From Single Nucleotide Polymorphism to Transcriptional Mechanism

A Model for FRMD3 in Diabetic Nephropathy

  1. Matthias Kretzler1
  1. 1Departments of Internal Medicine and Nephrology, University of Michigan, Ann Arbor, Michigan
  2. 2National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
  3. 3Research and Clinic Divisions, Joslin Diabetes Center, Boston, Massachusetts
  4. 4Department of Computer Science, Eastern Michigan University, Ypsilanti, Michigan
  5. 5Genomatix Software GmbH, Munich, Germany
  1. Corresponding author: Matthias Kretzler, kretzler{at}


Genome-wide association studies have proven to be highly effective at defining relationships between single nucleotide polymorphisms (SNPs) and clinical phenotypes in complex diseases. Establishing a mechanistic link between a noncoding SNP and the clinical outcome is a significant hurdle in translating associations into biological insight. We demonstrate an approach to assess the functional context of a diabetic nephropathy (DN)-associated SNP located in the promoter region of the gene FRMD3. The approach integrates pathway analyses with transcriptional regulatory pattern-based promoter modeling and allows the identification of a transcriptional framework affected by the DN-associated SNP in the FRMD3 promoter. This framework provides a testable hypothesis for mechanisms of genomic variation and transcriptional regulation in the context of DN. Our model proposes a possible transcriptional link through which the polymorphism in the FRMD3 promoter could influence transcriptional regulation within the bone morphogenetic protein (BMP)-signaling pathway. These findings provide the rationale to interrogate the biological link between FRMD3 and the BMP pathway and serve as an example of functional genomics-based hypothesis generation.


  • Received October 12, 2012.
  • Accepted February 17, 2013.

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