ORPHA: 797;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.32 | {Sarcoidosis, susceptibility to, 2} | 612387 | Autosomal dominant | 3 | BTNL2 | 606000 |
A number sign (#) is used with this entry because of evidence that susceptibility to sarcoidosis-2 (SS2) is conferred by variation in the BTNL2 gene (606000) on chromosome 6p21.
For a general description and a discussion of genetic heterogeneity of sarcoidosis, see 181000.
Valentonyte et al. (2005) noted that genomewide linkage analyses had indicated that the extended MHC locus on 6p is linked to susceptibility to sarcoidosis, a polygenic immune disorder with predominant manifestation in the lung; see HLA-DRB1 (142857). Valentonyte et al. (2005) carried out a systematic 3-stage SNP scan of 16.4 Mb on 6p21 in 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the BTNL2 gene was associated with the disease.
Rybicki et al. (2005) sought to replicate the BTNL2 association with sarcoidosis that had been reported by Valentonyte et al. (2005) in a white German population, but noted that the close proximity of BTNL2 to HLA-DRB1 and HLA-DQB1 complicates association studies. Following the suggestion of Just et al. (1997) that increased haplotype diversity in the MHC class II region in populations of African origin may help in differentiating specific gene effects, they studied variation in the exon/intron-5 region of BTNL2 in an African American family sample and in 2 case-control samples, 1 of which was African American and 1 white. They detected 10 SNPs within a 490-bp region. Haplotype variation within this region was significantly associated with sarcoidosis in all 3 study populations but more so in the white sample than in the African American case-control or family-based samples.
In family-based (TDT) and population-based (case-control) studies, Valentonyte et al. (2005) showed that a primary disease-associated variant of BTNL2 (rs2076530; 606000.0001) represents a risk factor for sarcoidosis that is independent of variation in HLA-DRB1. The change resulted in the use of an alternative splice site located 4 bp upstream. The mutant protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting localization of the protein.
In their study of the BTNL2 association with sarcoidosis risk in an African American family-based study population (219 nuclear families) and 2 case-control populations--1 African American (295 pairs) and 1 white (366 pairs), Rybicki et al. (2005) found that the A allele of rs2076530, which results in a premature exon-splice site, increased risk for sarcoidosis (odds ratio = 2.03). Multivariable logistic regression analyses showed that BTNL2 effects were independent of HLA class II genes in whites but may interact antagonistically in African Americans. Rybicki et al. (2005) stated that the clinical characteristics of the study patients were described by Baughman et al. (2001).
Baughman, R. P., Teirstein, A. S., Judson, M. A., Rossman, M. D., Yeager, H., Jr., Bresnitz, E. A., DePalo, L., Hunninghake, G., Iannuzzi, M. C., Johns, C. J., McLennan, G., Moller, D. R., and 9 others. Clinical characteristics of patients in a case control study of sarcoidosis. Am. J. Resp. Crit. Care Med. 164: 1885-1889, 2001. [PubMed: 11734441] [Full Text: https://doi.org/10.1164/ajrccm.164.10.2104046]
Just, J. J., King, M. C., Thomson, G., Klitz, W. African-American HLA class II allele and haplotype diversity. Tissue Antigens 49: 547-555, 1997. [PubMed: 9174158] [Full Text: https://doi.org/10.1111/j.1399-0039.1997.tb02801.x]
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. 77: 491-499, 2005. [PubMed: 16080124] [Full Text: https://doi.org/10.1086/444435]
Valentonyte, R., Hampe, J., Huse, K., Rosenstiel, P., Albrecht, M., Stenzel, A., Nagy, M., Gaede, K. I., Franke, A., Haesler, R., Koch, A., Lengauer, T., and 9 others. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nature Genet. 37: 357-364, 2005. Note: Erratum: Nature Genet. 37: 602 only, 2005. [PubMed: 15735647] [Full Text: https://doi.org/10.1038/ng1519]