Sequence Variants in <i>BMPR2</i> and Genes Involved in the Serotonin and Nitric Oxide Pathways in Idiopathic Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: Relation to Clinical Parameters and Comparison with Left Heart Disease

Abstract

Background: Idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) share important pathogenic and clinical features. BMPR2 mutations are important in the pathogenesis of IPAH, but little is known about the genetic background in CTEPH. Objective: To search for mutations and polymorphisms in genes involved in the BMPR2, serotonin and nitric oxide pathways possibly associated with pulmonary and cardiac disorders in IPAH and CTEPH. Methods: In a cohort of Swiss patients with IPAH (n = 16) and CTEPH (n = 16), and in 24 controls with left heart disease without PH, polymorphisms in the BMPR2, 5-HHT, 5-HTR-2A and eNOS genes were analyzed and correlated with various clinical, functional and hemodynamic parameters. Results: We found a BMPR2 missense mutation in a patient with coronary artery disease (CAD) without PH but no BMPR2 mutations in our collective with late-onset sporadic PH. In patients with polymorphic variants of the BMPR2 gene, the number of blood platelets and oxygen saturation were increased. The c.600A→C synonymous variant was associated with worse exercise capacity and decreased quality of life in PH. We found no significant differences for any measured parameter according to the eNOS, 5-HTR2A and the 5-HTT polymorphisms, although there was a higher allelic frequency of the 5-HTT long variant in IPAH than in CTEPH and controls. Conclusion: Our first report of a BMPR2 mutation in a patient with CAD without PH is interesting and warrants further investigation. Our study may reflect the clinical status and genetic background in a typical PH cohort as seen in a single tertiary care referral center.

Platelet Serotonin Content and Transpulmonary Platelet Serotonin Gradient in Patients with Pulmonary Hypertension

“…It could therefore be hypothesized that in PH patients serotonin is consumed or degraded in the lung, either through enhanced monoamine oxidase activity or increased uptake by the stressed endothelium, e.g. by increased serotonin uptake by 5-HTT on pulmonary vascular endothelial and smooth muscle cells, with increased 5-HTT expression on these cells in PAH patients compared with controls [25,26,27]. However, we do not know why platelet serotonin values were considerably higher in arterial compared with mixed venous blood in controls.…”

Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension

“…Mutations in this gene have been identified in more than 80% of patients with HPAH, although only 20% of carriers eventually develop the disease 4, 8–11 . On the other hand, the frequency of BMPR2 mutations in IPAH patients is much lower, ranging from 6–40% 12–15 . BMPR2 encodes for a transmembrane serine/threonine kinase receptor belonging to the transforming growth factor beta (TGF-β) superfamily, and is specifically recognized by bone morphogenetic proteins (BMPs), which are involved in several signalling pathways that regulate cellular differentiation, proliferation and apoptosis 16, 17 .…”

Pulmonary Hypertension for Clinicians: Time to Call on Genetics?

“…The presence of a BMPR2 mutation in a patient with coronary artery disease without phenotype of family history of PAH could indicate that BMPR2 mutation is not exclusively linked to PAH. However, this patient should be closely followed up [4] .…”

“…In the current issue of Respiration , Ulrich et al [4] describe genetic changes in patients with idiopathic PAH and chronic thromboembolic pulmonary hypertension (CTEPH) who were referred to the pulmonary hypertension centre in Zürich (Switzerland). They performed extensive genetic studies including the analysis of the BMPR2 gene, and polymorphisms in a variety of genes involved in the serotonin and nitric oxide pathway.…”