Genetic Insights into Pulmonary Arterial Hypertension. Application of Whole-Exome Sequencing to the Study of Pathogenic Mechanisms

Background Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5 , which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD , which encodes thrombomodulin. Moreover, thrombin‐activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.

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Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Genome Medicine ◽

10.1186/s13073-019-0685-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 21

Author(s):

Na Zhu ◽

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Michael W. Pauciulo ◽

Carrie L. Welch ◽

Katie A. Lutz ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Exome Sequencing ◽

Receptor Type ◽

Data Repository ◽

Risk Genes ◽

New Genes ◽

Genome Wide ◽

Pulmonary Arterial

Abstract Background Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. Methods To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni’s correction for multiple testing. Results Tissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH. Conclusions We report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.

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Late-onset pulmonary arterial hypertension in repaired D-transposition of great arteries: an uncommon complication

Pulmonary Circulation ◽

10.1177/2045893217699228 ◽

2017 ◽

Vol 7 (2) ◽

pp. 547-550 ◽

Cited By ~ 1

Author(s):

Janani Baskaran ◽

Kimara S. March ◽

Thenappan Thenappan

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Surgical Repair ◽

Late Onset ◽

Fatal Complication ◽

Transposition Of Great Arteries ◽

Pathogenic Mechanisms ◽

Pulmonary Arterial ◽

Uncommon Complication

Late-onset pulmonary arterial hypertension (PAH) is a rare but fatal complication in patients with childhood surgical repair of dextro-transposition of great arteries (D-TGA), especially with the Mustard and Senning procedures. The pathogenic mechanisms of PAH in patients with repaired D-TGA are not well understood and treatment is not standardized. In this manuscript, we present a case of late-onset PAH in an adult D-TGA patient after Mustard repair and discuss the pathogenic mechanisms, diagnosis, and treatment of pulmonary hypertension in repaired D-TGA.

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