Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502
Butyrophilin-like 2 gene is associated with ulcerative colitis in the Japanese under strong linkage disequilibrium with HLA-DRB1*1502
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DOI：
10.1111/j.1399-0039.2007.00866.x
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发表时间：
2007-08-01
期刊：
影响因子：
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通讯作者：
Shimosegawa, T.
中科院分区：
文献类型：
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作者：
Mochida, A.;Kinouchi, Y.;Shimosegawa, T.
人类白细胞抗原（HLA）区域与炎症性肠病（IBD）的发病机制有关，IBD分为克罗恩病（CD）和溃疡性结肠炎（UC）。最近，有报道称结节病与嗜乳脂蛋白样2（BTNL2）基因之间存在关联。BTNL2位于HLA区域，其信使RNA在肠道中表达最为丰富。在本研究中，我们对日本IBD患者进行了BTNL2的病例 - 对照关联研究，并对BTNL2和HLA - DRB1之间进行了连锁不平衡（LD）分析。我们分析了直接测序后选择的8种多态性，发现这些多态性与日本CD队列均无关联。相反，有5种多态性与UC显著相关，特别是3种单核苷酸多态性（BTNL2_19、BTNL2_22和BTNL2_23）作为一个单倍型相关。最常见的单倍型（GGC单倍型）是低风险单倍型（P = 0.000052），而另一种TCT单倍型是高风险单倍型（P = 0.0000085）。在这8种多态性中，与UC关联最强的是BTNL2_19（比值比 = 1.92，P = 0.0000035）。正如预期的那样，BTNL2_19 - T等位基因与DRB1*1502呈现强连锁不平衡（D' = 0.92）。当以DRB1*1502携带状态为条件对BTNL2_19进行检测时，显著关联消失，这表明这种关联是由于其与DRB1*1502的强连锁不平衡。我们得出结论，BTNL2对日本CD的易感性没有影响，但由于与HLA - DRB1*1502的强连锁不平衡而与日本UC相关。BTNL2和HLA - DRB1之间的强连锁不平衡引发了关于BTNL2在其他与HLA - DRB1相关疾病中潜在作用的另一个问题。
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.