Semin Respir Crit Care Med 2013; 34(05): 568-580
DOI: 10.1055/s-0033-1355443
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Heritable Forms of Pulmonary Arterial Hypertension

Eric D. Austin
1   Division of Pulmonary, Allergy, and Immunology Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
,
James E. Loyd
2   Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
› Author Affiliations
Further Information

Publication History

Publication Date:
13 September 2013 (online)

Abstract

Tremendous progress has been made in understanding the genetics of heritable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). Recent advancements in gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH (CAV1, KCNK3). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. These characteristics suggest that genetic and nongenetic factors modify disease expression, highlighting areas of active investigation. The reduced penetrance makes genetic counseling complex, as the majority of carriers of PAH-related mutations will never be diagnosed with the disease. This issue is increasingly important, as clinical testing for BMPR2 and other mutations is now available for the evaluation of patients and their at-risk kin. The possibilities to avoid mutation transmission, such as the rapidly advancing field of preimplantation genetic testing, highlight the need for all clinicians to understand the genetic features of PAH risk.

 
  • References

  • 1 Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 1951; 11 (6) 686-705
  • 2 Dresdale DT, Michtom RJ, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance. Bull N Y Acad Med 1954; 30 (3) 195-207
  • 3 Machado RD, Eickelberg O, Elliott CG , et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S32-S42
  • 4 Loyd JE, Primm RK, Newman JH. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 1984; 129 (1) 194-197
  • 5 Thomas AQ, Gaddipati R, Newman JH, Loyd JE. Genetics of primary pulmonary hypertension. Clin Chest Med 2001; 22 (3) 477-491 , ix
  • 6 Thomson JR, Machado RD, Pauciulo MW , et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37 (10) 741-745
  • 7 Rich S, Dantzker DR, Ayres SM , et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107 (2) 216-223
  • 8 Nichols WC, Koller DL, Slovis B , et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 1997; 15 (3) 277-280
  • 9 Morse JH, Barst RJ. Detection of familial primary pulmonary hypertension by genetic testing. N Engl J Med 1997; 337 (3) 202-203
  • 10 Lane KB, Machado RD, Pauciulo MW , et al; International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26 (1) 81-84
  • 11 Deng Z, Morse JH, Slager SL , et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67 (3) 737-744
  • 12 Newman JH, Phillips III JA, Loyd JE. Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med 2008; 148 (4) 278-283
  • 13 Sztrymf B, Yaïci A, Girerd B, Humbert M. Genes and pulmonary arterial hypertension. Respiration 2007; 74 (2) 123-132
  • 14 Loyd JE, Butler MG, Foroud TM, Conneally PM, Phillips III JA, Newman JH. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 152 (1) 93-97
  • 15 Simonneau G, Robbins IM, Beghetti M , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S43-S54
  • 16 Sztrymf B, Yaici A, Jaïs X, Simonneau G, Sitbon O, Humbert M. Genetics of pulmonary arterial hypertension: recent data and practical applications [in French]. Rev Mal Respir 2005; 22 (5, Pt 1) 796-805
  • 17 Pearson CE, Nichol Edamura K, Cleary JD. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 2005; 6 (10) 729-742
  • 18 Armanios M, Chen JL, Chang YP , et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005; 102 (44) 15960-15964
  • 19 Larkin EK, Newman JH, Austin ED , et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186 (9) 892-896
  • 20 Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352 (9129) 719-725
  • 21 Machado RD, James V, Southwood M , et al. Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation 2005; 111 (5) 607-613
  • 22 Irey NS, Manion WC, Taylor HB. Vascular lesions in women taking oral contraceptives. Arch Pathol 1970; 89 (1) 1-8
  • 23 Morse JH, Horn EM, Barst RJ. Hormone replacement therapy: a possible risk factor in carriers of familial primary pulmonary hypertension. Chest 1999; 116 (3) 847
  • 24 Sweeney L, Voelkel NF. Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension. Eur J Med Res 2009; 14 (10) 433-442
  • 25 West J, Cogan J, Geraci M , et al. Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 2008; 1: 45
  • 26 Austin ED, Cogan JD, West JD , et al. Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 2009; 34 (5) 1093-1099
  • 27 Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet 2003; 361 (9368) 1533-1544
  • 28 Sztrymf BCF, Coulet F, Girerd B , et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008; 177 (12) 1377-1383
  • 29 Montani D, Marcelin AG, Sitbon O, Calvez V, Simonneau G, Humbert M. Human herpes virus 8 in HIV and non-HIV infected patients with pulmonary arterial hypertension in France. AIDS 2005; 19 (11) 1239-1240
  • 30 Archer SL, Michelakis ED. An evidence-based approach to the management of pulmonary arterial hypertension. Curr Opin Cardiol 2006; 21 (4) 385-392
  • 31 Elliott CG, Glissmeyer EW, Havlena GT , et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006; 113 (21) 2509-2515
  • 32 Rosenzweig EB, Morse JH, Knowles JA , et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008; 27 (6) 668-674
  • 33 Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005; 172 (9) 1072-1077
  • 34 Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Familial primary pulmonary hypertension locus mapped to chromosome 2q31-q32. Chest 1998; 114 (1, Suppl): 57S-58S
  • 35 Morse JH, Jones AC, Barst RJ, Hodge SE, Wilhelmsen KC, Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 1997; 95 (12) 2603-2606
  • 36 Newman JH, Trembath RC, Morse JA , et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol 2004; 43 (12, Suppl S ): 33S-39S
  • 37 Machado RD, Aldred MA, James V , et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006; 27 (2) 121-132
  • 38 Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 2009; 46 (5) 331-337
  • 39 Johnson DW, Berg JN, Baldwin MA , et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13 (2) 189-195
  • 40 McAllister KA, Grogg KM, Johnson DW , et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8 (4) 345-351
  • 41 Harrison RE, Flanagan JA, Sankelo M , et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 2003; 40 (12) 865-871
  • 42 Trembath RC, Thomson JR, Machado RD , et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345 (5) 325-334
  • 43 Chaouat A, Coulet F, Favre C , et al. Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 2004; 59 (5) 446-448
  • 44 Harrison RE, Berger R, Haworth SG , et al. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 2005; 111 (4) 435-441
  • 45 Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113 (6) 685-700
  • 46 Fernández-L A, Sanz-Rodriguez F, Blanco FJ, Bernabéu C, Botella LM. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res 2006; 4 (1) 66-78
  • 47 Bamshad MJ, Ng SB, Bigham AW , et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12 (11) 745-755
  • 48 Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009; 25 (14) 1754-1760
  • 49 Li H, Handsaker B, Wysoker A , et al; 1000 Genome Project Data Processing Subgroup. The sequence alignment/map format and SAMtools. Bioinformatics 2009; 25 (16) 2078-2079
  • 50 Austin ED, Ma L, LeDuc C , et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012; 5 (3) 336-343
  • 51 Chidlow Jr JH, Sessa WC. Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res 2010; 86 (2) 219-225
  • 52 Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of caveolae and caveolins in health and disease. Physiol Rev 2004; 84 (4) 1341-1379
  • 53 Frank PG, Cheung MW, Pavlides S, Llaverias G, Park DS, Lisanti MP. Caveolin-1 and regulation of cellular cholesterol homeostasis. Am J Physiol Heart Circ Physiol 2006; 291 (2) H677-H686
  • 54 Mercier I, Jasmin JF, Pavlides S , et al. Clinical and translational implications of the caveolin gene family: lessons from mouse models and human genetic disorders. Lab Invest 2009; 89 (6) 614-623
  • 55 Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol 2007; 8 (3) 185-194
  • 56 Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 2008; 48: 359-391
  • 57 Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG. Caveolin, a protein component of caveolae membrane coats. Cell 1992; 68 (4) 673-682
  • 58 Minshall RD, Sessa WC, Stan RV, Anderson RG, Malik AB. Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol 2003; 285 (6) L1179-L1183
  • 59 Xu Y, Buikema H, van Gilst WH, Henning RH. Caveolae and endothelial dysfunction: filling the caves in cardiovascular disease. Eur J Pharmacol 2008; 585 (2-3) 256-260
  • 60 Razani B, Engelman JA, Wang XB , et al. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 2001; 276 (41) 38121-38138
  • 61 Zhao YY, Liu Y, Stan RV , et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A 2002; 99 (17) 11375-11380
  • 62 Maniatis NA, Shinin V, Schraufnagel DE , et al. Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice. Am J Physiol Lung Cell Mol Physiol 2008; 294 (5) L865-L873
  • 63 Frank PG, Hassan GS, Rodriguez-Feo JA, Lisanti MP. Caveolae and caveolin-1: novel potential targets for the treatment of cardiovascular disease. Curr Pharm Des 2007; 13 (17) 1761-1769
  • 64 Drab M, Verkade P, Elger M , et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 2001; 293 (5539) 2449-2452
  • 65 Murata T, Lin MI, Huang Y , et al. Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice. J Exp Med 2007; 204 (10) 2373-2382
  • 66 Wertz JW, Bauer PM. Caveolin-1 regulates BMPRII localization and signaling in vascular smooth muscle cells. Biochem Biophys Res Commun 2008; 375 (4) 557-561
  • 67 Nohe A, Keating E, Underhill TM, Knaus P, Petersen NO. Dynamics and interaction of caveolin-1 isoforms with BMP-receptors. J Cell Sci 2005; 118 (Pt 3) 643-650
  • 68 Ramos M, Lamé MW, Segall HJ, Wilson DW. The BMP type II receptor is located in lipid rafts, including caveolae, of pulmonary endothelium in vivo and in vitro. Vascul Pharmacol 2006; 44 (1) 50-59
  • 69 Hartung A, Bitton-Worms K, Rechtman MM , et al. Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling. Mol Cell Biol 2006; 26 (20) 7791-7805
  • 70 García-Cardeña G, Oh P, Liu J, Schnitzer JE, Sessa WC. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci U S A 1996; 93 (13) 6448-6453
  • 71 García-Cardeña G, Martasek P, Masters BS , et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 1997; 272 (41) 25437-25440
  • 72 Sbaa E, Frérart F, Feron O. The double regulation of endothelial nitric oxide synthase by caveolae and caveolin: a paradox solved through the study of angiogenesis. Trends Cardiovasc Med 2005; 15 (5) 157-162
  • 73 Feron O, Balligand JL. Caveolins and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res 2006; 69 (4) 788-797
  • 74 Li XA, Everson W, Smart EJ. Nitric oxide, caveolae, and vascular pathology. Cardiovasc Toxicol 2006; 6 (1) 1-13
  • 75 Maniatis NA, Brovkovych V, Allen SE , et al. Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res 2006; 99 (8) 870-877
  • 76 Rath G, Dessy C, Feron O. Caveolae, caveolin and control of vascular tone: nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF) regulation. J Physiol Pharmacol 2009; 60 (Suppl. 04) 105-109
  • 77 Dessy C, Feron O, Balligand JL. The regulation of endothelial nitric oxide synthase by caveolin: a paradigm validated in vivo and shared by the 'endothelium-derived hyperpolarizing factor'. Pflugers Arch 2010; 459 (6) 817-827
  • 78 Rahman A, Swärd K. The role of caveolin-1 in cardiovascular regulation. Acta Physiol (Oxf) 2009; 195 (2) 231-245
  • 79 Patel HH, Zhang S, Murray F , et al. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. FASEB J 2007; 21 (11) 2970-2979
  • 80 Mathew R, Huang J, Gewitz MH. Pulmonary artery hypertension: caveolin-1 and eNOS interrelationship: a new perspective. Cardiol Rev 2007; 15 (3) 143-149
  • 81 Zhao YY, Malik AB. A novel insight into the mechanism of pulmonary hypertension involving caveolin-1 deficiency and endothelial nitric oxide synthase activation. Trends Cardiovasc Med 2009; 19 (7) 238-242
  • 82 Zhao YY, Zhao YD, Mirza MK , et al. Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 2009; 119 (7) 2009-2018
  • 83 Ma L, Roman-Campos D, Austin ED , et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369 (4) 351-361
  • 84 Olschewski A, Li Y, Tang B , et al. Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ Res 2006; 98 (8) 1072-1080
  • 85 Kuhr FK, Smith KA, Song MY, Levitan I, Yuan JX. New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. Am J Physiol Heart Circ Physiol 2012; 302 (8) H1546-H1562
  • 86 Streit AK, Netter MF, Kempf F , et al. A specific two-pore domain potassium channel blocker defines the structure of the TASK-1 open pore. J Biol Chem 2011; 286 (16) 13977-13984
  • 87 De Caestecker M, Meyrick B. Bone morphogenetic proteins, genetics and the pathophysiology of primary pulmonary hypertension. Respir Res 2001; 2 (4) 193-197
  • 88 Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425 (6958) 577-584
  • 89 Davies RJ, Morrell NW. Molecular mechanisms of pulmonary arterial hypertension: role of mutations in the bone morphogenetic protein type II receptor. Chest 2008; 134 (6) 1271-1277
  • 90 Machado RD, Pauciulo MW, Thomson JR , et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001; 68 (1) 92-102
  • 91 Koehler R, Grünig E, Pauciulo MW , et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet 2004; 41 (12) e127
  • 92 Morisaki H, Nakanishi N, Kyotani S, Takashima A, Tomoike H, Morisaki T. BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Hum Mutat 2004; 23 (6) 632
  • 93 Elliott CG. Genetics of pulmonary arterial hypertension: current and future implications. Semin Respir Crit Care Med 2005; 26 (4) 365-371
  • 94 Cogan JD, Pauciulo MW, Batchman AP , et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174 (5) 590-598
  • 95 Aldred MA, Vijayakrishnan J, James V , et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006; 27 (2) 212-213
  • 96 Fujiwara M, Yagi H, Matsuoka R , et al. Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J 2008; 72 (1) 127-133
  • 97 Rudarakanchana N, Flanagan JA, Chen H , et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 2002; 11 (13) 1517-1525
  • 98 Nishihara A, Watabe T, Imamura T, Miyazono K. Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 2002; 13 (9) 3055-3063
  • 99 Humbert M, Deng Z, Simonneau G , et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 2002; 20 (3) 518-523
  • 100 Khajavi M, Inoue K, Lupski JR. Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 2006; 14 (10) 1074-1081
  • 101 Yang X, Long L, Southwood M , et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005; 96 (10) 1053-1063
  • 102 Phillips III JA, Poling JS, Phillips CA , et al. Synergistic heterozygosity for TGFbeta1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet Med 2008; 10 (5) 359-365
  • 103 Hamid R, Cogan JD, Hedges LK , et al. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum Mutat 2009; 30 (4) 649-654
  • 104 Atkinson C, Stewart S, Upton PD , et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 2002; 105 (14) 1672-1678
  • 105 Aldred MA, Comhair SA, Varella-Garcia M , et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 182 (9) 1153-1160
  • 106 Abraham WT, Raynolds MV, Badesch DB , et al. Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics. J Renin Angiotensin Aldosterone Syst 2003; 4 (1) 27-30
  • 107 Hoeper MM, Tacacs A, Stellmacher U, Lichtinghagen R. Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension. Heart 2003; 89 (4) 445-446
  • 108 Koehler R, Olschewski H, Hoeper M, Janssen B, Grünig E. Serotonin transporter gene polymorphism in a cohort of German patients with idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Chest 2005; 128 (6, Suppl): 619S
  • 109 Machado RD, Koehler R, Glissmeyer E , et al. Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 173 (7) 793-797
  • 110 Willers ED, Newman JH, Loyd JE , et al. Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 173 (7) 798-802
  • 111 Remillard CV, Tigno DD, Platoshyn O , et al. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 2007; 292 (5) C1837-C1853
  • 112 Morrell NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling?. Proc Am Thorac Soc 2006; 3 (8) 680-686
  • 113 Morrell NW, Yang X, Upton PD , et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 2001; 104 (7) 790-795
  • 114 Zaiman AL, Podowski M, Medicherla S , et al. Role of the TGF-beta/Alk5 signaling pathway in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 2008; 177 (8) 896-905
  • 115 Germain M, Eyries M, Montani D , et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013; 45 (5) 518-521
  • 116 Yiangou Y, Burnet P, Nikou G, Chrysanthou BJ, Bloom SR. Purification and characterisation of cerebellins from human and porcine cerebellum. J Neurochem 1989; 53 (3) 886-889
  • 117 Runo JR, Vnencak-Jones CL, Prince M , et al. Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med 2003; 167 (6) 889-894
  • 118 Montani D, Achouh L, Dorfmüller P , et al. Pulmonary veno-occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore) 2008; 87 (4) 220-233
  • 119 Simonneau G, Galiè N, Rubin LJ , et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43 (12, Suppl S ): 5S-12S
  • 120 Abenhaim L, Moride Y, Brenot F , et al; International Primary Pulmonary Hypertension Study Group. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335 (9) 609-616
  • 121 Sztrymf B, Yaïci A, Jaïs X, Sitbon O, Simonneau G, Humbert M. Idiopathic pulmonary hypertension: what did we learn from genes?. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22 (Suppl. 01) S91-S100
  • 122 Roberts KE, McElroy JJ, Wong WP , et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004; 24 (3) 371-374
  • 123 Rubin LJ. BMPR2 mutation and outcome in pulmonary arterial hypertension: clinical relevance to physicians and patients. Am J Respir Crit Care Med 2008; 177 (12) 1300-1301
  • 124 McGoon M, Gutterman D, Steen V , et al; American College of Chest Physicians. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126 (1, Suppl): 14S-34S
  • 125 Jones DL, Sandberg JC, Rosenthal MJ, Saunders RC, Hannig VL, Clayton EW. What patients and their relatives think about testing for BMPR2. J Genet Couns 2008; 17 (5) 452-458
  • 126 Grünig E, Dehnert C, Mereles D , et al. Enhanced hypoxic pulmonary vasoconstriction in families of adults or children with idiopathic pulmonary arterial hypertension. Chest 2005; 128 (6, Suppl): 630S-633S
  • 127 Frydman N, Steffann J, Girerd B , et al. Pre-implantation genetic diagnosis in pulmonary arterial hypertension due to BMPR2 mutation. Eur Respir J 2012; 39 (6) 1534-1535
  • 128 Hamid R, Loyd J. Pre-implantation genetic testing for hereditary pulmonary arterial hypertension: promise and caution. Eur Respir J 2012; 39 (6) 1292-1293