BTNL2 allele associations with chronic beryllium disease in HLD-DPB1*Glu69-negative individuals

Butyrophilin-like 2 (BTNL2) polymorphisms have been associated with sarcoidosis. We hypothesized that BTNL2 variants might confer a human leukocyte antigen (HLA)-independent risk for chronic beryllium disease (CBD), a granulomatous lung disease with similar clinical, radiological, and pathological features to sarcoidosis. GenomicDNA was obtained fromCBD(n ¼ 88), berylliumsensitized (BeS, n ¼ 86), and beryllium exposed nondiseased control subjects (Be-exp, n ¼ 173). Six BTNL2 polymorphisms, HLA-DPB1, DRB1, and DQB1 alleles were determined by sequence-specific primer-PCR. All BTNL2 polymorphismswere inHardy–Weinberg equilibrium. No significant differences were found between BTNL2 polymorphisms or haplotypes and CBD, BeS, or Be-exp. In HLA-DPB1*Glu69–negative subjects (n ¼ 10 CBD, n ¼ 13 BeS, n ¼ 102 Be-exp), DRB1*13 and BTNL2 rs3117099TT homozygosity were increased in CBD (70% and 40%, respectively) vs Be-exp (16%,P ¼ 0.001 and 2.9%, P ¼ 0.001, respectively). The BTNL2 rs3117099T–HLADRB1* 13 combination was significantly increased in CBD (50%) compared with Be-exp (6.9%, P ¼ 0.001). In conclusion, both DRB1*13 and rs3117099TT homozygosity are associated with CBD in *Glu69-negative subjects, while DPB1*Glu69 is associated with CBD and BeS compared with Be-exp. As a result of the small sample size and strong linkage disequilibrium between DRB1*13-DQB1*0603/4/9 and the BTNL2 rs3117099T allele, it is difficult to assess the primary association in DPB1*Glu69-negative CBD cases.