Johnson Matthew E, Schug Jonathan, Wells Andrew D, Kaestner Klaus H, Grant Struan F A
Division of Human Genetics (M.E.J., S.F.A.G.) and Department of Pathology and Laboratory Medicine (A.D.W.), The Children's Hospital of Philadelphia, and Department of Genetics and Institute of Diabetes, Obesity, and Metabolism (J.S., K.H.K., S.F.A.G.), and Department of Pediatrics (S.F.A.G.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
J Clin Endocrinol Metab. 2014 Aug;99(8):E1580-5. doi: 10.1210/jc.2013-4503. Epub 2014 May 30.
Forkhead Box A2 (FOXA2) exerts an influence on glucose homeostasis via activity in the liver. In addition, a key genome-wide association study (GWAS) recently demonstrated that genetic variation, namely rs6048205, at the FOXA2 locus is robustly associated with fasting glucose levels. Our hypothesis was that this DNA-binding protein regulates the expression of a set of molecular pathways critical to endocrine traits.
Drawing on our laboratory and bioinformatic experience with chromatin immunoprecipitation followed by massively parallel sequencing, we analyzed our existing FOXA2 chromatin immunoprecipitation followed by massively parallel sequencing data generated in human liver, using the algorithm hypergeometric optimization of motif enrichment, to gain insight into its global genomic binding pattern from a disease perspective.
We performed a pathway analysis of the gene list using the gene set enrichment analysis algorithm, which yielded a number of significant annotations. Motivated by the fact that the FOXA2 locus has been implicated by GWAS, we cross-referenced the occupancy sites with the National Institutes of Health GWAS catalog and found strong evidence for the enrichment of loci implicated in endocrine, neuropsychiatric, cardiovascular, and cancer trait categories, but interestingly there was no evidence for enrichment for inflammation related traits. Intriguingly, a FOXA2 occupancy site coincided with rs6048205, suggesting that this variant confers its effect, at least partially, via a perturbation of a FOXA2 feedback mechanism.
Our data strongly suggest that FOXA2 is acting as a master regulator of key pathways that are enriched for loci implicated by GWAS for most trait categories, with the clear exception of inflammation, suggesting that this factor exerts its effect in this context via noninflammatory processes.
叉头框A2（FOXA2）通过在肝脏中的活性对葡萄糖稳态产生影响。此外，一项关键的全基因组关联研究（GWAS）最近表明，FOXA2基因座处的遗传变异，即rs6048205，与空腹血糖水平密切相关。我们的假设是，这种DNA结合蛋白调节一组对内分泌特征至关重要的分子途径的表达。
利用我们实验室和生物信息学在染色质免疫沉淀后进行大规模平行测序的经验，我们使用基序富集的超几何优化算法分析了我们现有的在人类肝脏中生成的FOXA2染色质免疫沉淀后大规模平行测序数据，以便从疾病角度深入了解其全局基因组结合模式。
我们使用基因集富集分析算法对基因列表进行了通路分析，得出了许多重要注释。鉴于FOXA2基因座已被GWAS所涉及，我们将占用位点与美国国立卫生研究院GWAS目录进行了交叉参考，发现了有力证据表明在内分泌、神经精神、心血管和癌症特征类别中涉及的基因座得到了富集，但有趣的是，没有证据表明与炎症相关的特征得到了富集。有趣的是，一个FOXA2占用位点与rs6048205重合，表明该变体至少部分地通过干扰FOXA2反馈机制发挥其作用。
我们的数据有力地表明，FOXA2作为关键通路的主要调节因子，这些通路在大多数特征类别中因GWAS涉及的基因座而富集，但炎症明显除外，这表明该因子在这种情况下通过非炎症过程发挥其作用。
