Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology

Abstract

Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD), affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of this disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is currently focused on the potential role of genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the transforming growth factor-beta (TGF-β) pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future, as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield reliable results that will allow a better understanding of SCD-related PH as a part of the disease's clinical spectrum. This review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.

Keywords: gene polymorphisms; gene sequencing; pulmonary hypertension; sickle cell disease.

Figure 1

Schematic representation of sickle cell disease complications. SCD: sickle cell disease, CNS: central nervous system. Created with https://gitmind.com/app/docs, 16 April 2024.

Figure 2

Pathophysiology of sickle cell-related pulmonary hypertension. NO: nitric oxide. (Created with https://gitmind.com/app/docs, 16 April 2024).

Figure 3

Gene polymorphisms associated with pulmonary hypertension mechanisms in SCD. TGF-β:transforming growth factor-β, ACVRL1: activin receptor-like kinase 1, BMP6: bone morphogenetic protein 6, ADRB1: beta-1 adrenergic receptor, TGFBR3: transforming growth factor beta receptor 3, TSP1: thrombospondin 1, NEDD4L: neural precursor cell-expressed developmentally downregulated gene 4-like, MTHFR: methylenetetrahydrofolate reductase, ET-1: endothelin-1, PRELP: proline/arginine-rich end leucine-rich repeat protein, RASA3: RAS P21 protein activator 3, MAPK8: mitogen-activated protein kinase 8, GST: glutathione S-transferase, ADORA2B: adenosine A2B receptor, GALNT13: polypeptide N-acetylgalactosaminyltransferase 13, eNOS: endothelial nitric oxide synthase, CYBR5: cytochrome b5 reductase, NO: nitric oxide. (Created with https://gitmind.com/app/docs, 16 April 2024).