Genetic studies of pulmonary arterial hypertension

Abstract

These genetic studies of primary pulmonary hypertension (PPH) initially tried to define immunogenetic subsets. Because only small subsets could be classified when defined by HLA=autoantibodyassociationsand the familial form of PPH failed to segregate with the HLA class II locus, the focus shifted to a genome scan of families with PPH (FPPH). This approach identified a gene on chromosome 2q33,34 called PPH1. Mutations in this gene, now known to be bone morphogenetic protein receptor 2 (BMPR2), can cause PPH. Mutations in a second gene, ALK-1, present in families with hereditary hemorrhagic telangiectasia type 2, also causes PPH. Both genes, involved in TGF-B signaling, provide exciting clues for defining the pathogenesis of PPH.

Keywords

bone morphogenetic protein receptor 2 primary pulmonary hypertension appetite suppressant PPH pulmonary arterial hypertension activin-like receptor 1 autoimmune pulmonary hypertension

Get full access to this article

View all access options for this article.

References

Morse JH , Barst RJ , Whitman HH III , Fotino, Jacobs JC.

Isolated pulmonary hypertension in the grandchild of a kindred with scleroderma (systemic sclerosis): ‘Neonatal Scleroderma?’

J Rheumatol 1989; 16: 1536-1541 .

Rich S. Executive summary of the World Symposium on PPH. 1999. Available at: www.who.int=ncd=cvd=pph.html. Accessed 8 November 2000.

Rich S , Kieras K , Groves BM , Stobo JD , Brundage BH. Antinuclear antibodies in primary pulmonary hypertension . Am Coll Cardiol 1986; 8: 1307-1311 .

Isern RA , Yaneva M , Wiener E et al. Antibodies in patients with primary pulmonary hypertension: association with anti-Ku . Am J Med 1992; 93: 307-312 .

Rich S , Dantzker DR , Ayres SM et al. Primary pulmonary hypertension: a national; prospective study . Ann Intern Med 1987; 107: 216-223 .

Winslow TM , Ossipov MA , Fazio GP , Simonson JS , Redberg RF , Schiller NB. Five-year follow-up study of the prevalence and progression of pulmonary hypertension in systemic lupus erythematosus . Am Heart J 1995; 129: 510-515 .

Todd GRG , McAteer EJ , Jack CM , Haire M , Roberts SD , Buchanan KD. Pulmonary hypertension, systemic lupus erythematosus and the contraceptive pill . Ann Rheum Dis 1985; 44: 266-267 .

Graziano FM , Friedman LC , Grossman J. Pulmonary hypertension in a patient with mixed connective tissue disease: clinical and pathological findings and a review of the literature . Clin Exp Rheumatol 1983; 1: 251-255 .

Asherson RA , Morgan SH , Hackett D , Montanes P , Oakley C , Hughes GRV. Rheumatoid arthritis and pulmonary hypertension: a report of three cases . J Rheumatol 1985; 12: 154-159 .

10.

Stupi AM , Steen VD , Owens GR , Barnes EL , Rodnan GP , Medsger TA Jr. Primary hypertension in the CREST syndrome variant of systemic sclerosis . Arthritis Rheum 1986; 29: 515-524 .

11.

Koh ET , Lee P , Gladman DD , Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients . Br J Rheumatol 1996; 35: 989-993 .

12.

Curnock AL , Dweik RA , Higgins BH et al. High prevalence of hypothyroidismin patients with primary pulmonary hypertension . Am J Med Sci 1999; 318: 289-292 .

13.

Ferris A , Jacobs T , Widlitz A , Barst RJ , Morse JH.

Pulmonary arterial hypertension and thyroid disease. (Letter.)

Chest 2001; 119: 1980-1981 .

14.

Morse JH , Barst RJ , Fotino M , Zhang Y , Flaster E , Fritzler, MJ. Primary pulmonary hypertension: Immunogenetic response to histone and HMG proteins . Clin Exp Immunol 1996; 106: 389-395 .

15.

Ayer LM , Rubin RL , Dixon GH , Fritzler MJ. Antibodies to HMG proteins in patients with drug-induced autoimmunity . Arthritis Rheum 1994; 37: 98-103 .

16.

Ayer LM , Senecal J , Martin L , Dixon GH , Fritzler MJ. Antibodies to high mobility group (HMG) proteins in systemic sclerosis . J Rheumatol 1994; 21: 2071-2075 .

17.

Morse JH , Barst RJ , Fotino M , Zhang Y , Flaster E , Gharavi A , Fritzler MJ , Dominguez M , Angles-Cano E. Primary pulmonary hypertension, tissue plasminogen activator antibodies, and HLA-DQ7 . Am J Respir Crit Care Med 1997; 155: 274-278 .

18.

Fritzler MJ , Hart DA , Wilson D , Garcia-De La Torre I , Salazar-Paramo M , Vasquez-Del Mercado M , Senecal J-L , Angles-Cano E. Antibodies to fibrin bound tissue type plasminogen activator in systemic sclerosis . J Rheumatol 1995; 22: 1688-1693 .

19.

Salazar-Paramo M , Garcia de la Torre I , Fritzler MJ , Loyau S , Angles-Cano E. Antibodies to fibrin-bound tissue-type plasminogen activator in systemic lupus erythematosus (SLE) are associated with Raynaud’s phenomenon and thrombosis . Lupus 1996; 5: 275-278 .

20.

Morse JH , Antohi S , Kasturi K , Saito S , Fotino M , Humbert M , Simonneau G , Barst RJ , Bona C. Fine specificity of anti-fibrillin-1 autoantibodies in primary pulmonary hypertension . Scand J Immunol 2000; 51: 607-611 .

21.

Tan, FK , Arnett FC , Reveille JD et al. Autoantibodies to fibrillin 1 in systemic sclerosis . Arthritis Rheum 2000; 11: 2462-2471 .

22.

Morse JH , Barst RJ , Itescu S et al. Primary pulmonary hypertension in human immunodeficiency virus infection: an outcome determined by particular major histocompatibility complex class II alleles . Am J Respir Crit Care Med 1996; 153: 1299-1301 .

23.

Itescu S , Rose S , Dwyer E , Winchester R. Certain HLA-DR5 and -DR6 major histocompatibility complex class II alleles are associated with a CD8 lymphocytichost response to human immunodeficiency virustypeI characterized by low lymphocyte viral strain heterogeneity and slow disease progression . Proc Natl Acad Sci USA 1994; 91: 11472-11476 .

24.

Langevitz P , Buskila D , Gladman DD , Darlington GA , Farewell VT , Lee P. HLA alleles in systemic sclerosis: association with pulmonary hypertension and outcome . Br J Rheumatol 1992; 31: 609-613 .

25.

Hanaoka M , Kubo K , Yamazaki Y et al. Association of high-altitude pulmonary edema with the major histocompatibility complex . Circulation 1998; 97: 1124-1128 .

26.

Morse JH , Barst RJ , Fotino M. Familial pulmonary hypertension: immunogenetic findings in four Caucasian kindreds . Am Rev Respir Dis 1992; 145: 787-792 .

27.

Loyd JE , Primm RK , Newman JH. Familial primary pulmonary hypertension: clinical patterns . Am Rev Respir Dis 1984; 129: 194-197 .

28.

Morse JH , Jones A , Barst RJ , Hodge SE , Wilhelmsen KC , Nygaard TG. Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-32 . Circulation 1997; 95: 2603-2606 .

29.

Nichols WC , Koller DL , Slovis B et al. Localization of the gene for familial pulmonary hypertension to chromosome 2q31-32 . Nat Genet 1997; 15: 277-280 .

30.

Morse JH , Barst RJ.

Detection of familial primary pulmonary hypertension by genetic testing. (Letter.)

New Engl J Med 1997; 337: 202-203 .

31.

Deng Z , Haghighi R , Helleby L et al. Further localization of a gene for familial primary pulmonary hypertension, PPH1, to a 3-cM region on chromosome 2q33 . Am J Respir Crit Care Med 2000; 161: 1055-1059 .

32.

Grunig E , Janssen B , Mereles D et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene . Circulation 2000; 102: 1145-1150 .

33.

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: 737-744 .

34.

The International PPH Consortium , Lane KB , Machado RD et al. Heterozygous germline mutation in BMPR2, encoding a TGF-B receptor, cause familial primary pulmonary hypertension . Nat Genet 2000; 26: 81-84 .

35.

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-B family . J Med Genet 2000; 37: 741-775 .

36.

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: 92-102 .

37.

Morse JH , Knowles JA. Genetics of primary pulmonary hypertension . Prog Pediat Cardiol 2001; 12: 271-278 .

38.

Morse JH , Deng Z , Knowles JA. Genetic aspects of pulmonary arterial hypertension . Ann Med 2001; 33: 596-603 .

39.

Trembath RC , Thomson JR , Machado RD et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia . New Engl J Med 2001; 345: 325-334 .

40.

Howe JR , Roth S , Ringold JC et al. Mutations in the SMAD4=DPC4 gene in juvenile polyposis . Science 1998; 280: 1086-1088 .

41.

Lu S-L , Kawabata M , Imamura T et al. HNPCC associated with germline mutation in the TGF-B type II receptor gene . Nat Genet 1998; 19: 17-18 .

42.

Voelkel NF , Cool C , Lee SD , Wright L , Geraci MW , Tuder RM. Primary pulmonary hypertension between inflammation and cancer . Chest 1998; 114: 225S-230S .

43.

Humbert M , Deng Z , Simonneau G , Barst J , Sitbon O , Wolf M , Cuervo N , Moore KJ , Hodge SE , Deng Z , Knowles JA , Morse JH. BMPR2 germaline mutations in pulmonary hypertension associated with fenfluramine derivatives . Eur Respir J 2002; 20: 518-523 .

44.

Abenhaim L , Moride Y , Brenot F et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension . New Engl J Med 1996; 335: 609-616 .

45.

Nunes H , Humbert M , Sitbon O , Morse JH , Deng Z , Knowles JA , Le Gall C , Parent F , Garcia G , Herve P , Barst RJ , Simonneau G. Prognostic factors for survival in HIV-associated pulmonary arterial hypertension . Am J Resp Crit Care Med (in press).

46.

Morse J , Barst R , Horn E , Cuervo N , Deng Z , Knowles J. Pulmonary hypertension in scleroderma spectrum of disease: Lack of bone morphogenetic protein receptor 2 mutations . J Rheumatol 2002; 29: 2379-2381 .