Heritable forms of pulmonary arterial hypertension

Seminars in Respiratory and Critical Care Medicine

Volumn 34, Issue 5, 2013, Pages 568-580

  Austin, Ericd ^a   Loyd, Jamese ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

bone morphogenetic protein receptor type 2; caveolin 1; CBLN2; genetics; hereditary hemorrhagic telangiectasia; KCNK3; modifiers; pulmonary arterial hypertension

Indexed keywords

ACTIVIN RECEPTOR LIKE KINASE 1; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CALCIUM CHANNEL BLOCKING AGENT; CAVEOLIN 1; CYTOCHROME P450 1B1; ENDOGLIN; MESSENGER RNA; PROSTACYCLIN; PROTEIN; SMAD9 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ARTICLE; AUTOSOMAL DOMINANT INHERITANCE; CHROMOSOME 12; CHROMOSOME 9; EXON; FAMILY HISTORY; GENE EXPRESSION; GENE MUTATION; GENETIC COUNSELING; GENETIC RISK; GENETIC SCREENING; GENETIC SUSCEPTIBILITY; GENOTYPE; HERITABLE PULMONARY ARTERIAL HYPERTENSION; HETEROZYGOSITY; HUMAN; LUNG ARTERY PRESSURE; PENETRANCE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; SIGNAL TRANSDUCTION; VASOCONSTRICTION;

ACTIVIN RECEPTORS, TYPE II; ANTIGENS, CD; BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; CAVEOLIN 1; FEMALE; GENE-ENVIRONMENT INTERACTION; GENETIC COUNSELING; GENETIC TESTING; GERM-LINE MUTATION; HUMANS; HYPERTENSION, PULMONARY; MALE; NERVE TISSUE PROTEINS; PENETRANCE; POTASSIUM CHANNELS, TANDEM PORE DOMAIN; PREGNANCY; PREIMPLANTATION DIAGNOSIS; RECEPTORS, CELL SURFACE; SEX DISTRIBUTION; TGF-BETA SUPERFAMILY PROTEINS;

EID: 84884241770     PISSN: 10693424     EISSN: 10989048     Source Type: Journal    
DOI: 10.1055/s-0033-1355443     Document Type: Article

References (128)

1. Dresdale D. T., Schultz M., Michtom R. J. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med: 1951; 11 6 686 705
2. Dresdale D. T., Michtom R. J., 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 R. D., Eickelberg O., Elliott C. G., et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol: 2009; 54 (1, Suppl): S32 S42
4. Loyd J. E., Primm R. K., Newman J. H. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis: 1984; 129 1 194 197
5. Thomas A. Q., Gaddipati R., Newman J. H., Loyd J. E. Genetics of primary pulmonary hypertension. Clin Chest Med: 2001; 22 3 477 491, ix
6. Thomson J. R., Machado R. D., Pauciulo M. W., 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 D. R., Ayres S. M., et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med: 1987; 107 2 216 223
8. Nichols W. C., Koller D. L., 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 J. H., Barst R. J. Detection of familial primary pulmonary hypertension by genetic testing. N Engl J Med: 1997; 337 3 202 203
10. Lane K. B., Machado R. D., Pauciulo M. W., 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 J. H., Slager S. L., 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 J. H., Phillips J. A. III, Loyd J. E. 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 J. E., Butler M. G., Foroud T. M., Conneally P. M., Phillips J. A. III, Newman J. H. 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 I. M., 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 C. E., Nichol Edamura K., Cleary J. D. Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet: 2005; 6 10 729 742
18. Armanios M., Chen J. L., Chang Y. P., 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 E. K., Newman J. H., Austin E. D., 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 S. P., Rubin L. J. Primary pulmonary hypertension. Lancet: 1998; 352 9129 719 725
21. Machado R. D., 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 N. S., Manion W. C., Taylor H. B. Vascular lesions in women taking oral contraceptives. Arch Pathol: 1970; 89 1 1 8
23. Morse J. H., Horn E. M., Barst R. J. Hormone replacement therapy: a possible risk factor in carriers of familial primary pulmonary hypertension. Chest: 1999; 116 3 847
24. Sweeney L., Voelkel N. F. 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 E. D., Cogan J. D., West J. D., 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 J. R., Loyd J. E. Primary pulmonary hypertension. Lancet: 2003; 361 9368 1533 1544
28. Sztrymf B. CF, 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 A. G., 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 S. L., Michelakis E. D. An evidence-based approach to the management of pulmonary arterial hypertension. Curr Opin Cardiol: 2006; 21 4 385 392
31. Elliott C. G., Glissmeyer E. W., Havlena G. T., et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation: 2006; 113 21 2509 2515
32. Rosenzweig E. B., Morse J. H., Knowles J. A., 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 J. H. Pulmonary hypertension. Am J Respir Crit Care Med: 2005; 172 9 1072 1077
34. Morse J. H., Jones A. C., Barst R. J., Hodge S. E., Wilhelmsen K. C., Nygaard T. G. Familial primary pulmonary hypertension locus mapped to chromosome 2q31-q32. Chest: 1998; 114 (1, Suppl): 57S 58S
35. Morse J. H., Jones A. C., Barst R. J., Hodge S. E., Wilhelmsen K. C., Nygaard T. G. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation: 1997; 95 12 2603 2606
36. Newman J. H., Trembath R. C., Morse J. A., 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 R. D., Aldred M. A., 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 D. W., Berg J. N., Baldwin M. A., 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 K. A., Grogg K. M., Johnson D. W., 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 R. E., Flanagan J. A., 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 R. C., Thomson J. R., Machado R. D., 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 R. E., Berger R., Haworth S. G., 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 F. J., Bernabéu C., Botella L. M. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res: 2006; 4 1 66 78
47. Bamshad M. J., Ng S. B., Bigham A. W., 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 E. D., 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 J. H. Jr, Sessa W. C. Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res: 2010; 86 2 219 225
52. Cohen A. W., Hnasko R., Schubert W., Lisanti M. P. Role of caveolae and caveolins in health and disease. Physiol Rev: 2004; 84 4 1341 1379
53. Frank P. G., Cheung M. W., Pavlides S., Llaverias G., Park D. S., Lisanti M. P. Caveolin-1 and regulation of cellular cholesterol homeostasis. Am J Physiol Heart Circ Physiol: 2006; 291 2 H677 H686
54. Mercier I., Jasmin J. F., 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 R. G., Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol: 2007; 8 3 185 194
56. Patel H. H., Murray F., Insel P. A. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol: 2008; 48 359 391
57. Rothberg K. G., Heuser J. E., Donzell W. C., Ying Y. S., Glenney J. R., Anderson R. G. Caveolin, a protein component of caveolae membrane coats. Cell: 1992; 68 4 673 682
58. Minshall R. D., Sessa W. C., Stan R. V., Anderson R. G., Malik A. B. Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol: 2003; 285 6 L1179 L1183
59. Xu Y., Buikema H., van Gilst W. H., Henning R. H. Caveolae and endothelial dysfunction: filling the caves in cardiovascular disease. Eur J Pharmacol: 2008; 585 2-3 256 260
60. Razani B., Engelman J. A., Wang X. B., 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 Y. Y., Liu Y., Stan R. V., 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 N. A., Shinin V., Schraufnagel D. E., 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 P. G., Hassan G. S., Rodriguez-Feo J. A., Lisanti M. P. 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 M. I., 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 J. W., Bauer P. M. 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 T. M., Knaus P., Petersen N. O. Dynamics and interaction of caveolin-1 isoforms with BMP-receptors. J Cell Sci: 2005; 118 Pt 3 643 650
68. Ramos M., Lamé M. W., Segall H. J., Wilson D. W. 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 M. M., 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 J. E., Sessa W. C. 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 B. S., 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 J. L. Caveolins and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res: 2006; 69 4 788 797
74. Li X. A., Everson W., Smart E. J. Nitric oxide, caveolae, and vascular pathology. Cardiovasc Toxicol: 2006; 6 1 1 13
75. Maniatis N. A., Brovkovych V., Allen S. E., 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 04 105 109
77. Dessy C., Feron O., Balligand J. L. 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 H. H., 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 M. H. Pulmonary artery hypertension: caveolin-1 and eNOS interrelationship: a new perspective. Cardiol Rev: 2007; 15 3 143 149
81. Zhao Y. Y., Malik A. B. 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 Y. Y., Zhao Y. D., Mirza M. K., 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 E. D., 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. 2+ signaling. Am J Physiol Heart Circ Physiol: 2012; 302 8 H1546 H1562
86. Streit A. K., Netter M. F., 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 Y. E. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature: 2003; 425 6958 577 584
89. Davies R. J., Morrell N. W. 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 R. D., Pauciulo M. W., Thomson J. R., 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 M. W., 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 C. G. Genetics of pulmonary arterial hypertension: current and future implications. Semin Respir Crit Care Med: 2005; 26 4 365 371
94. Cogan J. D., Pauciulo M. W., Batchman A. P., 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 M. A., 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 J. A., 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 J. R. 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 J. A. III, Poling J. S., Phillips C. A., 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 J. D., Hedges L. K., 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 P. D., 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 M. A., Comhair S. A., 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 W. T., Raynolds M. V., Badesch D. B., 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 M. M., 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 R. D., 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 E. D., Newman J. H., Loyd J. E., 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 C. V., Tigno D. D., 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 N. W. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc: 2006; 3 8 680 686
113. Morrell N. W., Yang X., Upton P. D., 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 A. L., 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 B. J., Bloom S. R. Purification and characterisation of cerebellins from human and porcine cerebellum. J Neurochem: 1989; 53 3 886 889
117. Runo J. R., Vnencak-Jones C. L., 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 L. J., 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 01 S91 S100
122. Roberts K. E., McElroy J. J., Wong W. P., et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J: 2004; 24 3 371 374
123. Rubin L. J. 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 D. L., Sandberg J. C., Rosenthal M. J., Saunders R. C., Hannig V. L., Clayton E. W. 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