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 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, P(c) = 0.0003], DRB1*12 (OR = 2.5, P(c) = 0.003), and BTNL2 rs2076530 A allele (OR = 1.49, P(c) = 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.
Spagnolo
P
P
Clinical Genomic Group, National Heart and Lung Institute, Department of Occupational and Environmental Medicine, Imperial College, 1B Manresa Road, London, UK. P.Spagnolo@imperial.ac.uk
Sato
H
H
Grutters
J C
JC
Renzoni
E A
EA
Marshall
S E
SE
Ruven
H J T
HJ
Wells
A U
AU
Tzouvelekis
A
A
van Moorsel
C H M
CH
van den Bosch
J M M
JM
du Bois
R M
RM
Welsh
K I
KI
D000071797:Butyrophilins; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D012507:Sarcoidosis / Q000235:genetics*; D006113:United Kingdom
C408263:BTNL2 protein, human; D000071797:Butyrophilins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008562:Membrane Glycoproteins