Jing Guo1,2, Owen J L Rackham2, Niina Sandholm3,4,5, Bing He1, Anne-May Österholm1,2, Erkka Valo3,4,5, Valma Harjutsalo3,4,5,6, Carol Forsblom3,4,5, Iiro Toppila3,4,5, Maija Parkkonen3,4,5, Qibin Li7, Wenjuan Zhu7, Nathan Harmston2,8, Sonia Chothani2, Miina K Öhman2, Eudora Eng2, Yang Sun2, Enrico Petretto9,10, Per-Henrik Groop11,4,5,12, Karl Tryggvason13,2,14. 1. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 2. Cardiovascular and Metabolic Disorders Programme, Duke-National University of Singapore Medical School, Singapore. 3. Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland. 4. Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. 5. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. 6. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland. 7. Complex Disease Research Center, BGI Genomics, Shenzhen, China. 8. Science Division, Yale-National University of Singapore College, National University of Singapore, Singapore. 9. Cardiovascular and Metabolic Disorders Programme, Duke-National University of Singapore Medical School, Singapore; karl.tryggvason@duke-nus.edu.sg enrico.petretto@duke-nus.edu.sg. 10. MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom. 11. Folkhälsan Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland; karl.tryggvason@duke-nus.edu.sg enrico.petretto@duke-nus.edu.sg. 12. Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia; and. 13. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; karl.tryggvason@duke-nus.edu.sg enrico.petretto@duke-nus.edu.sg. 14. Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina.
Abstract
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 ε and ι) 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.
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 ε and ι) 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.
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