Genetik der Sarkoidose: Ein Schlüssel zum Verständnis ihrer Pathogenese[1]

Zusammenfassung

Die Sarkoidose ist eine multifaktorielle und polygene Erkrankung. Der aktuelle genetische Kenntnisstand wird dargestellt und im Kontext anderer granulomatöser Erkrankungen bekannter und unbekannter Ätiologie diskutiert. Unterschiede und Gemeinsamkeiten führen zu dem Ausblick, dass es in naher Zukunft möglich sein wird, Genotyp-Phänotyp-Korrelationen zu etablieren, die prognostische Aussagen zum Verlauf und zur Therapieantwort in einem individuellen Fall erlauben.

Abstract

Sarcoidosis is a multifactorial and polygenic disorder. The current knowledge of its genetics will be presented and discussed in the context of other granulomatous disorders of known and unknown aetiology. The differing and common features of these disorders lead to the perspective that in near future it will be possible to establish genotype-phenotype correlations which will predict the course and therapy response in an individual case.

1 Diese Arbeit wurde unterstützt durch das Deutsche Genomforschungsnetzwerk (01GSS0426) und die Deutsche Forschungsgemeinschaft (MU692/7-1 und 8-1).

Literatur

• 1 American Thoracic Society . Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.  Am J Respir Crit Care Med. 1999;  160 (2) 736-755
• 2 Müller-Quernheim J. Sarcoidosis: immunopathogenetic concepts and their clinical application.  Eur Respir J. 1998 Sep;  12 716-738
• 3 Iannuzzi M C, Rybicki B A, Teirstein A S. Sarcoidosis.  N Engl J Med. 2007;  357 2153-2165
• 4 Zissel G, Prasse A, Müller-Quernheim J. Sarcoidosis-immunopathogenetic concepts.  Semin Respir Crit Care Med. 2007;  28 3-14
• 5 Hillerdal G, Nöu E, Osterman K. et al . Sarcoidosis: epidemiology and prognosis. A 15-year European study.  Am Rev Respir Dis. 1984;  130 29-232
• 6 Rybicki Jr B A, Major M, Popovich J. et al . Racial differences in sarcoidosis incidence: A 5-year study in health maintenance organization.  Rev1. 1997;  145 234-241
• 7 James D G, Neville E, Siltzbach L E. A worldwide review of sarcoidosis.  Ann N Y Acad Sci. 1976;  278 321-334
• 8 Baughman R P, Teirstein A S, Judson M A. et al . Clinical characteristics of patients in a case control study of sarcoidosis.  Am J Respir Crit Care Med. 2001;  164 1885-1889
• 9 Rose C S, Martyny J W, Newman L S. et al . “Lifeguard lung”: endemic granulomatous pneumonitis in an indoor swimming pool.  Am J Public Health. 1998;  88 795-800
• 10 Newman L S, Mroz M M, Balkissoon R. et al . Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk.  Am J Respir Crit Care Med. 2005;  171 54-60
• 11 Müller-Quernheim J, Gaede K I, Fireman E. et al . Diagnoses of chronic beryllium disease within cohorts of sarcoidosis patients.  Eur Respir J. 2006;  27 1190-1195
• 12 Richeldi L, Sorrentino R, Saltini C. HLA-DPB 1 glutamate 69: a genetic marker of beryllium disease.  Science. 1993;  262 242-244
• 13 Maier L A, McGrath D S, Sato H. et al . Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease.  J Immunol. 2003;  171 6910-6918
• 14 Newman L S. Metals that cause sarcoidosis.  Semin Respir Infect. 1998;  13 212-220
• 15 Rafnsson V, Ingimarsson O, Hjalmarsson I. et al . Association between exposure to crystalline silica and risk of sarcoidosis.  Occup Environ Med. 1998;  55 657-660
• 16 Jörgensen G. Die Genetik der Sarkoidose.  Acta Med Scand. 1964;  425 209-212
• 17 Kirsten D. Sarcoidosis in Germany. Analysis of a questionnaire survey in 1992 of patients of the German Sarcoidosis Group.  Pneumologie. 1995;  49 378-382
• 18 Wirnsberger R M, Vries J de, Wouters E F. et al . Clinical presentation of sarcoidosis in The Netherlands an epidemiological study.  Neth J Med. 1998;  53 53-60
• 19 McGrath D S, Daniil Z, Foley P. et al . Epidemiology of familial sarcoidosis in the UK.  Thorax. 2000;  55 751-754
• 20 Fite E, Alsina J M, Anto J M. et al . Sarcoidosis: family contact study.  Respiration. 1998;  65 34-39
• 21 Rybicki B A, Harrington D, Major M. et al . Heterogeneity of familial risk in sarcoidosis.  Genet Epidemiol. 1996;  13 23-33
• 22 Sverrild A, Backer V, Kyvik K O. et al . Heredity In Sarcoidosis – A Registry-Based Twin Study.  Thorax. 2008;  63 894-896
• 23 Welcome Trust Case Control Consortium . Genome-wide association study of 14,000 cases of seven common diseases and 3.000 shared controls.  Nature. 2007;  447 661-678
• 24 Tromp G, Kuivaniemi H, Raphael S. et al . Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16.  Am J Hum Genet. 1996;  59 1097-1107
• 25 Hugot J P, Laurent-Puig P, Gower-Rousseau C. et al . Mapping of a susceptibility locus for Crohn's disease on chromosome 16.  Nature. 1996;  379 821-823
• 26 Hampe J, Cuthbert A, Croucher P J. et al . Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.  Lancet. 2001 Jun 16;  357 (9272) 1925-1928
• 27 Miceli-Richard C, Lesage S, Rybojad M. et al . CARD15 mutations in Blau syndrome.  Nat Genet. 2001 Sep;  29 (1) 19-20
• 28 Schürmann M, Valentonyte R, Hampe J. et al . CARD15 gene mutations in sarcoidosis.  Eur Respir J. 2003 Nov;  22 (5) 748-754
• 29 Schürmann M, Lympany P A, Reichel P. et al . Familial sarcoidosis is linked to the major histocompatibility complex region.  Am J Respir Crit Care Med. 2000;  162 (3 Pt 1) 861-864
• 30 Schürmann M, Reichel P, Müller-Myhsok B. et al . Results from a genome-wide search for predisposing genes in sarcoidosis.  Am J Respir Crit Care Med. 2001;  164 (5) 840-846
• 31 Valentonyte R, Hampe J, Huse K. et al . Sarcoidosis is associated with a truncating splice site mutation in BTNL2.  Nat Genet. 2005 Apr;  37 (4) 357-364
• 32 Thompson C L, Rybicki B A, Iannuzzi M C. et al . Reduction of sample heterogeneity through use of population substructure: an example from a population of African American families with sarcoidosis.  Am J Hum Genet. 2006 Oct;  79 (4) 606-613
• 33 Judson M A, Hirst K, Iyengar S K. et al . Comparison of sarcoidosis phenotypes among affected African-American siblings.  Chest. 2006 Sep;  130 (3) 855-862
• 34 Valentonyte R, Hampe J, Croucher P J. et al . Study of C-C chemokine receptor 2 alleles in sarcoidosis, with emphasis on family-based analysis.  Am J Respir Crit Care Med. 2005 May 15;  171 (10) 1136-1141
• 35 Brewerton D A, Cockburn C, James D C. et al . HLA antigens in sarcoidosis.  Clin Exp Immunol. 1977 Feb;  27 (2) 227-229
• 36 Moller E, Hedfors E, Wiman L G. HL-A genotypes and MLR in familial sarcoidosis.  Tissue Antigens. 1974;  4(4) 299-305
• 37 Smith M J, Turton C W, Mitchell D N. et al . Association of HLA B8 with spontaneous resolution in sarcoidosis.  Thorax. 1981 Apr;  36 (4) 296-298
• 38 Dubaniewicz A, Szczerkowska Z, Hoppe A. Comparative analysis of HLA class I antigens in pulmonary sarcoidosis and tuberculosis in the same ethnic group.  Mayo Clin Proc. 2003 Apr;  78 (4) 436-442
• 39 Hedfors E, Lindstrom F. HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis.  Tissue Antigens. 1983 Sep;  22 (3) 200-203
• 40 Lio D, Candore G, Romano G C. et al . Modification of cytokine patterns in subjects bearing the HLA-B8,DR3 phenotype: implications for autoimmunity.  Cytokines Cell Mol Ther. 1997 Dec;  3 (4) 217-224
• 41 Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients.  Am J Respir Crit Care Med. 2004 Mar 15;  169 (6) 696-702
• 42 Berlin M, Fogdell-Hahn A, Olerup O. et al . HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1997 Nov;  156 (5) 1601-1605
• 43 Bogunia-Kubik K, Tomeczko J, Suchnicki K. et al . HLA-DRB1*03, DRB1*11 or DRB1*12 and their respective DRB3 specificities in clinical variants of sarcoidosis.  Tissue Antigens. 2001 Jan;  57 (1) 87-90
• 44 Rutherford R M, Brutsche M H, Kearns M. et al . HLA-DR2 predicts susceptibility and disease chronicity in Irish sarcoidosis patients.  Sarcoidosis Vasc Diffuse Lung Dis. 2004 Oct;  21 (3) 191-198
• 45 Schürmann M, Bein G, Kirsten D. et al . HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis.  Respir Med. 1998;  92 649-652
• 46 Naruse T K, Matsuzawa Y, Ota M. et al . HLA-DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis.  Tissue Antigens. 2000 Jul;  56 (1) 52-57
• 47 Rossman M D, Thompson B, Frederick M. et al . HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.  Am J Hum Genet. 2003 Oct;  73 (4) 720-735
• 48 Voorter C E, Drent M, Hoitsma E. et al . Association of HLA DQB1 0602 in sarcoidosis patients with small fiber neuropathy.  Sarcoidosis Vasc Diffuse Lung Dis. 2005 Jun;  22 (2) 129-132
• 49 Voorter C E, Drent M, Berg-Loonen E M van den. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150 101.  Hum Immunol. 2005 Jul;  66 (7) 826-835
• 50 Sato H, Grutters J C, Pantelidis P. et al . HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis.  Am J Respir Cell Mol Biol. 2002 Oct;  27 (4) 406-412
• 51 Grunewald J, Olerup O, Persson U. et al . T-cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients.  Proc Natl Acad Sci U S A. 1994 May 24;  91 (11) 4965-4969
• 52 Grunewald J, Berlin M, Olerup O. et al . Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2000 Mar;  161 (3 Pt 1) 814-818
• 53 Grunewald J, Eklund A. Sex-specific manifestations of Löfgren's syndrome.  Am J Respir Crit Care Med. 2007 Jan 1;  175 (1) 40-44
• 54 Foley P J, McGrath D S, Puscinska E. et al . Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis.  Am J Respir Cell Mol Biol. 2001;  25 (3) 272-277
• 55 Wang Z, White P S, Petrovic M. et al . Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles.  J Immunol. 1999;  163 (3) 1647-1653
• 56 Lombardi G, Germain C, Uren J. et al . HLA-DP allele-specific T cell responses to beryllium account for DP- associated susceptibility to chronic beryllium disease.  J Immunol. 2001;  166 (5) 3549-3555
• 57 Maliarik M J, Chen K M, Major M L. et al . Analysis of HLA-DPB1 polymorphisms in african-americans with sarcoidosis.  Am J Respir Crit Care Med. 1998;  158 (1) 111-114
• 58 Li Y, Wollnik B, Pabst S. et al . BTNL2 gene variant and sarcoidosis.  Thorax. 2006 Mar;  61 (3) 273-274
• 59 Rybicki B A, Walewski J L, Maliarik M J. et al . The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites.  Am J Hum Genet. 2005 Sep;  77 (3) 491-499
• 60 Spagnolo P, Sato H, Grutters J C. et al . Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis.  Tissue Antigens. 2007 Sep;  70 (3) 219-227
• 61 Nguyen T, Liu X K, Zhang Y. et al . BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation.  J Immunol. 2006 Jun 15;  176 (12) 7354-7360
• 62 Toews G B, Vial W C, Dunn M M. et al . The accessory cell function of human alveolar macrophages in specific T cell proliferation.  The Journal of Immunology. 1984;  132 (1) 181-186
• 63 Zissel G, Ernst M, Schlaak M. et al . Accessory function of alveolar macrophages from patients with sarcoidosis and other granulomatous and non-granulomatous lung diseases.  J Invest Med. 1997;  45 (2) 75-86
• 64 Hofmann S, Franke A, Fischer A. et al . Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.  Nat Genet. 2008;  Epub ahead of print
• 65 Hayes M J, Longbottom R E, Evans M A. et al . Annexinopathies.  Subcell Biochem. 2007;  45 1-28
• 66 Gerke V, Moss S E. Annexins: from structure to function.  Physiol Rev. 2002 Apr;  82 (2) 331-371
• 67 Moss S E, Morgan R O. The annexins.  Genome Biol. 2004;  5 (4) 219
• 68 Jorgensen C S, Levantino G, Houen G. et al . Determination of autoantibodies to annexin XI in systemic autoimmune diseases.  Lupus. 2000;  9 (7) 515-520
• 69 Ziegenhagen M W, Rothe M E, Zissel G. et al . Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2002 Oct;  19 (3) 185-190
• 70 Zissel G, Homolka J, Schlaak J. et al . Anti-inflammatory cytokine release by alveolar macrophages in pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1996;  154 713-719
• 71 El-Gamel A, Awad M R, Hasleton P S. et al . Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis.  J Heart Lung Transplant. 1999 Jun;  18 (6) 517-523
• 72 Ludviksson B R, Gunnlaugsdottir B. Transforming growth factor-beta as a regulator of site-specific T-cell inflammatory response.  Scand J Immunol. 2003 Aug;  58 (2) 129-138
• 73 Jonth A C, Silveira L, Fingerlin T E. et al . TGF-beta1 variants in chronic beryllium disease and sarcoidosis.  J Immunol. 2007 Sep 15;  179 (6) 4255-4262
• 74 Muraközy G, Gaede K I, Zissel G. et al . Analysis of gene polymorphisms in interleukin-10 and transforming growth factor-beta 1 in sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2001;  18 (2) 165-169
• 75 Awad M R, El-Gamel A, Hasleton P. et al . Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation.  Transplantation. 1998 Oct 27;  66 (8) 1014-1020
• 76 Kruit A, Grutters J C, Ruven H J. et al . Transforming growth factor-beta gene polymorphisms in sarcoidosis patients with and without fibrosis.  Chest. 2006 Jun;  129 (6) 1584-1591
• 77 Müller-Quernheim J, Pfeifer S, Männel D. et al . Lung-restricted activation of the alveolar macrophage/monocyte system in pulmonary sarcoidosis.  Am Rev Respir Dis. 1992 Jan;  145 (1) 187-192
• 78 McGuire W, Hill A, Allsopp C. et al . Variation in the TNF-α promoter region associated with susceptibility to cerebral malaria.  Nature. 1994;  371 508-511
• 79 Cabrera M, Shaw M A, Sharples C. et al . Polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis.  J Exp Med. 1995;  182 (5) 1259-1264
• 80 Huang D, Giscombe R, Zhou Y. et al . Polymorphisms in CTLA-4 but not tumor necrosis factor-alpha or interleukin-1-beta genes are associated with Wegener's granulomatosis.  J Rheumatol. 2000 Feb;  27 (2) 397-401
• 81 Seitzer U, Swider C, Stüber F. et al . Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis.  Cytokine. 1997;  9 (10) 787-790
• 82 Somoskövi A, Zissel G, Seitzer U. et al . Polymorphism at position -308 in the promotor region of the TNF-alpha and in the first intron o the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis.  Cytokine. 1999;  11 (11) 882-887
• 83 Ziegenhagen M W, Benner U K, Zissel G. et al . Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers.  Am J Respir Crit Care Med. 1997 Nov;  156 (5) 1586-1592
• 84 Ziegenhagen M W, Schrum S, Zissel G. et al . Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis.  J Investig Med. 1998 Jun;  46 (5) 223-231
• 85 Idali F, Wiken M, Wahlstrom J. et al . Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis.  Eur Respir J. 2006 Mar;  27 (3) 451-459
• 86 Seitzer U, Gerdes J, Müller-Quernheim J. Evidence for disease phenotype associated haplotypes (DR.TNF) in sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2001 Oct;  18 (3) 279-283
• 87 Grutters J C, Sato H, Pantelidis P. et al . Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis.  Am J Respir Crit Care Med. 2002 Apr 15;  165 (8) 1119-1124
• 88 Spagnolo P, Renzoni E A, Wells A U. et al . C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis.  Am J Respir Crit Care Med. 2005 Sep 15;  172 (6) 721-728
• 89 Spagnolo P, Renzoni E A, Wells A U. et al . C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome.  Am J Respir Crit Care Med. 2003 Nov 15;  168 (10) 1162-1166
• 90 Schürmann M, Kwiatkowski R, Albrecht M. et al . Study of Toll-like receptor gene loci in sarcoidosis.  Clin Exp Immunol. 2008;  152 423-431
• 91 Hill M R, Papafili A, Booth H. et al . Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis.  Am J Respir Crit Care Med. 2006 Oct 15;  174 (8) 915-922
• 92 Abel L, Sanchez F O, Oberti J. et al . Susceptibility to leprosy is linked to the human NRAMP1 gene.  J Infect Dis. 1998 Jan;  177 (1) 133-145
• 93 Bellamy R. Identifying genetic susceptibility factors for tuberculosis in Africans: a combined approach using a candidate gene study and a genome-wide screen.  Clin Sci (Lond). 2000 Mar;  98 (3) 245-250
• 94 Dubaniewicz A, Jamieson S E, Dubaniewicz-Wybieralska M. et al . Association between SLC11A1 (formerly NRAMP1) and the risk of sarcoidosis in Poland.  Eur J Hum Genet. 2005 Jul;  13 (7) 829-834
• 95 Medica I, Kastrin A, Maver A. et al . Role of genetic polymorphisms in ACE and TNF-alpha gene in sarcoidosis: a meta-analysis.  J Hum Genet. 2007;  52 (10) 836-847
• 96 Biller H, Zissel G, Ruprecht B. et al . Genotype-corrected reference values for serum angiotensin-converting enzyme.  Eur Respir J. 2006 Dec;  28 (6) 1085-1090
• 97 Baughman R P, Lower E E, Bois R M du. Sarcoidosis.  Lancet. 2003 Mar 29;  361 (9363) 1111-1118
• 98 Judson M A, Thompson B W, Rabin D L. et al . The diagnostic pathway to sarcoidosis.  Chest. 2003 Feb;  123 (2) 406-412
• 99 Rybicki B A, Sinha R, Iyengar S. et al . Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study.  Genes Immun. 2007 Jul;  8 (5) 379-386
• 100 Wasfi Y S, Rose C S, Murphy J R. et al . A new tool to assess sarcoidosis severity.  Chest. 2006 May;  129 (5) 1234-1245
• 101 Prasse A, Katic C, Germann M. et al . Phenotyping sarcoidosis from a pulmonary perspective.  Am J Respir Crit Care Med. 2008 Feb 1;  177 (3) 330-336
• 102 Müller-Quernheim J, Gaede K I, Prasse A. et al . Chronische Berylliose.  Pneumologie. 2007 Feb;  61 (2) 109-116
• 103 Newman L S, Lloyd J, Daniloff E. The Natural History of Beryllium Sensitization and Chronic Beryllium Disease.  Environ Health Perspect. 1996;  104S (5) 937-943
• 104 Gaede K I, Amicosante M, Schürmann M. et al . Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease.  J Mol Med. 2005 May;  83 (5) 397-405
• 105 Maier L A, Sawyer R T, Bauer R A. et al . High beryllium-stimulated TNF-alpha is associated with the -308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease.  Am J Respir Crit Care Med. 2001 Oct 1;  164 (7) 1192-1199
• 106 Sato H, Silveira L, Fingerlin T. et al . TNF polymorphism and bronchoalveolar lavage cell TNF-alpha levels in chronic beryllium disease and beryllium sensitization.  J Allergy Clin Immunol. 2007 Mar;  119 (3) 687-696
• 107 Maier L A, Raynolds M V, Young D A. et al . Angiotensin-1 converting enzyme polymorphisms in chronic beryllium disease.  Am J Respir Crit Care Med. 1999;  159 (4 Pt 1) 1342-1350
• 108 Blau E B. Familial granulomatous arthritis, iritis, and rash.  J Pediatr. 1985 Nov;  107 (5) 689-693
• 109 Becker M L, Rose C D. Blau syndrome and related genetic disorders causing childhood arthritis.  Curr Rheumatol Rep. 2005 Dec;  7 (6) 427-433
• 110 Mathew C G. New links to the pathogenesis of Crohn disease provided by genome-wide association scans.  Nat Rev Genet. 2008 Jan;  9 (1) 9-14
• 111 Schreiber S, Rosenstiel P, Albrecht M. et al . Genetics of Crohn disease, an archetypal inflammatory barrier disease.  Nat Rev Genet. 2005 May;  6 (5) 376-388
• 112 Franke A, Fischer A, Nothnagel M. et al . Genome-Wide Association Analysis in Sarcoidosis and Crohn's Disease Unravels a Common Susceptibility Locus on 10p12.2.  Gastroenterology. 2008;  135 1207-1215
• 113 Pieters K, Pettersson A, Gullberg U. et al . The - 564 A/G polymorphism in the promoter region of the proteinase 3 gene associated with Wegener's granulomatosis does not increase the promoter activity.  Clin Exp Immunol. 2004 Nov;  138 (2) 266-270
• 114 Muraközy G, Gaede K I, Ruprecht B. et al . Gene polymorphisms of immunoregulatory cytokines and angiotensin-converting enzyme in Wegener's granulomatosis.  J Mol Med. 2001 Nov;  79 (11) 665-670
• 115 Bartfai Z, Gaede K I, Russell K A. et al . Different gender-associated genotype risks of Wegener's granulomatosis and microscopic polyangiitis.  Clin Immunol. 2003 Dec;  109 (3) 330-337
• 116 Rybicki B A, Hirst K, Iyengar S K. et al . A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.  Sarcoidosis, vasculitis, and diffuse lung diseases.. 2005 Jun;  22 (2) 115-122
• 117 Grutters J C, Sato H, Welsh K I. et al . The importance of sarcoidosis genotype to lung phenotype.  Am J Respir Cell Mol Biol. 2003 Sep;  29 (3 Suppl) S59-62
• 118 Takashige N, Naruse T K, Matsumori A. et al . Genetic polymorphisms at the tumour necrosis factor loci (TNFA and TNFB) in cardiac sarcoidosis.  Tissue Antigens. 1999 Aug;  54 (2) 191-193
• 119 Sabounchi-Schutt F, Astrom J, Hellman U. et al . Changes in bronchoalveolar lavage fluid proteins in sarcoidosis: a proteomics approach.  Eur Respir J. 2003 Mar;  21 (3) 414-420
• 120 Magi B, Bini L, Perari M G. et al . Bronchoalveolar lavage fluid protein composition in patients with sarcoidosis and idiopathic pulmonary fibrosis: a two-dimensional electrophoretic study.  Electrophoresis. 2002 Sep;  23 (19) 3434-3444
• 121 Rottoli P, Magi B, Perari M G. et al . Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis.  Proteomics. 2005 Apr;  5 (5) 1423-1430
• 122 Wahlstrom J, Dengjel J, Persson B. et al . Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis.  J Clin Invest. 2007 Nov 1;  117 (11) 3576-3582

1 Diese Arbeit wurde unterstützt durch das Deutsche Genomforschungsnetzwerk (01GSS0426) und die Deutsche Forschungsgemeinschaft (MU692/7-1 und 8-1).