From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy.

Publication Type:

Journal Article


Diabetes, Volume 62, Issue 7, p.2605-12 (2013)


asb, Diabetic Nephropathies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney, Models, Genetic, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription, Genetic, Tumor Suppressor Proteins


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.