Butyrophilin‐like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA‐DRB1*1502

Abstract

The human leukocyte antigen (HLA) region has been implicated in the pathogenesis of inflammatory bowel disease (IBD), which is classified into Crohn's disease (CD) and ulcerative colitis (UC). Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene was reported. BTNL2 is located in the HLA region and its messenger RNA is expressed most abundantly in the intestine. In this study, we performed a case-control association study of BTNL2 in the Japanese patients with IBD and performed linkage disequilibrium (LD) analysis between BTNL2 and HLA-DRB1. We analyzed eight polymorphisms selected after direct sequencing and found that none of the polymorphisms were associated with the Japanese CD cohort. In contrast, five polymorphisms were significantly associated with UC, especially three single nucleotide polymorphisms (BTNL2_19, BTNL2_22 and BTNL2_23) were associated as a haplotype. The most frequent haplotype (GGC haplotype) was a low-risk haplotype (P= 0.000052), whereas the other TCT haplotype was a high-risk haplotype (P= 0.0000085). Among the eight polymorphisms, the strongest association with UC was found in BTNL2_19 (OR = 1.92, P= 0.0000035). As expected, the BTNL2_19-T allele showed strong LD with DRB1*1502 (D'= 0.92). When BTNL2_19 was tested as conditional on the DRB1*1502 carrier status, the significant association disappeared, suggesting that the association was because of its strong LD with DRB1*1502. We conclude that BTNL2 does not contribute to the susceptibility to Japanese CD but is associated with Japanese UC because of the strong LD with HLA-DRB1*1502. The strong LD between BTNL2 and HLA-DRB1 raises another issue about the potential role of BTNL2 in other diseases associated with HLA-DRB1.

Butyrophilin-like 1 encodes an enterocyte protein that selectively regulates functional interactions with T lymphocytes

“…Although such IL-6 is commonly attributed to intestinal DCs (45,46), its production by enterocytes may reinforce IL-17 production by infiltrating systemic T cells. Hence, attenuation of IL-6 expression may limit immunopathologies involving IL17-dependent neutrophilic infiltrates, consistent with the genetic associations of Btnl genes with colitis and sarcoidosis (16,18).…”

“…Among the criteria are: they are conserved in mice and humans; several are encoded within the MHC-locus; they share strong homologies with the B7-family of costimulators; and certain murine and human Btnl/Btn gene products reportedly reduce the proliferative responses of costimulated T cells, with human BTN2A1 reportedly modulating DCs by engaging the lectin DC-SIGN (9)(10)(11)(12)(13)(14)(15). The potential importance of such interactions is further implied by genetic associations of human Btnl2 and Btn2A1 polymorphisms with sarcoidosis, myositis, and inflammatory bowel disease (16)(17)(18). Indeed, it has been proposed that Btnl proteins might be particularly important in mediating immune regulation in tissues, notably the gut (12), although the specific regulation of IEL-epithelial cell interactions by any Btnl/Btn gene has not hitherto been experimentally investigated.…”

Genetic Characterization and Susceptibility for Sarcoidosis in Japanese Patients: Risk Factors ofBTNL2Gene Polymorphisms and HLA Class II Alleles

“…8,11 However, subsequent studies have showed inconsistent results on a sarcoidosis risk factor of BTNL2 rs2076530_A and its independent effect of HLA-DRB1. 12,13 In other diseases, such as type 1 diabetes (T1D), 14 rheumatoid arthritis (RA), 15 systemic lupus erythematosus (SLE), 14 multiple sclerosis (MS), 15 Graves'disease (GD), 16 chronic beryllium disease (CBD), 17 and ulcerative colitis (UC), 18 a significant association with BTNL2 polymorphisms appeared to be secondary to the primary HLA-DRB1 association because of its strong linkage disequilibrium (LD) with DRB1 alleles.…”

Genetics of ulcerative colitis

“…50 In contrast to a previous Japanese study, stratification of the BTLN2 genotypes by DRB1*1502 status demonstrated residual association at BTLN2. 51 Following on from this work, the German UC GWAS demonstrated genome-wide levels of significance at three SNPs in this region: rs9268877 (P ¼ 5.23 Â 10…”