Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation
Estrogen, SNP-Dependent Chemokine Expression and Selective Estrogen Receptor Modulator Regulation
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DOI：
10.1210/me.2015-1267
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发表时间：
2016-03-01
影响因子：
--
通讯作者：
Weinshilboum, Richard M.
中科院分区：
文献类型：
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作者：
Ho, Ming-Fen;Bongartz, Tim;Weinshilboum, Richard M.
我们以前报道过，在芳香化酶诱导的肌肉骨骼症状的全基因组关联研究的基础上，T细胞白血病/淋巴瘤1A（TCL 1A）基因附近的单核苷酸多态性（SNP）与芳香化酶诱导的肌肉骨骼疼痛和雌二醇（E2）诱导的TCL 1A表达相关。此外，TCL 1A表达的变化影响促炎细胞因子和细胞因子受体的下游表达。具体而言，热门全基因组关联研究SNP rs 11849538创建了一个功能性雌激素反应元件（ERE），该元件显示雌激素受体（ER）结合，并仅对变体SNP基因型增加E2对TCL 1A表达的诱导。在本研究中，我们探讨了TCL 1A表达的E2-SNP依赖性调节的机制，同时，我们随后观察到与ERE有一定距离的SNP可以调节ER α结合，ER拮抗剂可以逆转与这些SNP相关的表型。具体而言，我们使用大量淋巴母细胞系进行了一系列功能基因组研究，这些细胞系具有密集的基因组数据，表明与ERE有一定距离的TCL 1A SNP可以调节TCL 1A的ER α结合和表达以及下游免疫介质的表达。此外，4-羟基他莫昔芬或氟维司群可以逆转这些SNP基因型效应。在IL 17 A细胞因子和CCR 6趋化因子受体基因的SNP中发现了类似的结果。这些观察结果大大扩展了我们以前的结果，并支持存在一种新的分子机制，有助于雌激素和免疫系统之间的复杂相互作用。它们还提高了以SNP基因型依赖性方式对促炎细胞因子和趋化因子表达进行药理学操作的可能性。
We previously reported, on the basis of a genome-wide association study for aromatase inhibitor-induced musculoskeletal symptoms, that single-nucleotide polymorphisms (SNPs) near the T-cell leukemia/lymphoma 1A (TCL1A) gene were associated with aromatase inhibitor-induced musculoskeletal pain and with estradiol (E2)-induced TCL1A expression. Furthermore, variation in TCL1A expression influenced the downstream expression of proinflammatory cytokines and cytokine receptors. Specifically, the top hit genome-wide association study SNP, rs11849538, created a functional estrogen response element (ERE) that displayed estrogen receptor (ER) binding and increased E2 induction of TCL1A expression only for the variant SNP genotype. In the present study, we pursued mechanisms underlying the E2-SNP-dependent regulation of TCL1A expression and, in parallel, our subsequent observations that SNPs at a distance from EREs can regulate ER alpha binding and that ER antagonists can reverse phenotypes associated with those SNPs. Specifically, we performed a series of functional genomic studies using a large panel of lymphoblastoid cell lines with dense genomic data that demonstrated that TCL1A SNPs at a distance from EREs can modulate ER alpha binding and expression of TCL1A as well as the expression of downstream immune mediators. Furthermore, 4-hydroxytamoxifen or fulvestrant could reverse these SNP-genotype effects. Similar results were found for SNPs in the IL17A cytokine and CCR6 chemokine receptor genes. These observations greatly expand our previous results and support the existence of a novel molecular mechanism that contributes to the complex interplay between estrogens and immune systems. They also raise the possibility of the pharmacological manipulation of the expression of proinflammatory cytokines and chemokines in a SNP genotype-dependent fashion.