Genetics
It is now well known that PAH can be either sporadic or clustered in families [111-114]. In 1954, Dresdale published a detailed description of a family that included three related subjects with severe PAH of unknown aetiology. Because of physician’s awareness of the familial occurrence of the disease, other cases of familial PAH were described. The National Institute of Health Registry (NIH Registry) provided the first estimate of this condition, and evaluated that at least 6% of individuals diagnosed with sporadic PAH have a family history of the disorder. In the French PAH registry, 26 cases of familial PAH were identified in the cohort of 674 patients, which corresponds to a prevalence of 3.9% of all cases of PAH and a proportion of 7.3% of familial PAH in the subgroup of idiopathic, familial or anorexigen-associated PAH [108]. Studies of genealogies of familial PAH advanced our understanding that the disease segregates an autosomal dominant trait with a markedly reduced penetrance, since only 10-20% of necessary carriers of the mutation will develop PAH [115,116]. In 2000, linkage analysis in PAH affected families found mutations within the bone morphogenetic protein receptor type 2 gene (BMPR2) [117,118]. BMPR2 gene encodes for a type 2 receptor member of the transforming growth factor beta (TGF-β) family. Nowadays, germline BMPR2 mutations are detected in 58-74% of PAH patients with a family history of the disease, and in 3.5-40% of so called idiopathic PAH patients [6,11,108,119-123]. The observation of the development of PAH in patients displaying hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular dysplasia, allowed us to identify two other PAH predisposing genes: ACVRL1 (Activin A receptor type II-like kinase 1) and ENG (endoglin) genes. Mutations in these two genes are infrequent in PAH but are frequently identified in HHT [120,124-130]. Moreover, recent reports described two PAH patients carriers of a mutation in Smad8 gene, one PAH patient carrier of a Smad1 mutation and one PAH patient carrier of a Smad5 mutation [8,9]. BMPR2 gene, ACVRL1, ENG, Smad8, Smad1 and Smad5 genes are encoding proteins which are involved in the TGF-β signaling pathway. More recently, using whole exome sequencing in a large PAH family, Austin et al. demonstrated the involved of mutations in caveolin-1 gene in the development of PAH [10] They confirmed their findinds identifying a caveolin-1 mutation in an unrelated PAH patient. Caveolin-1 protein is necessary for the formation of calveola, which are crucial for joining membrane receptors and initiating cellular signaling cascade such as TGF-β signalling pathway. This supports the hypothesis that mutations in genes involved in the TGF-β signaling pathway may be a trigger for pulmonary vascular remodeling. Moreover, this signaling pathway controls growth, differentiation and apoptosis of various cell types like pulmonary vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Thereby, mutations in genes involved in the TGF-β signaling pathway may be responsible for abnormal proliferation of pulmonary vascular SMCs and may promote ECs apoptosis, which might lead to the selection of apoptosis resistant cells and formation of plexiform lesions, the hallmark of idiopathic PAH [131,132].
The analysis of clinical, functional and hemodynamic characteristics of PAH patients revealed that patients carriers of a BMPR2 or an ACVRL1 mutation are younger at diagnosis than patients with idiopathic PAH. In addition, they have more severe hemodynamic parameters at diagnosis [114,120]. 
Several lines of evidence point to the potential requirement of additional factors, either environmental or genetic, in the pathogenesis of the disease. As mentioned, Humbert and co-workers have shown that exposure to fenfluramine derivatives greatly increase the risk of developing severe PAH in patients with BMPR2 mutations [111]. Moreover, modified genes could participate or facilitate the development of PAH. In fact, recent studies have suggested the potential role of serotonin transporters, serotonin receptors, potassium channels, or angiopoietin-1 [133]. Finally, PAH mostly occurs in females irrespective of BMPR2 mutation status [134]. To explain overrepresentation of PAH female patients, it was suggested that estrogen metabolism might participate in the pathogenesis of PAH [135,136].