Myeloproliferative Diseases as Possible Risk Factor for Development of Chronic Thromboembolic Pulmonary Hypertension—A Genetic Study

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected (p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients.

Integrated Bioinformatics Analysis Reveals Marker Genes and Potential Therapeutic Targets for Pulmonary Arterial Hypertension

“…PHAX was not specific in CTEPH. ZFYVE16 was reported to be associated with CTEPH [ 25 ], which is consistent with our result.…”

“…Belonging to the FYVE structural domain family, the candidate marker gene ZFYVE16 participates in pathways closely related to PAH, such as the TGF-Beta, BMP and EGFR signaling pathways [ 26 , 27 ]. A recent study detected its sequence variants in peripheral blood of CTEPH patients [ 25 ]. Additionally, it has been identified as one of the candidate genes related with PAH [ 28 ].…”

Cardiovascular Disease in Myeloproliferative Neoplasms

“… 51 , 57 , 58 Additionally, patients with MPNs have a heightened risk for pulmonary embolism and recurrent venous thromboembolism; thus, chronic thromboembolic pulmonary hypertension likely contributes to the prevalence of pulmonary hypertension in this patient population. 59 , 60 …”

Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension

“…Although significant increases in proliferation and cell viability were observed, lower NOTCH3 levels were detected in mutant cells and luciferase reporter assays indicated impaired NOTCH3-HES5 signalling (128). Targeted sequencing in other cohorts (13,85,(129)(130)(131) identified only two additional NOTCH3 missense variants in H/IPAH that meet our curation thresholds. The NOTCH3 receptor is one of four Notch human homologues and regulates vascular homeostasis by maintaining smooth muscle cells in an undifferentiated state (132,133).…”