Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis

Sarcoidosis is a heterogeneous disorder, both phenotypically and genetically. Two independent studies have recently shown that a functional polymorphism within butyrophilin-like 2 (BTNL2) gene predisposes to sarcoidosis independently of the human leukocyte antigen (HLA)-DRB1 alleles. However, in both studies, data analysis was not stratified by Lo¨ fgrens syndrome, a clinically and genetically distinct sarcoidosis subset. BTNL2, potentially encoding an immune coreceptor, is adjacent and in linkage disequilibrium (LD) with HLA-DRB1. We investigated six BTNL2 variants, including the functional rs2076530 (G > A), as well as HLADRB1 alleles, by sequence-specific primers–polymerase chain reaction, in 288 patients and 446 controls from two European countries. In the patient group as a whole, the HLA-DRB1*14 [odds ratio (OR) ¼ 3.1, Pc ¼ 0.0003], DRB1*12 (OR ¼ 2.5, Pc ¼ 0.003), and BTNL2 rs2076530 A allele (OR ¼ 1.49, Pc ¼ 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Lo¨ fgrens syndrome and after adjusting for HLA-DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P ¼ 0.23). By contrast, both HLA-DRB1*14 and DRB1*12 remained strongly significant (OR ¼ 3.60, P < 0.0001 and OR ¼ 3.03, P ¼ 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non-Lo¨ fgren sarcoidosis after adjusting for HLA-DRB1 alleles (OR 0.37, P ¼ 0.016). In summary, HLA-DRB1*14, DRB1*12, and BTNL2 haplotype 4 – but not rs2076530 A – are associated with non-Lo¨ fgren sarcoidosis. However, the tight LD across the HLA complex makes it difficult to identify the precise location of the susceptibility locus/i. Larger sample sets from different ethnic groups, finer mapping, and more robust LD analyses across the HLA region are needed.