scholarly journals BMPR2 Promoter Variants Effect Gene Expression in Pulmonary Arterial Hypertension Patients

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1168
Author(s):  
Jie Song ◽  
Katrin Hinderhofer ◽  
Lilian T. Kaufmann ◽  
Nicola Benjamin ◽  
Christine Fischer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transcriptional Activity ◽  
Disease Manifestation ◽  
Pathogenic Variants ◽  
Protein Receptor ◽  
Transcriptional Effect ◽  
Pulmonary Arterial ◽  
Human Pulmonary Artery

Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 (BMPR2) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930_-928dupGGC, c.-933_-928dupGGCGGC, c.-930_-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation.

scholarly journals Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

2018 ◽  
Vol 3 (3) ◽  
pp. 242-248 ◽  
Author(s):  
Matthew Moll ◽  
Romy B Christmann ◽  
Yuqing Zhang ◽  
Michael L Whitfield ◽  
Yu Mei Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Interstitial Lung Disease ◽  
Arterial Hypertension ◽  
Lung Disease ◽  
Expression Profiles ◽  
Area Under The Curve ◽  
Gene Expression Profiles ◽  
Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

scholarly journals At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1371
Author(s):  
Meghan M. Cirulis ◽  
Mark W. Dodson ◽  
Lynn M. Brown ◽  
Samuel M. Brown ◽  
Tim Lahm ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bone Morphogenetic Protein ◽  
Pulmonary Arteries ◽  
Bmp Signaling ◽  
Signaling Cascades ◽  
Estrogen Signaling ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

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