SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans.
SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans.
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DOI：
10.1038/nm.4370
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发表时间：
2017-08
期刊：
影响因子：
82.9
通讯作者：
Thomas PG
中科院分区：
文献类型：
--
作者：
Allen EK;Randolph AG;Bhangale T;Dogra P;Ohlson M;Oshansky CM;Zamora AE;Shannon JP;Finkelstein D;Dressen A;DeVincenzo J;Caniza M;Youngblood B;Rosenberger CM;Thomas PG
先前的研究报道了IFITM3 SNP rs12252与严重流感的关联，但关联的证据和风险机制仍然存在争议。我们根据推测的生物学功能对IFITM3中的SNP进行了优先排序，并在5′ UTR中鉴定了rs34481144。我们发现rs34481144与三个流感感染队列中严重流感的新关联的证据，其特征在于流感疾病严重程度不同。我们确定rs34481144作为IFITM3的表达数量性状位点（eQTL）的作用，其风险等位基因与较低的mRNA表达相关。在启动子结合试验中发现风险等位基因具有降低的IRF3结合和增加的CTCF结合，并且风险等位基因携带降低了邻近基因之间的转录相关性，指示CTCF边界活性。此外，风险等位基因破坏了在CD8 T细胞亚群中经历差异甲基化的CpG位点。在自然流感感染期间，风险等位基因的携带者在其气道中具有减少的CD8 T细胞，这与IFITM3促进气道CD8 T细胞积累一致，表明IFITM3的关键功能可能是促进免疫细胞在粘膜部位的持久性。我们的研究确定了一种新的IFITM3表达调节因子，它与气道中的CD8 T细胞水平和一系列临床结果相关。
Previous studies reported associations of IFITM3 SNP rs12252 with severe influenza, but evidence of association and the mechanism of risk remains controversial. We prioritized SNPs in IFITM3 based on putative biological function and identified rs34481144 in the 5′ UTR. We found evidence of a novel association of rs34481144 with severe influenza in three influenza-infected cohorts characterized by different levels of influenza illness severity. We determined the role of rs34481144 as an expression quantitative trait loci (eQTL) for IFITM3, with the risk allele associated with lower mRNA expression. The risk allele was found to have decreased IRF3 binding and increased CTCF binding in promoter-binding assays, and risk allele carriage diminished transcriptional correlations among neighboring genes, indicative of CTCF boundary activity. Furthermore, the risk allele disrupts a CpG site that undergoes differential methylation in CD8 T-cell subsets. Carriers of the risk allele had reduced CD8 T-cells in their airways during natural influenza infection, consistent with IFITM3 promoting airway CD8 T-cell accumulation, indicating that a critical function for IFITM3 may be to promote immune cell persistence at mucosal sites. Our study identifies a new regulator of IFITM3 expression that associates with CD8 T-cell levels in the airways and a spectrum of clinical outcomes.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
3.5
作者：
Ea V;Baudement MO;Lesne A;Forné T
通讯作者：
Forné T
影响因子：
30.3
作者：
Amini-Bavil-Olyaee S;Choi YJ;Lee JH;Shi M;Huang IC;Farzan M;Jung JU
通讯作者：
Jung JU
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
DOI：
10.1126/science.aaa1578
发表时间：
2015-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ciancanelli MJ;Huang SX;Luthra P;Garner H;Itan Y;Volpi S;Lafaille FG;Trouillet C;Schmolke M;Albrecht RA;Israelsson E;Lim HK;Casadio M;Hermesh T;Lorenzo L;Leung LW;Pedergnana V;Boisson B;Okada S;Picard C;Ringuier B;Troussier F;Chaussabel D;Abel L;Pellier I;Notarangelo LD;García-Sastre A;Basler CF;Geissmann F;Zhang SY;Snoeck HW;Casanova JL
通讯作者：
Casanova JL