Proteome-wide analysis of disease-associated SNPs that show allele-specific transcription factor binding

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 rs12722508*A, rs12722522*C, rs41295061*A, and rs2104286*A 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / metabolism
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genome, Human
  • High-Throughput Screening Assays
  • Humans
  • Interleukin-2 Receptor alpha Subunit / genetics*
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Binding
  • Proteome* / analysis
  • Proteome* / genetics


  • CREB1 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Cyclic AMP Response Element-Binding Protein
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Proteome
  • RUNX1 protein, human