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Proteome-Wide Analysis of Disease-Associated SNPs That Show Allele-Specific Transcription Factor Binding

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons77831

Butter,  Falk
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78972

Viturawong,  Tar
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78974

Scheibe,  Marion
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78356

Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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pgen.1002982.pdf
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Citation

Butter, F., Davison, L., Viturawong, T., Scheibe, M., Vermeulen, M., Todd, J. A., et al. (2012). Proteome-Wide Analysis of Disease-Associated SNPs That Show Allele-Specific Transcription Factor Binding. PLOS GENETICS, 8(9): e1002982. doi:10.1371/journal.pgen.1002982.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-7771-2
Abstract
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.