Deriving mechanisms of immune-mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune-mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune-mediated diseases but cannot be fine-mapped. By studying the lead expression-modulating SNP, we uncovered an NF-κB-driven regulatory circuit which constrains T-cell activation through the dynamic formation of a super-enhancer that upregulates TNFAIP3 (A20), a key NF-κB inhibitor. In activated T cells, this feedback circuit is disrupted-and super-enhancer formation prevented-by the risk variant at the lead SNP, leading to unrestrained T-cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.

中文翻译：

---

解决原代 CD4 T 细胞中免疫介导疾病的机制。


从 GWAS 数据中推导免疫介导疾病的机制仍然是一个艰巨的挑战，试图识别因果变异常常受到强连锁不平衡的阻碍。为了确定是否可以从其功能效应中识别出因果变异，我们采用了大规模并行报告基因测定法，用于初级 CD4 T 细胞，这种细胞类型的调节 DNA 中免疫介导疾病 SNP 最为丰富。这使得候选 SNP 的作用能够在相关的细胞环境中进行检查，并产生疾病机制的可检验假设。为了说明这种方法的威力，我们研究了一个与六种免疫介导的疾病相关但无法精细定位的位点。通过研究先导表达调节 SNP，我们发现了一个 NF-κB 驱动的调节回路，该回路通过动态形成上调 TNFAIP3 (A20)（一种关键 NF-κB 抑制剂）的超级增强子来限制 T 细胞激活。在激活的 T 细胞中，这种反馈回路被先导 SNP 处的风险变异破坏，并阻止了超级增强子的形成，从而通过似乎广泛易感人类自身免疫的分子机制导致不受限制的 T 细胞激活。