Department of Medicine and Norman Cousins Center, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5681-6. doi: 10.1073/pnas.0911515107. Epub 2010 Feb 22.
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 polymorphisms 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.
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，该策略结合了基于表达谱的环境响应转录因子的检测和调控多态性的计算机发现，以预测调节转录对应激环境反应的遗传基因座。对人类 IL6 启动子中一个预测的相互作用基因座（SNP rs1800795）的测试证实，它调节了体外 GATA1 转录因子的β-肾上腺素激活的转录反应。体内验证研究证实了不利的社会条件与初级神经、免疫和癌细胞中 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 年死亡率风险增加来验证这些分子相互作用的健康意义，而这些抑郁症状仅发生在 rs1800795 的 GATA1 敏感 G 等位基因的纯合子携带者中。IL6 基因型对抑郁相关死亡率的控制仅与炎症相关的死亡原因有关，并与血浆 C 反应蛋白所示的慢性炎症增加有关。分子相互作用的计算模型、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汇聚在一起，确定 GATA1 的β-肾上腺素激活是一种分子途径，通过该途径，社会逆境可以根据 IL6 基因座的个体遗传状态选择性地改变人类健康风险。
