Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
PLoS Genet. 2012 Sep;8(9):e1002982. doi: 10.1371/journal.pgen.1002982. Epub 2012 Sep 27.
A causative role for single nucleotide polymorphisms (SNPs) in many genetic disorders has become evident through numerous genome-wide association studies. However, identification of these common causal variants and the molecular mechanisms underlying these associations remains a major challenge. Differential transcription factor binding at a SNP resulting in altered gene expression is one possible mechanism. Here we apply PWAS ("proteome-wide analysis of SNPs"), a methodology based on quantitative mass spectrometry that enables rapid screening of SNPs for differential transcription factor binding, to 12 SNPs that are highly associated with type 1 diabetes at the IL2RA locus, encoding the interleukin-2 receptor CD25. We report differential, allele-specific binding of the transcription factors RUNX1, LEF1, CREB, and TFAP4 to IL2RA SNPs rs12722508A, rs12722522C, rs41295061A, and rs2104286A and demonstrate the functional influence of RUNX1 at rs12722508 by reporter gene assay. Thus, PWAS may be able to contribute to our understanding of the molecular consequences of human genetic variability underpinning susceptibility to multi-factorial disease.
通过大量全基因组关联研究，单核苷酸多态性（SNPs）在许多遗传疾病中的因果作用已经变得明显。然而，这些常见的因果变异体的识别以及这些关联的分子机制仍然是一个主要挑战。SNP 处转录因子结合的差异导致基因表达的改变是一种可能的机制。在这里，我们应用 PWAS（“SNP 的蛋白质组分析”），一种基于定量质谱的方法，能够快速筛选与 IL2RA 基因座上的 1 型糖尿病高度相关的 12 个 SNP 的差异转录因子结合，该基因座编码白细胞介素 2 受体 CD25。我们报告了转录因子 RUNX1、LEF1、CREB 和 TFAP4 对 IL2RA SNP rs12722508A、rs12722522C、rs41295061A 和 rs2104286A 的差异、等位基因特异性结合，并通过报告基因检测证明了 RUNX1 在 rs12722508 处的功能影响。因此，PWAS 可能有助于我们理解多因素疾病易感性所基于的人类遗传变异性的分子后果。
