PDF(Pubmed)
Abstract：
Identifying cellular functions dysregulated by disease-associated variants could implicate novel pathways for drug targeting or modulation in cell therapies. However, follow-up studies can be challenging if disease-relevant cell types are difficult to sample. Variants associated with immune diseases point toward the role of CD4+ regulatory T cells (Treg cells). We mapped genetic regulation (quantitative trait loci [QTL]) of gene expression and chromatin activity in Treg cells, and we identified 133 colocalizing loci with immune disease variants. Colocalizations of immune disease genome-wide association study (GWAS) variants with expression QTLs (eQTLs) controlling the expression of CD28 and STAT5A, involved in Treg cell activation and interleukin-2 (IL-2) signaling, support the contribution of Treg cells to the pathobiology of immune diseases. Finally, we identified seven known drug targets suitable for drug repurposing and suggested 63 targets with drug tractability evidence among the GWAS signals that colocalized with Treg cell QTLs. Our study is the first in-depth characterization of immune disease variant effects on Treg cell gene expression modulation and dysregulation of Treg cell function.
摘要：
鉴定疾病相关变体失调的细胞功能可能涉及细胞疗法中药物靶向或调节的新途径。然而,如果疾病相关细胞类型难以取样,那么后续研究可能具有挑战性.与免疫疾病相关的变体指向CD4+调节性T细胞(Treg细胞)的作用。我们绘制了Treg细胞中基因表达和染色质活性的遗传调控（数量性状基因座[QTL]），我们确定了133个与免疫疾病变异的共定位位点。免疫疾病全基因组关联研究（GWAS）变体与表达QTL（eQTL）控制CD28和STAT5A的表达的共同定位，参与Treg细胞活化和白细胞介素-2（IL-2）信号，支持Treg细胞对免疫疾病病理生物学的贡献。最后,我们确定了7个适合药物再利用的已知药物靶点,并在与Treg细胞QTL共定位的GWAS信号中,提示了63个具有药物易处理性证据的靶点.我们的研究是第一个深入表征免疫性疾病变异对Treg细胞基因表达调控和Treg细胞功能失调的影响。
