Genetics of Sarcoidosis

ABSTRACT

Sarcoidosis likely results from an interplay of environmental and genetic factors. Despite a recent large multicenter study, A Case-Control Etiologic Study of Sarcoidosis (ACCESS), no single causative environmental agent has been identified. Family clustering and differences in racial incidence of sarcoidosis support an inherited susceptibility to sarcoidosis. Siblings of patients with sarcoidosis have about a fivefold increased risk of developing sarcoidosis. Certain human leukocyte antigen (HLA) alleles have been consistently associated with sarcoidosis susceptibility. Furthermore, HLA-DRB1*0301/DQB1*0201 has been associated with good prognosis in Löfgren's syndrome. Many candidate genes studied based on their potential function in immunopathogenesis have been evaluated in case-control studies, but few have been consistently associated with sarcoidosis across populations. Two genome scans have been reported in sarcoidosis. One in African Americans reporting linkage to chromosome 5 and the other in German families reporting linkage to chromosome 6. Follow-up studies on chromosome 6 identified the BTNL2 gene, a B7 family costimulatory molecule to be associated with sarcoidosis. Advances in genotyping and statistical analysis are helping to elucidate the genetics of sarcoidosis.

Sarcoidosis - genetics - BTNL2 - linkage

REFERENCES

• 1 Martenstein H. Knochveranderungen bei lupus Pernio.  Z Haut Geschlechtskr. 1923;  7 308
• 2 Robinson R, Hahn R. Sarcoidosis in siblings.  Arch Intern Med. 1947;  80 249
• 3 Wirnsberger R M, de Vries J, Wouters E F, Drent M. Clinical presentation of sarcoidosis in the Netherlands an epidemiological study.  Neth J Med. 1998;  53 53-60
• 4 Kirsten D. Sarcoidosis in Germany. Analysis of a questionnaire survey in 1992 of patients of the German Sarcoidosis Group.  Pneumologie. 1995;  49 378-382
• 5 McGrath D S, Daniil Z, Foley P et al.. Epidemiology of familial sarcoidosis in the UK.  Thorax. 2000;  55 751-754
• 6 Pietinalho A, Ohmichi M, Hirasawa M, Hiraga Y, Lofroos A B, Selroos O. Familial sarcoidosis in Finland and Hokkaido, Japan: a comparative study.  Respir Med. 1999;  93 408-412
• 7 Fite E, Alsina J M, Anto J M, Morera J. Sarcoidosis: family contact study.  Respiration. 1998;  65 34-39
• 8 Harrington D, Major M, Rybicki B, Popovich Jr J, Maliarik M, Iannuzzi M C. Familial analysis of 91 families.  Sarcoidosis. 1994;  11 240-243
• 9 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
• 10 Rybicki B A, Iannuzzi M C, Frederick M M et al.. Familial aggregation of sarcoidosis: a case-control etiologic study of sarcoidosis (ACCESS).  Am J Respir Crit Care Med. 2001;  164 2085-2091
• 11 James D G. Epidemiology of sarcoidosis.  Sarcoidosis. 1992;  9 79-87
• 12 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
• 13 Brewerton D A, Cockburn C, James D C, James D G, Neville E. HLA antigens in sarcoidosis.  Clin Exp Immunol. 1977;  27 227-229
• 14 Hedfors E, Lindstrom F. HLA-B8/DR3 in sarcoidosis: correlation to acute onset disease with arthritis.  Tissue Antigens. 1983;  22 200-203
• 15 Smith M J, Turton C W, Mitchell D N, Turner-Warwick M, Morris L M, Lawler S D. Association of HLA B8 with spontaneous resolution in sarcoidosis.  Thorax. 1981;  36 296-298
• 16 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
• 17 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;  73 720-735
• 18 Ishihara M, Ohno S, Ishida T et al.. Molecular genetic studies of HLA class II alleles in sarcoidosis.  Tissue Antigens. 1994;  43 238-241
• 19 Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease.  Science. 1993;  262 242-244
• 20 Saltini C, Sorrentino R, Richeldi L, Luisetti M, Bisetti A. Role of the HLA-DP gene in susceptibility to lung granulomas.  Sarcoidosis. 1993;  10 171-172
• 21 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;  158 111-114
• 22 Schurmann 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;  162 861-864
• 23 Foley P J, Lympany P A, Puscinska E, Zielinski J, Welsh K I, du Bois R M. Analysis of MHC encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis.  Am J Respir Crit Care Med. 1999;  160 1009-1014
• 24 Iannuzzi M C, Maliarik M J, Poisson L M, Rybicki B A. Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans.  Am J Respir Crit Care Med. 2003;  167 1225-1231
• 25 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
• 26 James D G. A comparison of Blau's syndrome and sarcoidosis.  Sarcoidosis. 1994;  11 100-101
• 27 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
• 28 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
• 29 Ogura Y, Bonen D K, Inohara N et al.. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.  Nature. 2001;  411 603-606
• 30 Hugot J P, Chamaillard M, Zouali H et al.. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.  Nature. 2001;  411 599-603
• 31 Chamaillard M, Philpott D, Girardin S E et al.. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases.  Proc Natl Acad Sci USA. 2003;  100 3455-3460
• 32 Inohara N, Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis.  Nat Rev Immunol. 2003;  3 371-382
• 33 Rybicki B A, Maliarik M J, Bock C H et al.. The Blau syndrome gene is not a major risk factor for sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 1999;  16 203-208
• 34 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
• 35 Schurmann M, Reichel P, Muller-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
• 36 Schurmann M, Valentonyte R, Hampe J, Müller-Quernheim J, Schwinger E, Schreiber S. CARD15 gene mutations in sarcoidosis.  Eur Respir J. 2003;  22 748-754
• 37 Kanazawa N, Okafuji I, Kambe N et al.. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome.  Blood. 2005;  105 1195-1197
• 38 Rybicki B A, Maliarik M J, Poisson L M, Iannuzzi M C. Sarcoidosis and granuloma genes: a family-based study in African-Americans.  Eur Respir J. 2004;  24 251-257
• 39 McGrath D S, Foley P J, Petrek M et al.. Ace gene I/D polymorphism and sarcoidosis pulmonary disease severity.  Am J Respir Crit Care Med. 2001;  164 197-201
• 40 Maliarik M J, Rybicki B A, Malvitz E et al.. Angiotensin-converting enzyme gene polymorphism and risk of sarcoidosis.  Am J Respir Crit Care Med. 1998;  158 1566-1570
• 41 Furuya K, Yamaguchi E, Itoh A et al.. Deletion polymorphism in the angiotensin I converting enzyme (ACE) gene as a genetic risk factor for sarcoidosis.  Thorax. 1996;  51 777-780
• 42 Arbustini E, Grasso M, Leo G et al.. Polymorphism of angiotensin-converting enzyme gene in sarcoidosis.  Am J Respir Crit Care Med. 1996;  153 851-854
• 43 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
• 44 Spagnolo P, Renzoni E A, Wells A U et al.. C-C chemokine receptor 2 and sarcoidosis: association with Löfgren's syndrome.  Am J Respir Crit Care Med. 2003;  168 1162-1166
• 45 Petrek M, Drabek J, Kolek V et al.. CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2000;  162 1000-1003
• 46 Hizawa N, Yamaguchi E, Furuya K, Jinushi E, Ito A, Kawakami Y. The role of the C-C chemokine receptor 2 gene polymorphism V64I (CCR2- 64I) in sarcoidosis in a Japanese population.  Am J Respir Crit Care Med. 1999;  159 2021-2023
• 47 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;  172 721-728
• 48 Handa T, Nagai S, Ito I et al.. Polymorphisms of B7 (CD80 and CD86) genes do not affect disease susceptibility to sarcoidosis.  Respiration. 2005;  72 243-248
• 49 Ohchi T, Shijubo N, Kawabata I et al.. Polymorphism of Clara cell 10-kD protein gene of sarcoidosis.  Am J Respir Crit Care Med. 2004;  169 180-186
• 50 Zorzetto M, Bombieri C, Ferrarotti I et al.. Complement receptor 1 gene polymorphisms in sarcoidosis.  Am J Respir Cell Mol Biol. 2002;  27 17-23
• 51 Bombieri C, Luisetti M, Belpinati F et al.. Increased frequency of CFTR gene mutations in sarcoidosis: a case/control association study.  Eur J Hum Genet. 2000;  8 717-720
• 52 Schurmann M, Albrecht M, Schwinger E, Stuhrmann M. CFTR gene mutations in sarcoidosis.  Eur J Hum Genet. 2002;  10 729-732
• 53 Bogunia-Kubik K, Koscinska K, Suchnicki K, Lange A. HSP70-hom gene single nucleotide ( + 2763 G/A and + 2437 C/T) polymorphisms in sarcoidosis.  Int J Immunogenet. 2006;  33 135-140
• 54 Abdallah A, Sato H, Grutters J C et al.. Inhibitor kappa B-alpha (IkappaB-alpha) promoter polymorphisms in UK and Dutch sarcoidosis.  Genes Immun. 2003;  4 450-454
• 55 Hutyrova B, Pantelidis P, Drabek J et al.. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2002;  165 148-151
• 56 Bohnert A, Schurmann M, Hartung A, Hackstein H, Müller-Quernheim J, Bein G. No linkage of the interleukin-4 receptor locus on chromosome 16p11.2-12.1 with sarcoidosis in German multiplex families.  Eur J Immunogenet. 2002;  29 269-272
• 57 Kelly D M, Greene C M, Meachery G et al.. Endotoxin up-regulates interleukin-18: potential role for gram-negative colonization in sarcoidosis.  Am J Respir Crit Care Med. 2005;  172 1299-1307
• 58 Janssen R, Grutters J C, Ruven H J et al.. No association between interleukin-18 gene polymorphisms and haplotypes in Dutch sarcoidosis patients.  Tissue Antigens. 2004;  63 578-583
• 59 Takada T, Suzuki E, Morohashi K, Gejyo F. Association of single nucleotide polymorphisms in the IL-18 gene with sarcoidosis in a Japanese population.  Tissue Antigens. 2002;  60 36-42
• 60 Zhou Y, Yamaguchi E, Hizawa N, Nishimura M. Roles of functional polymorphisms in the interleukin-18 gene promoter in sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 105-113
• 61 Akahoshi M, Ishihara M, Remus N et al.. Association between IFNA genotype and the risk of sarcoidosis.  Hum Genet. 2004;  114 503-509
• 62 Maliarik M J, Chen K M, Sheffer R G et al.. The natural resistance-associated macrophage protein gene in African Americans with sarcoidosis.  Am J Respir Cell Mol Biol. 2000;  22 672-675
• 63 Pabst S, Baumgarten G, Stremmel A et al.. Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis.  Clin Exp Immunol. 2006;  143 420-426
• 64 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
• 65 Somoskovi A, Zissel G, Seitzer U, Gerdes J, Schlaak M, Müller-Quernheim J. Polymorphisms at position -308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis.  Cytokine. 1999;  11 882-887
• 66 Seitzer U, Swider C, Stuber F et al.. Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis.  Cytokine. 1997;  9 787-790
• 67 Labunski S, Posern G, Ludwig S, Kundt G, Brocker E B, Kunz M. Tumour necrosis factor-alpha promoter polymorphism in Erythema nodosum .  Acta Derm Venereol. 2001;  81 18-21
• 68 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
• 69 Morohashi K, Takada T, Omori K, Suzuki E, Gejyo F. Vascular endothelial growth factor gene polymorphisms in Japanese patients with sarcoidosis.  Chest. 2003;  123 1520-1526
• 70 Guleva I, Seitzer U. Vitamin D receptor gene polymorphism in patients with sarcoidosis.  Am J Respir Crit Care Med. 2000;  162 760-761
• 71 Niimi T, Tomita H, Sato S et al.. Vitamin D receptor gene polymorphism in patients with sarcoidosis.  Am J Respir Crit Care Med. 1999;  160 1107-1109
• 72 Iannuzzi M C. Genetics of sarcoidosis.  Monaldi Arch Chest Dis. 1998;  53 609-613
• 73 Iannuzzi M C, Maliarik M, Rybicki B. Genetic polymorphisms in lung disease: bandwagon or breakthrough?.  Respir Res. 2002;  3 15
• 74 Rybicki B A, Maliarik M J, Major M, Popovich Jr J, Iannuzzi M C. Genetics of sarcoidosis.  Clin Chest Med. 1997;  18 707-717
• 75 Rybicki B A, Maliarik M J, Malvitz E et al.. The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans.  Hum Immunol. 1999;  60 867-874
• 76 Rybicki B A, Hirst K, Iyengar S K et al.. A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 115-122
• 77 Gray-McGuire C, Sinha R, Iyengar S K et al.. Genetic characterization and fine mapping of susceptibility genes for sarcoidosis in African Americans on chromosome 5.  Hum Genet. 2006;  120 420-430
• 78 Parra E J, Marcini A, Akey J et al.. Estimating African American admixture proportions by use of population-specific alleles.  Am J Hum Genet. 1998;  63 1839-1851
• 79 Thompson C L, Rybicki B A, Iannuzzi M C, Elston R C, Iyengar S K, Gray-McGuire C. 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;  79 606-613
• 80 Valentonyte R, Hampe J, Huse K et al.. Sarcoidosis is associated with a truncating splice site mutation in BTNL2.  Nat Genet. 2005;  37 357-364
• 81 Rhodes D A, Stammers M, Malcherek G, Beck S, Trowsdale J. The cluster of BTN genes in the extended major histocompatibility complex.  Genomics. 2001;  71 351-362
• 82 Sharpe A H, Freeman G J. The B7-CD28 superfamily.  Nat Rev Immunol. 2002;  2 116-126
• 83 Jack L J, Mather I H. Cloning and analysis of cDNA encoding bovine butyrophilin, an apical glycoprotein expressed in mammary tissue and secreted in association with the milk-fat globule membrane during lactation.  J Biol Chem. 1990;  265 14481-14486
• 84 Rybicki B A, Walewski J L, Maliarik M J, Kian H, Iannuzzi M C. The BTNL2 gene and sarcoidosis susceptibility in African Americans and whites.  Am J Hum Genet. 2005;  77 491-499
• 85 Li Y, Wollnik B, Pabst S et al.. BTNL2 gene variant and sarcoidosis.  Thorax. 2006;  61 273-274
• 86 Simmonds M J, Heward J M, Barrett J C, Franklyn J A, Gough S C. Association of the BTNL2 rs2076530 single nucleotide polymorphism with Graves' disease appears to be secondary to DRB1 exon 2 position beta74.  Clin Endocrinol (Oxf). 2006;  65 429-432
• 87 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
• 88 Szyld P, Jagiello P, Csernok E, Gross W L, Epplen J T. On the Wegener granulomatosis associated region on chromosome 6p21.3  BMC Med Genet. 2006;  7 21
• 89 Orozco G, Eerligh P, Sanchez E et al.. Analysis of a functional BTNL2 polymorphism in type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus.  Hum Immunol. 2005;  66 1235-1241
• 90 Judson M A, Hirst K, Iyengar S K et al.. Comparison of sarcoidosis phenotypes among affected African-American siblings.  Chest. 2006;  130 855-862