Functional annotations of diabetes nephropathy susceptibility loci through analysis of genome-wide renal gene expression in rat models of diabetes mellitus
- Equal contributors
1 The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
2 Steno Diabetes Center, Copenhagen, Denmark
3 Department of Medicine, Division of Nephrology, Helsinki University Central Hospital and Folkhälsan Institute of Genetics, Helsinki, Finland
4 CHU Poitiers, University Hospital, Endocrinology and INSERM, ERM 324, Poitiers, France
5 Department of Diabetology, Bichat Hospital and INSERM, U695, Xavier Bichat University of Medicine, Paris, France
6 Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
7 MRC Mammalian Genome Unit, Harwell OX11 0RD, UK
8 National Genotyping Centre, Evry, France
9 INSERM, UMR S 525, Université Pierre et Marie Curie-Paris 6, Paris, France
10 INSERM, U872, Centre de Recherche des Cordeliers, Paris, France
BMC Medical Genomics 2009, 2:41 doi:10.1186/1755-8794-2-41Published: 9 July 2009
Hyperglycaemia in diabetes mellitus (DM) alters gene expression regulation in various organs and contributes to long term vascular and renal complications. We aimed to generate novel renal genome-wide gene transcription data in rat models of diabetes in order to test the responsiveness to hyperglycaemia and renal structural changes of positional candidate genes at selected diabetic nephropathy (DN) susceptibility loci.
Both Affymetrix and Illumina technologies were used to identify significant quantitative changes in the abundance of over 15,000 transcripts in kidney of models of spontaneous (genetically determined) mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK) and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ]).
Different patterns of transcription regulation in the two rat models of diabetes likely underlie the roles of genetic variants and hyperglycaemia severity. The impact of prolonged hyperglycaemia on gene expression changes was more profound in STZ-WKY rats than in GK rats and involved largely different sets of genes. These included genes already tested in genetic studies of DN and a large number of protein coding sequences of unknown function which can be considered as functional and, when they map to DN loci, positional candidates for DN. Further expression analysis of rat orthologs of human DN positional candidate genes provided functional annotations of known and novel genes that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations.
Combining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support for testing candidate genes in human genetics.