Identification of sarcoidosis susceptibility genes by association mapping and candidate gene approaches
Identification of a sarcoidosis susceptibility gene on chromosome 6 in this study has been performed using the association mapping approach.Here, a systematic three-stage single nucleotide polymorphism (SNP) scan of 16.4 Mb on chromosome 6p21 was performed in up to 947 independent cases of familial and sporadic sarcoidosis. Using TDT and case-control analyses, a 15 kb segment located at the 3-prime end of the BTNL2 gene could be identified as being strongly associated with sarcoidosis. The major disease-associated variant, rs2076530, represents a risk factor that is entirely independent of the previously reported association between sarcoidosis and alleles of the DRB1 gene, located within ~200kb of BTNL2. BTNL2 is a member of the immunoglobulin superfamily. Homology to B7-1 implicates the BTNL2 as a co-stimulatory molecule. The risk allele A of rs2076530 leads to alternative splicing of the BTNL2 transcript, which introduces a premature stop. The resulting truncated protein lacks the C-terminal IgC domain and transmembrane helix, thereby disturbing the putative co-stimulatory function of this molecule.