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

• DOI: 10.1111/j.1399-0039.2007.00879.x
• Publication Date: 2007-06-16T13:27:09Z
• Authors: P. Spagnolo; H. Sato; J. C. Grutters; E. A. Renzoni; S. E. Marshall; H. J. T. Ruven; A. U. Wells; A. Tzouvelekis; C. H. M. Van Moorsel; J. M. M. Van Den ...; R. M. Du Bois; K. I. Welsh
• Keywords: 0301 basic medicine; Membrane Glycoproteins; Butyrophilins; Sarcoidosis; BTNL2; sarcoidosis; genetics; polymorphisms; HLA-DR Antigens; Polymorphism, Single Nucleotide; United Kingdom; 3. Good health; 03 medical and health sciences; Humans; Genetic Predisposition to Disease; HLA-DRB1 Chains; Netherlands

AbstractSarcoidosis 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 Löfgren’s 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 HLA‐DRB1 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) = 3.1, Pc = 0.0003], DRB1*12 (OR = 2.5, Pc = 0.003), and BTNL2 rs2076530 A allele (OR = 1.49, Pc = 0.002) were all associated with disease susceptibility. However, after exclusion of patients presenting with Löfgren’s syndrome and after adjusting for HLA‐DRB1 alleles, the association between BTNL2 rs2076530 A and disease disappeared (P = 0.23). By contrast, both HLA‐DRB1*14 and DRB1*12 remained strongly significant (OR = 3.60, P < 0.0001 and OR = 3.03, P = 0.003, respectively). BTNL2 haplotype 4, tagged by the rs2076530 G allele, also remained associated with non‐Löfgren sarcoidosis after adjusting for HLA‐DRB1 alleles (OR 0.37, P = 0.016). In summary, HLA‐DRB1*14, DRB1*12, and BTNL2 haplotype 4 – but not rs2076530 A – are associated with non‐Löfgren 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.