Alternative titles; symbols
ORPHA: 797;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.32 | {Sarcoidosis, susceptibility to, 1} | 181000 | Autosomal dominant | 3 | HLA-DRB1 | 142857 |
A number sign (#) is used with this entry because of evidence that variation in the HLA-DRB1 gene (142857.0001) on chromosome 6p21.3 is a major contributor to susceptibility to sarcoidosis (SS1).
For additional information on susceptibility loci for sarcoidosis, see MAPPING section.
Willoughby et al. (1971) described 3 sibs of whom 2 had sarcoidosis and 1 had Crohn disease. Gronhagen-Riska et al. (1983) commented on the occurrence of sarcoidosis and regional enteritis in the same family.
Nowack and Goebel (1987) found an unusually high frequency of HLA-DR5 (relative risk, 6.6) in patients with sarcoidosis. Their study was done in Marburg, West Germany, where, during the previous 18 years, 440 patients with sarcoidosis had 'regularly attended the University Hospital of Marburg or neighboring clinics.'
Kronauer et al. (1988) described sarcoidosis in a father and son of 1 family and in 2 sisters of a second family.
Among 76 patients with ocular sarcoidosis, Khalatbari et al. (2004) compared the frequency of posterior segment involvement (PSI), the prevalence of specific posterior segment signs, and visual acuity by race, sex, and age. Sixty-eight percent of the patients were black (34 females and 18 males) and 32% were white (18 females and 6 males). Sixty-eight patients (89%) had PSI: 85% of black patients and 100% of white patients. The most common findings of PSI were vitritis (69%); choroidal 'punched-out' lesions (56%); 'snowball' lesions (46%); cystoid macular edema (31%); and periphlebitis, vitreous opacity, and posterior vitreous detachment (29% each).
Familial aggregation of sarcoidosis was studied by Buck and McKusick (1961) and by Allison (1964), among others. The much greater frequency in US blacks than in US whites suggests a genetic contribution to etiology. The family pattern, however, does not conform to a simple mendelian mode of inheritance. In Allison's family affected persons were 2 brothers out of 4 sibs and 2 of the 4 children of one of these. In a family of 9 sibs, Sharma et al. (1971) described sarcoidosis in 4. The mode of onset and clinical representation were acute in 3. The fourth was asymptomatic. Headings et al. (1976) favored multifactorial inheritance of susceptibility.
SS1 on Chromosome 6p21.3
A susceptibility locus for sarcoidosis (SS1) has been mapped to chromosome 6p21.3 and is associated with variation in the HLA-DRB1 gene (142857) (Rossman et al., 2003).
SS2 on Chromosome 6p21.3
See SS2 (612387) for a susceptibility locus for sarcoidosis on chromosome 6p21.3 that is associated with variation in the BTNL2 gene (606000).
SS3 on Chromosome 10q22-q23
See SS3 (612388) for a susceptibility locus for sarcoidosis on chromosome 10q22-q23, which may be associated with variation in the ANXA11 gene (602572).
Associations Pending Confirmation
To identify key genetic factors in the pathogenesis of sarcoidosis, Akahoshi et al. (2004) investigated SNPs within 10 candidate genes involved in the type 1 immune process in an association-based study of 102 Japanese patients with sarcoidosis, 114 with tuberculosis, and 110 controls. After correction for multiple testing, a 551T-G polymorphism in the IFNA17 gene (147583) was found to be associated with susceptibility to sarcoidosis, but not tuberculosis. Akahoshi et al. (2004) further typed another IFNA polymorphism, 60T-A in the IFNA10 gene (147577), and confirmed 2 major haplotypes of these linked IFNA genes: allele 1, IFNA10 (60T)/IFNA17 (551T), and allele 2, IFNA10 (60A)/IFNA17 (551G). In healthy subjects, IFNA allele 2, which was overrepresented in patients with sarcoidosis, was significantly associated with increased production of interferon-alpha (147660) and interleukin-12 subunit p70 (see 161561) induced by Sendai virus in vitro. Akahoshi et al. (2004) suggested that possession of the particular IFNA allele on chromosome 9p22 with higher levels of interferon-alpha significantly increases the risk of sarcoidosis.
In a study of 86 sarcoidosis patients, 85 patients with tuberculosis (TB), and 93 healthy controls, Dubaniewicz et al. (2005) found a significant association between allele 3 of the functional (GT)n repeat polymorphism in the promoter region of the SLC11A1 gene (600266) on chromosome 2q35 in sarcoidosis patients compared to TB patients and controls (odds ratio = 1.68, p = 0.04; and odds ratio = 1.69, p = 0.03, respectively).
Because HSP70 molecules play a key role in the immune response by functioning both as chaperones and as inducers of proinflammatory cytokine secretion, Spagnolo et al. (2007) investigated 3 SNPs in the HSP70-1 (HSPA1A; 140550) gene and 2 SNPs in the HSP70-HOM (HSPA1L; 140559) gene, both on chromosome 6p21.3, in 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis; in 347 matched control subjects; and in 181 patients with idiopathic interior or intermediate uveitis. The HSPA1L rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoid-nonuveitis and control groups (83% vs 71%, OR, 2.00, P(c) = 0.01; and 83% vs 66%, OR, 2.45, P(c) = 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP70 haplotype 2) across the 3 study groups. In addition, the association was specific sarcoidosis, as the carriage of the G allele discriminated between sarcoidosis-related and idiopathic forms of uveitis.
Rossman et al. (2003) performed high-resolution typing for HLA-DPB1 (142858), HLA-DQB1 (604305), HLA-DRB1 (142857), and HLA-DRB3 (612735) loci and the presence of the DRB4 or DRB5 locus, to define HLA class II associations with sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS) enrolled 736 biopsy-confirmed cases from 10 centers in the United States; 706 controls were case-matched for age, race, sex, and geographic area (ACCESS Research Group, 1999). In the first 474 patients and case-matched controls, the HLA-DRB1 alleles were differentially distributed between cases and controls (P less than 0.0001). The HLA-DRB1*1101 allele was associated (p less than 0.01) with sarcoidosis in blacks and whites and had a population-attributable risk of 16% in blacks and 9% in whites. Phenylalanine-47 was the amino acid residue of HLA-DRB1 most associated with sarcoidosis and independently associated with sarcoidosis in whites. The HLA-DPB1 locus also contributed to susceptibility to sarcoidosis and, in contrast to chronic beryllium disease, a non-glu69-containing allele, HLA-DPB1*0101, conveyed most of the risk (see 142858.0001). Although significant differences were observed in the distribution of HLA class II alleles between blacks and whites, only HLA-DRB1*1501 was differentially associated with sarcoidosis (p less than 0.003). In addition to being susceptibility markers, HLA class II alleles may be markers for different phenotypes of sarcoidosis: DRB1*0401 for ocular involvement in blacks and whites, DRB3 for bone marrow involvement in blacks, and DPB1*0101 for hypercalcemia in whites. These studies confirmed a genetic predisposition to sarcoidosis and presented evidence for the allelic variation at the HLA-DRB1 locus as a major contributor.
ACCESS Research Group. Design of a case control etiologic study of sarcoidosis (ACCESS). J. Clin. Epidemiol. 52: 1173-1186, 1999. [PubMed: 10580780] [Full Text: https://doi.org/10.1016/s0895-4356(99)00142-0]
Akahoshi, M., Ishihara, M., Remus, N., Uno, K., Miyake, K., Hirota, T., Nakashima, K., Matsuda, A., Kanda, M., Enomoto, T., Ohno, S., Nakashima, H., Casanova, J.-L., Hopkin, J. M., Tamari, M., Mao, X.-Q., Shirakawa, T. Association between IFNA genotype and the risk of sarcoidosis. Hum. Genet. 114: 503-509, 2004. [PubMed: 15004750] [Full Text: https://doi.org/10.1007/s00439-004-1099-5]
Allison, J. R., Jr. Sarcoidosis. I. Familial occurrence. II. Pseudotumor cerebri and unusual skin lesions. Sth. Med. J. 57: 27-32, 1964. [PubMed: 14104643] [Full Text: https://doi.org/10.1097/00007611-196401000-00006]
Buck, A. A., McKusick, V. A. Epidemiologic investigations of sarcoidosis. III. Serum proteins, syphilis, association with tuberculosis: familial aggregation. Am. J. Hyg. 74: 174-188, 1961. [PubMed: 13874291] [Full Text: https://doi.org/10.1093/oxfordjournals.aje.a120209]
Dubaniewicz, A., Jamieson, S. E., Dubaniewicz-Wybieralska, M., Fakiola, M., Miller, E. N., Blackwell, J. M. Association between SLC11A1 (formerly NRAMP1) and the risk of sarcoidosis in Poland. Europ. J. Hum. Genet. 13: 829-834, 2005. [PubMed: 15702130] [Full Text: https://doi.org/10.1038/sj.ejhg.5201370]
Gronhagen-Riska, C., Fyhrquist, F., Hortling, L., Koskimies, S. Familial occurrence of sarcoidosis and Crohn's disease. (Letter) Lancet 321: 1287-1288, 1983. Note: Originally Volume I. [PubMed: 6134089] [Full Text: https://doi.org/10.1016/s0140-6736(83)92748-4]
Headings, V. E., Weston, D., Young, R. C., Jr., Hackney, R. L., Jr. Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance. Ann. N.Y. Acad. Sci. 278: 377-385, 1976. [PubMed: 1067023] [Full Text: https://doi.org/10.1111/j.1749-6632.1976.tb47049.x]
Khalatbari, D., Stinnett, S., McCallum, R. M., Jaffe, G. J. Demographic-related variations in posterior segment ocular sarcoidosis. Ophthalmology 111: 357-362, 2004. [PubMed: 15019390] [Full Text: https://doi.org/10.1016/S0161-6420(03)00793-0]
Kronauer, C. M., Medici, T. C., Russi, E. W. Familiare Sarkoidose: 4 Falle aus 2 Familien. Schweiz. Med. Wschr. 118: 1482-1486, 1988. [PubMed: 3070740]
Nowack, C., Goebel, K. M. Genetic aspects of sarcoidosis: class II histocompatibility antigens and a family study. Arch. Intern. Med. 147: 481-483, 1987. [PubMed: 3827423] [Full Text: https://doi.org/10.1001/archinte.147.3.481]
Rossman, M. D., Thompson, B., Frederick, M., Maliarik, M., Iannuzzi, M. C., Rybicki, B. A., Pandey, J. P., Newman, L. S., Magira, E., Beznik-Cizman, B., Monos, D., ACCESS Group. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am. J. Hum. Genet. 73: 720-735, 2003. [PubMed: 14508706] [Full Text: https://doi.org/10.1086/378097]
Schurmann, M., Reichel, P., Muller-Myhsok, B., Schlaak, M., Muller-Quernheim, J., Schwinger, E. Results from a genome-wide search for predisposing genes in sarcoidosis. Am. J. Resp. Crit. Care Med. 164: 840-846, 2001. [PubMed: 11549543] [Full Text: https://doi.org/10.1164/ajrccm.164.5.2007056]
Sharma, O. P., Johnson, C. S., Balchum, O. J. Familial sarcoidosis: report of four siblings with acute sarcoidosis. Am. Rev. Resp. Dis. 104: 255-257, 1971. [PubMed: 5558993] [Full Text: https://doi.org/10.1164/arrd.1971.104.2.255]
Sharma, O. P., Neville, E., Walker, A. N., James, D. G. Familial sarcoidosis: a possible genetic influence. Ann. N.Y. Acad. Sci. 278: 386-400, 1976. [PubMed: 1067024] [Full Text: https://doi.org/10.1111/j.1749-6632.1976.tb47050.x]
Spagnolo, P., Sato, H., Marshall, S. E., Antoniou, K. M., Ahmad, T., Wells, A. U., Ahad, M. A., Lightman, S., du Bois, R. M., Welsh, K. I. Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis. Invest. Ophthal. Vis. Sci. 48: 3019-3025, 2007. [PubMed: 17591867] [Full Text: https://doi.org/10.1167/iovs.06-1485]
Willoughby, J. M. T., Mitchell, D. N., Wilson, J. D. Sarcoidosis and Crohn's disease in siblings. Am. Rev. Resp. Dis. 104: 249-254, 1971. [PubMed: 5558992] [Full Text: https://doi.org/10.1164/arrd.1971.104.2.249]