Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy
| Autor: | Qibin Li, Maija Parkkonen, Valma Harjutsalo, Miina K. Öhman, Per-Henrik Groop, Carol Forsblom, Wenjuan Zhu, Yang Sun, Enrico Petretto, Jing Guo, Anne May Österholm, Iiro Toppila, Karl Tryggvason, Nathan Harmston, Niina Sandholm, Owen J. L. Rackham, Erkka Valo, Sonia Chothani, Bing He, Eudora Eng |
|---|---|
| Přispěvatelé: | Medicum, HUS Abdominal Center, Research Programs Unit, Department of Medicine, Nefrologian yksikkö, University of Helsinki, Helsinki University Hospital Area, CAMM - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, HUS Internal Medicine and Rehabilitation, Clinicum, University Management, Diabetes and Obesity Research Program, Per Henrik Groop / Principal Investigator |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent PROGRESSION Biology SUSCEPTIBILITY METABOLISM Polymorphism Single Nucleotide GLUCOSE Diabetic nephropathy ACTIVATION Young Adult 03 medical and health sciences 0302 clinical medicine Diabetes mellitus medicine Genetic predisposition Animals Humans Diabetic Nephropathies 12/15-LIPOXYGENASE OXIDATIVE STRESS Child Gene Protein Kinase C Zebrafish Protein kinase C Genetics Type 1 diabetes COMPLICATIONS Whole Genome Sequencing MUTATIONS Siblings General Medicine medicine.disease Basic Research Diabetes Mellitus Type 1 HEK293 Cells 030104 developmental biology Nephrology Tyrosine kinase 2 Child Preschool METHYLGLYOXAL 3121 General medicine internal medicine and other clinical medicine Female 030217 neurology & neurosurgery Kidney disease |
| Zdroj: | J Am Soc Nephrol |
| Popis: | Background Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated. Methods We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes. Results We observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy-associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms epsilon and iota and protein tyrosine kinase 2. Conclusions Our comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|