-specific pathogenic markers exhibited a marked increase in the severity of their PAH. The insights gleaned from our transcriptomic analysis reveal the intricate interplay between inflammatory mechanisms and the molecular substrates of PAH. This nuanced understanding paves the way for more targeted and effective therapeutic approaches for SLE-PAH.
| S-EPMC11921494 | biostudies-literature
Project description:ObjectiveThis study evaluated the prognostic value of the multivariable risk assessment for systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH).MethodsA multicenter prospective cohort of SLE-associated PAH (CSTAR-PAH cohort) diagnosed based on right heart catheterization (RHC) was established. Baseline and follow-up records were collected. Three methods of risk assessment, including (1) the number of low-risk criteria, based on World Health Organization functional class (WHO FC), 6-min walking distance (6MWD), right atrial pressure (RAP), and cardiac index (CI); (2) the three-strata stratification based on the average risk score of four variables (WHO FC, 6MWD, RAP, and CI); and (3) the four-strata stratification based on COMPARE 2.0 model were applied. A risk-assessment method using three noninvasive low-risk criteria was applied at the first follow-up visit. Survival curves between patients with different risk groups were compared by Kaplan-Meier's estimation and log-rank test.ResultsThree-hundred and ten patients were enrolled from 14 PAH centers. All methods of stratification at baseline and first follow-up significantly discriminated long-term survival. Survival rates were also significantly different based on the noninvasive risk assessment in first follow-up visit. Survival deteriorated with the escalation of risk from baseline to first follow-up. Patients with baseline serositis had a higher rate of risk improvement in their follow-up.ConclusionThe risk assessment has a significant prognostic value at both the baseline and first follow-up assessment of SLE-associated PAH. A noninvasive risk assessment can also be useful when RHC is not available during follow-up. Baseline serositis may be a predictor of good treatment response in patients with SLE-associated PAH.
| S-EPMC9310292 | biostudies-literature
Project description:BackgroundPulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension.Research questionTo develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension.MethodsA prognostic model was developed from a multicenter, longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. The study was conducted between November 2006 and February 2020. All-cause death was defined as the endpoint. Cox regression and least absolute shrinkage and selection operators were used to fit the model. Internal validation of the model was assessed by discrimination and calibration using bootstrapping.ResultsOf 310 patients included in the study, 81 (26.1%) died within a median follow-up of 5.94 years (interquartile range 4.67-7.46). The final prognostic model included eight variables: modified World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, estimated glomerular filtration rate, thrombocytopenia, mild interstitial lung disease, N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level, and direct bilirubin level. A 5-year death probability predictive algorithm was established and validated using the C-index (0.77) and a satisfactory calibration curve. Risk stratification was performed based on the predicted probability to improve clinical decision-making.ConclusionsThis new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors. External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.
| S-EPMC10492375 | biostudies-literature
Project description:Peking Union Medical College Hospital (PUMCH) has started a single-center right heart catheterization (RHC)-based pulmonary arterial hypertension (PAH) study in systemic lupus erythematosus (SLE) since 2006. The baseline characteristics of these patients were described and the risk factor for PAH in lupus was identified.The demographic, clinical, laboratory, and treatment characteristics of SLE patients with PAH when they were registered were collected as the baseline data. A case-control study was conducted by taking the admitted SLE-non-PAH patients adjusted for age and gender in a 4:1 ratio during the same period as the controls. The associated variables were examined by binary multivariate logistic regression analysis to identify possible risk factors. A total of 111 RHC-confirmed SLE-PAH patients were enrolled, with the onset age of 34.6 ± 8.6 years old and the average SLE duration of 5 years. RHC revealed mPAP as 46.4 ± 11.4 mm Hg, CI as 2.7 ± 0.8 L/min × m, and PVR as 10.5 ± 4.8 WU. 46% of patients were WHO Fc I-II. All patients were treated with immunosuppressive agents and 65% patients had PAH-targeted therapy. The case-control study had confirmed 2 independent risk factors previously published: pericardial effusion (OR = 21.290, P < 0.001) and anti-RNP antibody (OR = 12.399, P < 0.001). Meanwhile, 6 independent variables were discovered: baseline SLE duration (OR = 1.118, P = 0.007), interstitial lung disease (OR = 17.027, P < 0.001=, without acute rash (OR = 3.258, P = 0.019), anti-SSA antibody (OR = 4.836, P = 0.004), SLEDAI≤9 (OR = 26.426, P < 0.001), ESR≤20 mm/h (OR = 12.068, P < 0.001), and uric acid > 357 μmol/L (OR = 9.666, P < 0.001) to be associated with PAH in SLE patients.The PUMCH study has shown that SLE patients complicated with PAH are usually earlier diagnosed and have less disease severity than patients without PAH. The immunosuppressive therapy rate and the PAH target therapy rate were high, which is consistent with reports from Western countries. This study has confirmed that pericardial effusion and positive anti-RNP antibody are risk factors for SLE-associated PAH. Long SLE disease duration, the presence of interstitial lung disease, without acute skin rash, positive anti-SSA antibody, low SLEDAI and ESR, and high uric acid levels are also associated with PAH in SLE patients.
| S-EPMC4998855 | biostudies-literature
Project description:Growth-differentiation factor (GDF)-15 is a member of transforming growth factor-β-related cytokine and may respond to right ventricular overload. The objective of this article was to assess the diagnosis and prognostic value of GDF-15 in systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). Serum samples were obtained from 65 patients with SLE-PAH, 51 sex and age matched patients of SLE without PAH (SLE-non-PAH), and 32 healthy controls. Serum GDF-15 level was detected by enzyme-linked immunosorbent assay and the optimal cut-off point was determined by receiver operating characteristic curve. The primary end-point was death from any cause and the secondary end-point was target goal achievement (TGA). Cox regression analyses and Kaplan-Meier method were performed to identify the prognostic value of GDF-15. Serum GDF-15 levels were significantly higher in SLE-PAH patients (1112.14 ± 781.80 pg/mL) than SLE-non-PAH patients (810 ± 408 pg/mL) and healthy controls (442 ± 139 pg/mL) at baseline. The optimal cut-off value of GDF-15 in the diagnosis of SLE-PAH was 733 pg/mL (AUC = 0.84). In patients with SLE-PAH, GDF-15 level was associated with 6 min walking distance (ρ = -0.385, p = 0.017) and higher serum N terminal-pro brain natriuretic peptide (NT-proBNP) (ρ = 0.605, p < 0.001). Patients with GDF-15 > 733 pg/mL were more likely to death (adjusted hazard ratio [HR] = 4.01, 95% confidence intervals [CI]: 1.23-6.27, p = 0.041) and less likely to achieve treatment goal (adjusted HR = 0.57, 95% CI: 0.23-0.79, p = 0.028). In addition, patients with simultaneous elevation of GDF-15 and NT-proBNP showed lower proportion of TGA (p = 0.046). In conclusion, GDF-15 is a new and promising biomarker of development and prognosis in SLE-PAH. The combination of GDF-15 and NT-proBNP may provide more accurate prognostic information.
| S-EPMC9912020 | biostudies-literature
Project description:IntroductionPulmonary arterial hypertension (PAH) is a serious complication of systemic lupus erythematosus (SLE) with increased mortality. A prothrombotic state may contribute to pathogenesis of SLE-PAH. Extracellular vesicles (EVs) are known to be associated with thrombosis. Here, we investigated circulating EVs and their associations with SLE-PAH.MethodsEighteen SLE-PAH patients, 36 SLE-non-PAH patients, and 36 healthy controls (HCs) were enrolled. Flow cytometry was used to analyze circulating EVs from leukocytes (LEVs), red blood cells (REVs), platelets (PEVs), endothelial cells (EEVs), and Annexin V+ EVs with membrane phosphatidylserine (PS) exposure.ResultsPlasma levels of all EV subgroups were elevated in SLE patients with or without PAH compared to HCs. Furthermore, plasma Annexin V+ EVs, LEVs, PEVs, REVs, EEVs, and Annexin V+ REVs were significantly elevated in SLE-PAH patients compared to SLE-non-PAH patients. Additionally, PAH patients with moderate/high SLE showed a significant increase in LEVs, PEVs, REVs, Annexin V+ EVs, and Annexin V+ REVs compared to SLE-non-PAH patients. However, PAH patients with inactive/mild SLE only exhibited elevations in Annexin V+ EVs, REVs, and Annexin V+ REVs. In the SLE-PAH patients, EEVs were positively correlated with pulmonary arterial systolic pressure, while PEVs and EEVs were positively correlated with right ventricular diameter. Moreover, the receiver operating characteristic curve indicated that Annexin V+ EVs, LEVs, PEVs, REVs, EEVs and Annexin V+ REVs could predict the presence of PAH in SLE patients. Importantly, multivariate logistic regression analysis showed that circulating levels of LEVs or REVs, anti-nRNP antibody, and serositis were independent risk factors for PAH in SLE patients.DiscussionFindings reveal that specific subgroups of circulating EVs contribute to the hypercoagulation state and the severity of SLE-PAH. Higher plasma levels of LEVs or REVs may serve as biomarkers for SLE-PAH.
| S-EPMC11446868 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.
| S-EPMC3787920 | biostudies-other
Project description:BackgroundPulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE). This study aims to explore the clinical characteristics and prognosis in SLE-PAH based on consensus clustering and risk prediction model.MethodsA total of 205 PAH (including 163 SLE-PAH and 42 idiopathic PAH) patients were enrolled retrospectively based on medical records at the First Affiliated Hospital of Zhengzhou University from July 2014 to June 2021. Unsupervised consensus clustering was used to identify SLE-PAH subtypes that best represent the data pattern. The Kaplan-Meier survival was analyzed in different subtypes. Besides, the least absolute shrinkage and selection operator combined with Cox proportional hazards regression model were performed to construct the SLE-PAH risk prediction model.ResultsClustering analysis defined two subtypes, cluster 1 (n = 134) and cluster 2 (n = 29). Compared with cluster 1, SLE-PAH patients in cluster 2 had less favorable levels of poor cardiac, kidney, and coagulation function markers, with higher SLE disease activity, less frequency of PAH medications, and lower survival rate within 2 years (86.2% vs. 92.8%) (P < 0.05). The risk prediction model was also constructed, including older age at diagnosis (≥ 38 years), anti-dsDNA antibody, neuropsychiatric lupus, and platelet distribution width (PDW).ConclusionsConsensus clustering identified two distinct SLE-PAH subtypes which were associated with survival outcomes. Four prognostic factors for death were discovered to construct the SLE-PAH risk prediction model.
| S-EPMC10463535 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a devastating vascular complication of a number of connective tissue diseases, including systemic sclerosis (SSc), where it has a dramatic impact on the clinical course and overall survival and is the single most common cause of death in patients afflicted with this syndrome. Although remarkable advances have been achieved in elucidating the pathogenesis of PAH over the past 2 decades, leading to the development of disease-targeted therapies for the idiopathic form of this condition (IPAH), the response to therapy is suboptimal in SSc-related PAH (SSc-PAH), and survival remains very poor. Factors accounting for striking clinical and prognostic differences between these two syndromes are unclear but may include a more pronounced autoimmune, cellular, and inflammatory response, and a higher prevalence of comorbidities in SSc-PAH, including cardiac and pulmonary venous and parenchymal involvement. Furthermore, currently available markers of disease severity and clinical tools to assess response to therapy, which may be reliable in IPAH, are either limited or lacking in SSc-PAH. Thus, a more focused approach, including a better understanding of the pathogenesis and genetic factors underlying the development of SSc-PAH, a search for more specific and reliable tools to adequately assess functional impairment and monitor therapy, as well as the design of novel targeted therapies, are all urgently required to alter the dismal course of this syndrome.
| S-EPMC2894407 | biostudies-literature
Project description:ObjectiveThis study aimed to identify risk factors associated with the development of pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE).MethodsWe conducted a systematic literature review of studies focusing on adult patients classified as having SLE-related PAH by searching the electronic databases Embase, Medline, Medline in-progress, Wanfang, China National Knowledge Infrastructure, Ichushi Web, Kmbase, and KoreaMed. Based on the findings, we conducted a Delphi survey to build expert consensus on issues related to screening for PAH in patients with SLE and on the importance and feasibility of measuring the identified factors in clinical practice.ResultsWe included 21 eligible studies for data synthesis. Sixteen factors were associated with an increased risk of SLE-PAH: pericardial effusion, serositis, longer duration of SLE, arthritis, acute and subacute cutaneous lupus, scleroderma pattern on nailfold capillaroscopy, diffusion capacity of carbon monoxide in the lungs (DLCO) <70% predicted, interstitial lung disease, thrombocytopenia, and seven serological factors. Six factors were associated with a decreased risk of SLE-PAH: malar/acute rash, hematologic disorder, renal disorder, higher Systemic Lupus Erythematosus Disease Activity Index score, and two serological factors. Among these, there were six risk factors on which the panelists reached strong or general consensus (peak tricuspid regurgitation velocity on echocardiography >2.8 m/s, pericardial effusion, DLCO <70% predicted, scleroderma pattern on nailfold capillaroscopy, brain natriuretic peptide >50 ng/l, and N-terminal pro-brain natriuretic peptide >300 ng/l). The Delphi panel confirmed the need for a screening tool to identify patients with SLE at high risk of developing PAH and provided consensus on the importance and/or practicality of measuring the identified factors.ConclusionThe risk factors we identified could be used in a screening algorithm to identify patients with SLE with a high risk of developing PAH to facilitate early diagnosis, which could improve prognosis and management of these patients.
| S-EPMC10716809 | biostudies-literature