Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy.
Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy.
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精细图谱分析揭示了 TNFSF15 在原发性胆汁性胆管炎、克罗恩病和麻风病中的复杂多效作用和组织特异性调节机制
DOI：
10.1038/srep31429
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发表时间：
2016-08-10
影响因子：
4.6
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Sun Y;Irwanto A;Toyo-Oka L;Hong M;Liu H;Andiappan AK;Choi H;Hitomi Y;Yu G;Yu Y;Bao F;Wang C;Fu X;Yue Z;Wang H;Zhang H;Kawashima M;Kojima K;Nagasaki M;Nakamura M;Yang SK;Ye BD;Denise Y;Rotzschke O;Song K;Tokunaga K;Zhang F;Liu J
9 q32基因座内的遗传多态性与几种疾病的风险增加有关，包括克罗恩病（CD），原发性胆管炎（PBC）和麻风病。9 q32内最可能的致病基因是TNFSF 15，它编码促炎细胞因子TNF超家族成员15，但尚不清楚这些不同的疾病是否与9 q32中相同的遗传变异有关，以及该基因座内的变异如何导致病理学。利用已发表的CD、PBC和麻风病研究的遗传数据，我们发现携带rs6478108/rs6478109（r2 = 1）或rs 4979462的T等位基因与CD风险增加和麻风风险降低显著相关，而rs 4979462的T等位基因与PBC风险显著增加相关。体外分析显示，rs6478109基因型显著影响对照全血细胞中TNFSF 15的表达，而使用公开数据的功能注释揭示了rs6478109或rs 4979462的广泛细胞类型/组织特异性调节潜力。总之，我们提供的证据表明，TNFSF 15内的差异有可能影响一系列组织中细胞因子的表达，从而有助于预防麻风等传染病，同时增加免疫介导的疾病（包括CD和PBC）的风险。
Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r2 = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.