Review: Role of Genetics in Susceptibility and Outcome of Sarcoidosis

ABSTRACT

Sarcoidosis develops in genetically predisposed individuals that are exposed to unknown antigens. There is a statistically significant increased risk for the disease among family members of sarcoidosis patients, and the disease differs in different ethnic groups. It is a genetically complex disease, with many genes contributing, both as risk factors but also with an influence on the disease course. The strongest genetic associations with sarcoidosis are found within the major histocompatibility complex (MHC) [human leukocyte antigen (HLA) in humans]—region on chromosome six. This region includes, besides the HLA-class I and class-II genes, a large number of genes important for the immune response and inflammation. The well studied associations between sarcoidosis and HLA-class II molecules indicate specific antigen presentation for T helper cells, which is in agreement with the characteristic finding of lung-accumulated CD4+ T helper cells expressing a limited set of T cell receptors. Strong associations between distinct HLA-DRB1 alleles and the disease phenotype and course have been described, especially so in patient subgroups. Although a large number of genes are associated with sarcoidosis, this review focuses on gene associations and their influence on the disease phenotype, including the disease course.

KEYWORDS

Sarcoidosis - HLA - phenotype

REFERENCES

• 1 Hunninghake G W, Costabel U, Ando M et al.. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders.  Sarcoidosis Vasc Diffuse Lung Dis. 1999;  16 149-173
• 2 Moller D R. Pulmonary fibrosis of sarcoidosis: new approaches, old ideas.  Am J Respir Cell Mol Biol. 2003;  29(3, Suppl) S37-S41
• 3 Neville E, Walker A N, James D G. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients.  Q J Med. 1983;  52 525-533
• 4 Judson M A, Baughman R P, Thompson B W ACCESS Research Group et al. Two year prognosis of sarcoidosis: the ACCESS experience.  Sarcoidosis Vasc Diffuse Lung Dis. 2003;  20 204-211
• 5 Scadding J G. Prognosis of intrathoracic sarcoidosis in England: a review of 136 cases after five years’ observation.  BMJ. 1961;  2 1165-1172
• 6 Mañá J, Gómez-Vaquero C, Montero A et al.. Löfgren’s syndrome revisited: a study of 186 patients.  Am J Med. 1999;  107 240-245
• 7 Mañá J, Salazar A, Manresa F. Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases.  Respiration. 1994;  61 219-225
• 8 Müller-Quernheim J, Schürmann M, Hofmann S et al.. Genetics of sarcoidosis.  Clin Chest Med. 2008;  29 391-414, viii , 
• 9 Grunewald J. Genetics of sarcoidosis.  Curr Opin Pulm Med. 2008;  14 434-439
• 10 Spagnolo P, du Bois R M. Genetics of sarcoidosis.  Clin Dermatol. 2007;  25 242-249
• 11 Iannuzzi M C, Rybicki B A. Genetics of sarcoidosis: candidate genes and genome scans.  Proc Am Thorac Soc. 2007;  4 108-116
• 12 Iannuzzi M C. Genetics of sarcoidosis.  Semin Respir Crit Care Med. 2007;  28 15-21
• 13 Wiman L G. Familial occurrence of sarcoidosis.  Scand J Respir Dis Suppl. 1972;  80 115-119
• 14 Rybicki B A, Kirkey K L, Major M et al.. Familial risk ratio of sarcoidosis in African-American sibs and parents.  Am J Epidemiol. 2001;  153 188-193
• 15 Rybicki B A, Iannuzzi M C, Frederick M M ACCESS Research Group et al. Familial aggregation of sarcoidosis: a case-control etiologic study of sarcoidosis (ACCESS).  Am J Respir Crit Care Med. 2001;  164 2085-2091
• 16 Judson M A, Hirst K, Iyengar S K SAGA Study Consortium et al. Comparison of sarcoidosis phenotypes among affected African-American siblings.  Chest. 2006;  130 855-862
• 17 Scadding J, Beresford O, Sutherland I, Leckie W, Chappell A. Familial associations in sarcoidosis: a report to the Research Committee of the British Thoracic and Tuberculosis Association.  Tubercle. 1973;  54 87-98
• 18 Sverrild A, Backer V, Kyvik K O et al.. Heredity in sarcoidosis: a registry-based twin study.  Thorax. 2008;  63 894-896
• 19 Newman L S, Rose C S, Bresnitz E A ACCESS Research Group et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors.  Am J Respir Crit Care Med. 2004;  170 1324-1330
• 20 Iannuzzi M C, Rybicki B A, Teirstein A S. Sarcoidosis.  N Engl J Med. 2007;  357 2153-2165
• 21 Rybicki B A, Major M, Popovich Jr J, Maliarik M J, Iannuzzi M C. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization.  Am J Epidemiol. 1997;  145 234-241
• 22 Rybicki B A, Maliarik M J, Poisson L M et al.. The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans.  Am J Respir Crit Care Med. 2003;  167 444-449
• 23 Pietinalho A, Ohmichi M, Löfroos A B, Hiraga Y, Selroos O. The prognosis of pulmonary sarcoidosis in Finland and Hokkaido, Japan: a comparative five-year study of biopsy-proven cases.  Sarcoidosis Vasc Diffuse Lung Dis. 2000;  17 158-166
• 24 Pietinalho A, Ohmichi M, Hiraga Y, Löfroos A B, Selroos O. The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan: a comparative analysis of 571 Finnish and 686 Japanese patients.  Sarcoidosis Vasc Diffuse Lung Dis. 1996;  13 159-166
• 25 Löfgren S. Erythema nodosum: studies on etiology and pathogenesis in 185 adult cases.  Acta Med Scand. 1946;  124 1-197
• 26 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
• 27 Schürmann M, Reichel P, Müller-Myhsok B, Schlaak M, Müller-Quernheim J, Schwinger E. Results from a genome-wide search for predisposing genes in sarcoidosis.  Am J Respir Crit Care Med. 2001;  164 840-846
• 28 Iannuzzi M C, Iyengar S K, Gray-McGuire C et al.. Genome-wide search for sarcoidosis susceptibility genes in African Americans.  Genes Immun. 2005;  6 509-518
• 29 Gray-McGuire C, Sinha R, Iyengar S SAGA Study Consortium et al. Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5.  Hum Genet. 2006;  120 420-430
• 30 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;  171 1136-1141
• 31 Rybicki B A, Walewski J L, Maliarik M J, Kian H, Iannuzzi M C. ACCESS Research Group . The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites.  Am J Hum Genet. 2005;  77 491-499
• 32 Li Y, Wollnik B, Pabst S et al. BTNL2 gene variant and sarcoidosis.  Thorax. 2006;  61 273-274
• 33 Spagnolo P, Sato H, Grutters J C et al.. Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis.  Tissue Antigens. 2007;  70 219-227
• 34 Traherne J A, Barcellos L F, Sawcer S J et al.. Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15.  Hum Mol Genet. 2006;  15 155-161
• 35 Meyer T, Lauschke J, Ruppert V, Richter A, Pankuweit S, Maisch B. Isolated cardiac sarcoidosis associated with the expression of a splice variant coding for a truncated BTNL2 protein.  Cardiology. 2008;  109 117-121
• 36 Becker C D, Sridhar P, Iannuzzi M C. Cardiac sarcoidosis associated with BTNL2.  Cardiology. 2009;  112 76-77, author reply 78–79
• 37 Hofmann S, Franke A, Fischer A et al.. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.  Nat Genet. 2008;  40 1103-1106
• 38 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
• 39 Grunewald J, Janson C H, Eklund A et al.. Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3.  Eur J Immunol. 1992;  22 129-135
• 40 Grunewald J, Olerup O, Persson U, Ohrn M B, Wigzell H, Eklund A. 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;  91 4965-4969
• 41 Grunewald J, Eklund A. Role of CD4+ T cells in sarcoidosis.  Proc Am Thorac Soc. 2007;  4 461-464
• 42 Moller D R, Konishi K, Kirby M, Balbi B, Crystal R G. Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis.  J Clin Invest. 1988;  82 1183-1191
• 43 Forman J D, Klein J T, Silver R F, Liu M C, Greenlee B M, Moller D R. Selective activation and accumulation of oligoclonal V beta-specific T cells in active pulmonary sarcoidosis.  J Clin Invest. 1994;  94 1533-1542
• 44 Forrester J M, Wang Y, Ricalton N et al.. TCR expression of activated T cell clones in the lungs of patients with pulmonary sarcoidosis.  J Immunol. 1994;  153 4291-4302
• 45 Grutters J C, Sato H, Welsh K I, du Bois R M. The importance of sarcoidosis genotype to lung phenotype.  Am J Respir Cell Mol Biol. 2003;  29(3, Suppl) S59-S62
• 46 Hedfors E, Lindström F. HLA-B8/DR3 in sarcoidosis: correlation to acute onset disease with arthritis.  Tissue Antigens. 1983;  22 200-203
• 47 Gardner J, Kennedy H G, Hamblin A, Jones E. HLA associations in sarcoidosis: a study of two ethnic groups.  Thorax. 1984;  39 19-22
• 48 Martinetti M, Tinelli C, Kolek V et al.. “The sarcoidosis map”: a joint survey of clinical and immunogenetic findings in two European countries.  Am J Respir Crit Care Med. 1995;  152 557-564
• 49 Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1997;  156 1601-1605
• 50 Bogunia-Kubik K, Tomeczko J, Suchnicki K, Lange A. HLA-DRB1*03, DRB1*11 or DRB1*12 and their respective DRB3 specificities in clinical variants of sarcoidosis.  Tissue Antigens. 2001;  57 87-90
• 51 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;  169 696-702
• 52 Grubić Z, Zunec R, Peros-Golubicić T et al.. HLA class I and class II frequencies in patients with sarcoidosis from Croatia: role of HLA-B8, -DRB1*0301, and -DQB1*0201 haplotype in clinical variations of the disease.  Tissue Antigens. 2007;  70 301-306
• 53 Mrazek F, Holla L I, Hutyrova B et al.. Association of tumour necrosis factor-alpha, lymphotoxin-alpha and HLA-DRB1 gene polymorphisms with Löfgren’s syndrome in Czech patients with sarcoidosis.  Tissue Antigens. 2005;  65 163-171
• 54 Grunewald J, Shigematsu M, Nagai S et al.. T-cell receptor V gene expression in HLA-typed Japanese patients with pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1995;  151 151-156
• 55 Grunewald J, Eklund A. Sex-specific manifestations of Löfgren’s syndrome.  Am J Respir Crit Care Med. 2007;  175 40-44
• 56 Grunewald J, Eklund A. Löfgren’s syndrome: human leukocyte antigen strongly influences the disease course.  Am J Respir Crit Care Med. 2009;  179 307-312
• 57 Grunewald J, Eklund A. Human leukocyte antigen genes may outweigh racial background when generating a specific immune response in sarcoidosis.  Eur Respir J. 2001;  17 1046-1048
• 58 Baughman R P, Teirstein A S, Judson M A Case Control Etiologic Study of Sarcoidosis (ACCESS) research group et al. Clinical characteristics of patients in a case control study of sarcoidosis.  Am J Respir Crit Care Med. 2001;  164(10 Pt 1) 1885-1889
• 59 Thorsby E. Invited anniversary review: HLA associated diseases.  Hum Immunol. 1997;  53 1-11
• 60 Candore G, Modica M A, Lio D et al.. Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.  Biomed Pharmacother. 2003;  57 274-277
• 61 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;  27 406-412
• 62 Voorter C E, Drent M, van den Berg-Loonen E M. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101.  Hum Immunol. 2005;  66 826-835
• 63 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;  25 272-277
• 64 Voorter C E, Amicosante M, Berretta F, Groeneveld L, Drent M, van den Berg-Loonen E M. HLA class II amino acid epitopes as susceptibility markers of sarcoidosis.  Tissue Antigens. 2007;  70 18-27
• 65 Grunewald J, Wahlström J, Berlin M, Wigzell H, Eklund A, Olerup O. Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DRbeta chain conformation.  Thorax. 2002;  57 348-352
• 66 Grunewald J, Berlin M, Olerup O, Eklund A. Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2000;  161(3 Pt 1) 814-818
• 67 Grunewald I, Eklund A. Specific bronchoalveolar lavage fluid T cells associate with disease in a pair of monozygotic twins discordant for sarcoidosis.  J Intern Med. 2001;  250 535-539
• 68 Oswald-Richter K, Sato H, Hajizadeh R et al.. Mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by the American sarcoidosis susceptibility allele, DRB1*1101.  J Clin Immunol. 2010;  30 157-166
• 69 Rossman M D, Thompson B, Frederick M ACCESS Group et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.  Am J Hum Genet. 2003;  73 720-735
• 70 Song Z, Marzilli L, Greenlee B M et al.. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.  J Exp Med. 2005;  201 755-767
• 71 Saltini C, Pallante M, Puxeddu E et al.. M. avium binding to HLA-DR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2008;  25 100-116
• 72 Wahlström 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;  117 3576-3582
• 73 Wahlström J, Dengjel J, Winqvist O et al.. Autoimmune T-cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis.  2009;  133 353-363
• 74 Wahlström J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J. Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T cells in sarcoidosis.  Am J Respir Crit Care Med. 2001;  163 115-121
• 75 Voorter C E, Drent M, Hoitsma E, Faber K G, van den Berg-Loonen E M. Association of HLA DQB1 0602 in sarcoidosis patients with small fiber neuropathy.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 129-132
• 76 Sato H, Nagai S, du Bois R M et al.. HLA-DQB1 0602 allele is associated with splenomegaly in Japanese sarcoidosis.  J Intern Med. 2007;  262 449-457
• 77 Naruse T K, Matsuzawa Y, Ota M et al.. HLA-DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis.  Tissue Antigens. 2000;  56 52-57
• 78 Spagnolo P, Sato H, Marshall S E et al.. Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis.  Invest Ophthalmol Vis Sci. 2007;  48 3019-3025
• 79 Hattori N, Niimi T, Sato S et al.. Cytotoxic T-lymphocyte antigen 4 gene polymorphisms in sarcoidosis patients.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 27-32
• 80 Spagnolo P, Sato H, Grunewald J et al.. A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren’s syndrome.  J Intern Med. 2008;  264 433-441
• 81 Idali F, Wikén M, Wahlström J et al.. Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis.  Eur Respir J. 2006;  27 451-459
• 82 Idali F, Wahlström J, Dahlberg B et al.. Altered expression of T cell immunoglobulin-mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis.  Respir Res. 2009;  10 42
• 83 Seitzer U, Swider C, Stüber F et al.. Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis.  Cytokine. 1997;  9 787-790
• 84 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;  165 1119-1124
• 85 Yamaguchi E, Itoh A, Hizawa N, Kawakami Y. The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis.  Chest. 2001;  119 753-761
• 86 Oida T, Xu L, Weiner H L, Kitani A, Strober W. TGF-beta-mediated suppression by CD4+ CD25+ T cells is facilitated by CTLA-4 signaling.  J Immunol. 2006;  177 2331-2339
• 87 Jonth A C, Silveira L, Fingerlin T E ACCESS Group et al. TGF-beta 1 variants in chronic beryllium disease and sarcoidosis.  J Immunol. 2007;  179 4255-4262
• 88 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;  129 1584-1591
• 89 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;  174 915-922