Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.
Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles.
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DOI：
10.1038/ng.2205
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发表时间：
2012-03-25
期刊：
影响因子：
30.8
通讯作者：
Knight, Julian C.
中科院分区：
文献类型：
--
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
反式作用遗传变异在基因表达的遗传决定中起着重要作用，尽管其特征尚不明确。利用成对纯化的原代单核细胞和B细胞，我们鉴定出了新的、主要是细胞特异性的顺式和反式表达数量性状位点（eQTL）。这些包括单核细胞中与溶菌酶（LYZ）以及B细胞中与KLF4的多位点反式关联。此外，我们观察到在12q13.2处的rs11171739（一个已知的自身免疫疾病位点）与B细胞中的IP6K2（pB - cell = 5.8×10⁻¹⁵）、PRIC285（pB - cell = 3.0×10⁻¹⁰）以及CDKN1A的上游区域（pB - cell = 2×10⁻⁵²；p单核细胞 = 1.8×10⁻⁴）存在B细胞特异性反式关联，这表明细胞周期调控和过氧化物酶体增殖物激活受体γ（PPARγ）信号传导在疾病发病机制中起作用。我们还发现特定的人类白细胞抗原（HLA）等位基因与单核细胞中AOAH和ARHGAP24的表达形成反式关联，但在B细胞中则没有。总之，我们证明了在特定的原代细胞群中绘制基因表达图谱可识别新的细胞特异性反式调控网络，并为疾病易感性的遗传基础提供见解。
Trans-acting genetic variants play a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B-cells we identify novel, predominantly cell-specific, cis- and trans-eQTL (expression quantitative trait loci). These include multi-locus trans-associations to LYZ in monocytes and to KLF4 in B-cells. Additionally, we observe B-cell specific trans-association of rs11171739 at 12q13.2, a known autoimmune disease locus, to IP6K2 (pB-cell=5.8×10−15), PRIC285 (pB-cell=3.0×10−10) and an upstream region of CDKN1A (pB-cell=2×10−52; pmonocyte=1.8×10−4), suggesting roles for cell cycle regulation and PPARγ signaling in disease pathogenesis. We also find specific HLA alleles forming trans-association with the expression of AOAH and ARHGAP24 in monocytes but not in B-cells. In summary, we demonstrate that mapping gene expression in defined primary cell populations identifies new cell-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility.
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