title: From single nucleotide polymorphism to transcriptional mechanism: a model for FRMD3 in diabetic nephropathy.
abstract: 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.
authors: Departments of Internal Medicine and Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Sebastian
authors: S
authors: Martini
authors: Viji
authors: V
authors: Nair
authors: Sanjeevkumar R
authors: SR
authors: Patel
authors: Felix
authors: F
authors: Eichinger
authors: Robert G
authors: RG
authors: Nelson
authors: E Jennifer
authors: EJ
authors: Weil
authors: Marcus G
authors: MG
authors: Pezzolesi
authors: Andrzej S
authors: AS
authors: Krolewski
authors: Ann
authors: A
authors: Randolph
authors: Benjamin J
authors: BJ
authors: Keller
authors: Thomas
authors: T
authors: Werner
authors: Matthias
authors: M
authors: Kretzler
mesh_terms: D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C562024:FRMD3 protein, human; D025521:Tumor Suppressor Proteins