Computational identification of gene-social environment interaction at the human IL6 locus
Computational identification of gene-social environment interaction at the human IL6 locus
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DOI：
10.1073/pnas.0911515107
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发表时间：
2010-03-23
影响因子：
11.1
通讯作者：
Seeman, Teresa E.
中科院分区：
文献类型：
--
作者：
Cole, Steven W.;Arevalo, Jesusa M. G.;Seeman, Teresa E.
为了确定与社会环境相互作用影响人类健康的遗传因素，我们采用了一种生物信息学策略，该策略将基于表达阵列的环境响应转录因子检测与调控多态性的计算机模拟发现相结合，以预测调节对压力环境转录反应的基因位点。对人类白细胞介素6（IL6）启动子中一个预测的相互作用位点（单核苷酸多态性rs1800795）的测试证实，它在体外调节对GATA1转录因子的β -肾上腺素能激活的转录反应。体内验证研究证实了不良社会状况与原代神经细胞、免疫细胞和癌细胞中GATA1靶基因转录增加之间的联系。流行病学分析通过记录与晚年抑郁症状相关的10年死亡风险增加，证实了这些分子相互作用对健康的重要性，而这种死亡风险的增加仅发生在rs1800795的GATA1敏感G等位基因纯合携带者中。白细胞介素6基因型对抑郁相关死亡风险的调控仅与炎症相关的死亡原因有关，并且与血浆C -反应蛋白所反映的慢性炎症增加有关。分子相互作用的计算建模、体外生化分析、体内动物模型和人类分子流行病学分析因此共同确定了GATA1的β -肾上腺素能激活是一种分子途径，通过该途径，社会逆境可以根据白细胞介素6基因座的个体遗传状态选择性地改变人类健康风险。
To identify genetic factors that interact with social environments to impact human health, we used a bioinformatic strategy that couples expression array-based detection of environmentally responsive transcription factors with in silico discovery of regulatory polymor-phisms to predict genetic loci that modulate transcriptional responses to stressful environments. Tests of one predicted interaction locus in the human IL6 promoter (SNP rs1800795) verified that it modulates transcriptional response to beta-adrenergic activation of the GATA1 transcription factor in vitro. In vivo validation studies confirmed links between adverse social conditions and increased transcription of GATA1 target genes in primary neural, immune, and cancer cells. Epidemiologic analyses verified the health significance of those molecular interactions by documenting increased 10-year mortality risk associated with late-life depressive symptoms that occurred solely for homozygous carriers of the GATA1-sensitive G allele of rs1800795. Gating of depression-related mortality risk by IL6 genotype pertained only to inflammation-related causes of death and was associated with increased chronic inflammation as indexed by plasma C-reactive protein. Computational modeling of molecular interactions, in vitro biochemical analyses, in vivo animal modeling, and human molecular epidemiologic analyses thus converge in identifying beta-adrenergic activation of GATA1 as a molecular pathway by which social adversity can alter human health risk selectively depending on individual genetic status at the IL6 locus.