Skip to main content
PMC home page
Journal of Clinical Pathology logoLink to Journal of Clinical Pathology
. 2000 Dec;53(12):899–903. doi: 10.1136/jcp.53.12.899

Primary pulmonary hypertension: the pressure rises for a gene

J Thomson 1, R Trembath 1
PMCID: PMC1731125  PMID: 11265173

Abstract

Primary pulmonary hypertension (PPH) represents the end stage of a disruption of pulmonary vascular integrity, of unknown cause. Although PPH is associated with several systemic disorders, there have hitherto been few clues as to the aetiological factors responsible for the pathogenesis of this condition. As an example of the application of modern molecular genetics and positional cloning, this leader desribes the range of studies currently under way, which aim to find the gene that underlies PPH, and summarises the implications of the identification of such a gene.

Key Words: pulmonary hypertension • genetics • chromosome 2q33

Full Text

The Full Text of this article is available as a PDF (125.6 KB).

graphic file with name 0082.f1.jpg

Open in a new tab

Figure 1 Familial primary pulmonary hypertension (PPH). A hypothetical pedigree illustrating reduced genetic penetrance of the disease (that is, skipping of generations) as seen in individuals II:2 and III:2, "anticipation" (earlier age of onset in successive generations), and the female preponderance. Open square, unaffected male; open circle, unaffected female; closed square, affected male; closed circle, affected female; slash, deceased.

graphic file with name 0082.f2.jpg

Open in a new tab

Figure 2 Idiogram of the long arm of chromosome 2 (2q). The PPH1 gene location showing genetic markers D2S335 and D2S369 and the reduction of the critical interval from 25 to 6 centimorgans (cM).

graphic file with name 0082.f3.jpg

Open in a new tab

Figure 3 Idealised positional cloning strategy to identify the PPH1 gene. (1) First, further families with primary pulmonary hypertension (PPH) are required to reduce the PPH1 critical interval by the detection of recombinant events; that is, identifying that part of 2q33 shared by affected individuals within a family. (2) Use of data from the human genome project to identify genes and expressed sequence tags (ESTs or partially sequenced genes) that appear to be contained within the PPH1 critical interval (for example, genes A, B, C, and D). To place these genes, ESTs, and other DNA markers in the correct order, a series of overlapping DNA clones inserted into yeast, bacteria, or plasmid artificial chromosomes (YACs, BACs, and PACs, respectively) is created: a so called physical map. (3) Studies are undertaken to identify which of these genes are expressed in lung tissue and hence are good candidates for PPH1. (4) Finally, direct analysis of genes to detect a mutation in affected individuals compared with normal controls.

graphic file with name 0082.f4.jpg

Open in a new tab

Figure 4 Inhibition of voltage gated potassium channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension (PPH) causing membrane potential depolarisation, a rise in intracellular calcium, and vasoconstriction.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abenhaim L., Moride Y., Brenot F., Rich S., Benichou J., Kurz X., Higenbottam T., Oakley C., Wouters E., Aubier M. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996 Aug 29;335(9):609–616. doi: 10.1056/NEJM199608293350901. [DOI] [PubMed] [Google Scholar]
  2. Botney M. D., Bahadori L., Gold L. I. Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. Am J Pathol. 1994 Feb;144(2):286–295. [PMC free article] [PubMed] [Google Scholar]
  3. Brenot F., Herve P., Petitpretz P., Parent F., Duroux P., Simonneau G. Primary pulmonary hypertension and fenfluramine use. Br Heart J. 1993 Dec;70(6):537–541. doi: 10.1136/hrt.70.6.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. COLEMAN P. N., EDMUNDS A. W., TREGILLUS J. Primary pulmonary hypertension in three sibs. Br Heart J. 1959 Jan;21(1):81–88. doi: 10.1136/hrt.21.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Christman B. W., McPherson C. D., Newman J. H., King G. A., Bernard G. R., Groves B. M., Loyd J. E. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):70–75. doi: 10.1056/NEJM199207093270202. [DOI] [PubMed] [Google Scholar]
  6. D'Alonzo G. E., Barst R. J., Ayres S. M., Bergofsky E. H., Brundage B. H., Detre K. M., Fishman A. P., Goldring R. M., Groves B. M., Kernis J. T. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991 Sep 1;115(5):343–349. doi: 10.7326/0003-4819-115-5-343. [DOI] [PubMed] [Google Scholar]
  7. 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 Mar;30(3):195–207. [PMC free article] [PubMed] [Google Scholar]
  8. DRESDALE D. T., SCHULTZ M., MICHTOM R. J. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med. 1951 Dec;11(6):686–705. doi: 10.1016/0002-9343(51)90020-4. [DOI] [PubMed] [Google Scholar]
  9. Deng Z., Haghighi F., Helleby L., Vanterpool K., Horn E. M., Barst R. J., Hodge S. E., Morse J. H., Knowles J. A. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):1055–1059. doi: 10.1164/ajrccm.161.3.9906051. [DOI] [PubMed] [Google Scholar]
  10. Durand J. B. Genetic basis of cardiomyopathy. Curr Opin Cardiol. 1999 May;14(3):225–229. doi: 10.1097/00001573-199905000-00006. [DOI] [PubMed] [Google Scholar]
  11. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995 Jul 27;333(4):214–221. doi: 10.1056/NEJM199507273330403. [DOI] [PubMed] [Google Scholar]
  12. Giaid A., Yanagisawa M., Langleben D., Michel R. P., Levy R., Shennib H., Kimura S., Masaki T., Duguid W. P., Stewart D. J. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993 Jun 17;328(24):1732–1739. doi: 10.1056/NEJM199306173282402. [DOI] [PubMed] [Google Scholar]
  13. Gomez-Sanchez M. A., Saenz de la Calzada C., Gomez-Pajuelo C., Martinez-Tello F. J., Mestre de Juan M. J., James T. N. Clinical and pathologic manifestations of pulmonary vascular disease in the toxic oil syndrome. J Am Coll Cardiol. 1991 Nov 15;18(6):1539–1545. doi: 10.1016/0735-1097(91)90688-6. [DOI] [PubMed] [Google Scholar]
  14. Gurtner H. P. Aminorex and pulmonary hypertension. A review. Cor Vasa. 1985;27(2-3):160–171. [PubMed] [Google Scholar]
  15. Higenbottam T. W., Spiegelhalter D., Scott J. P., Fuster V., Dinh-Xuan A. T., Caine N., Wallwork J. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J. 1993 Oct;70(4):366–370. doi: 10.1136/hrt.70.4.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hood W. B., Jr, Spencer H., Lass R. W., Daley R. Primary pulmonary hypertension: familial occurrence. Br Heart J. 1968 May;30(3):336–343. doi: 10.1136/hrt.30.3.336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kim K. K., Factor S. M. Membranoproliferative glomerulonephritis and plexogenic pulmonary arteriopathy in a homosexual man with acquired immunodeficiency syndrome. Hum Pathol. 1987 Dec;18(12):1293–1296. doi: 10.1016/s0046-8177(87)80417-3. [DOI] [PubMed] [Google Scholar]
  18. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lee S. D., Shroyer K. R., Markham N. E., Cool C. D., Voelkel N. F., Tuder R. M. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998 Mar 1;101(5):927–934. doi: 10.1172/JCI1910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Loyd J. E., Butler M. G., Foroud T. M., Conneally P. M., Phillips J. A., 3rd, Newman J. H. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med. 1995 Jul;152(1):93–97. doi: 10.1164/ajrccm.152.1.7599869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Loyd J. E., Primm R. K., Newman J. H. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis. 1984 Jan;129(1):194–197. doi: 10.1164/arrd.1984.129.1.194. [DOI] [PubMed] [Google Scholar]
  22. Machado R. D., Pauciulo M. W., Fretwell N., Veal C., Thomson J. R., Vilariño Güell C., Aldred M., Brannon C. A., Trembath R. C., Nichols W. C. A physical and transcript map based upon refinement of the critical interval for PPH1, a gene for familial primary pulmonary hypertension. The International PPH Consortium. Genomics. 2000 Sep 1;68(2):220–228. doi: 10.1006/geno.2000.6291. [DOI] [PubMed] [Google Scholar]
  23. Mesa R. A., Edell E. S., Dunn W. F., Edwards W. D. Human immunodeficiency virus infection and pulmonary hypertension: two new cases and a review of 86 reported cases. Mayo Clin Proc. 1998 Jan;73(1):37–45. doi: 10.1016/S0025-6196(11)63616-1. [DOI] [PubMed] [Google Scholar]
  24. Morse J. H., Barst R. J. Detection of familial primary pulmonary hypertension by genetic testing. N Engl J Med. 1997 Jul 17;337(3):202–203. doi: 10.1056/NEJM199707173370315. [DOI] [PubMed] [Google Scholar]
  25. 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 Jun 17;95(12):2603–2606. doi: 10.1161/01.cir.95.12.2603. [DOI] [PubMed] [Google Scholar]
  26. Nichols W. C., Koller D. L., Slovis B., Foroud T., Terry V. H., Arnold N. D., Siemieniak D. R., Wheeler L., Phillips J. A., 3rd, Newman J. H. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet. 1997 Mar;15(3):277–280. doi: 10.1038/ng0397-277. [DOI] [PubMed] [Google Scholar]
  27. Opravil M., Pechère M., Speich R., Joller-Jemelka H. I., Jenni R., Russi E. W., Hirschel B., Lüthy R. HIV-associated primary pulmonary hypertension. A case control study. Swiss HIV Cohort Study. Am J Respir Crit Care Med. 1997 Mar;155(3):990–995. doi: 10.1164/ajrccm.155.3.9117037. [DOI] [PubMed] [Google Scholar]
  28. Rich S., Dantzker D. R., Ayres S. M., Bergofsky E. H., Brundage B. H., Detre K. M., Fishman A. P., Goldring R. M., Groves B. M., Koerner S. K. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987 Aug;107(2):216–223. doi: 10.7326/0003-4819-107-2-216. [DOI] [PubMed] [Google Scholar]
  29. Rich S., Kaufmann E., Levy P. S. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992 Jul 9;327(2):76–81. doi: 10.1056/NEJM199207093270203. [DOI] [PubMed] [Google Scholar]
  30. Rubin L. J. Primary pulmonary hypertension. Chest. 1993 Jul;104(1):236–250. doi: 10.1378/chest.104.1.236. [DOI] [PubMed] [Google Scholar]
  31. Schwartz S. M., Majesky M. W., Murry C. E. The intima: development and monoclonal responses to injury. Atherosclerosis. 1995 Dec;118 (Suppl):S125–S140. [PubMed] [Google Scholar]
  32. Stenmark K. R., Mecham R. P. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol. 1997;59:89–144. doi: 10.1146/annurev.physiol.59.1.89. [DOI] [PubMed] [Google Scholar]
  33. Voelkel N. F., Tuder R. M. Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J. 1995 Dec;8(12):2129–2138. doi: 10.1183/09031936.95.08122129. [DOI] [PubMed] [Google Scholar]
  34. Wang J., Juhaszova M., Conte J. V., Jr, Gaine S. P., Rubin L. J., Yuan J. X. Action of fenfluramine on voltage-gated K+ channels in human pulmonary-artery smooth-muscle cells. Lancet. 1998 Jul 25;352(9124):290–290. doi: 10.1016/s0140-6736(05)60264-4. [DOI] [PubMed] [Google Scholar]
  35. Yuan J. X., Aldinger A. M., Juhaszova M., Wang J., Conte J. V., Jr, Gaine S. P., Orens J. B., Rubin L. J. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998 Oct 6;98(14):1400–1406. doi: 10.1161/01.cir.98.14.1400. [DOI] [PubMed] [Google Scholar]
  36. Yuan X. J., Wang J., Juhaszova M., Gaine S. P., Rubin L. J. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet. 1998 Mar 7;351(9104):726–727. doi: 10.1016/S0140-6736(05)78495-6. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Pathology are provided here courtesy of BMJ Publishing Group

RESOURCES