| Literature DB >> 27647854 |
Niina Sandholm1,2,3, Natalie Van Zuydam4,5,6, Emma Ahlqvist7, Thorhildur Juliusdottir4, Harshal A Deshmukh8, N William Rayner4,5,9, Barbara Di Camillo10, Carol Forsblom1,2,3, Joao Fadista7, Daniel Ziemek11, Rany M Salem12,13,14, Linda T Hiraki15, Marcus Pezzolesi16, David Trégouët17,18, Emma Dahlström1,2,3, Erkka Valo1,2,3, Nikolay Oskolkov7, Claes Ladenvall7, M Loredana Marcovecchio19, Jason Cooper20, Francesco Sambo10, Alberto Malovini21,22, Marco Manfrini10, Amy Jayne McKnight23, Maria Lajer24, Valma Harjutsalo1,2,3,25, Daniel Gordin1,2,3, Maija Parkkonen1,2,3, Jaakko Tuomilehto25,26, Valeriya Lyssenko7,24, Paul M McKeigue27, Stephen S Rich28, Mary Julia Brosnan29, Eric Fauman30, Riccardo Bellazzi21, Peter Rossing24,31,32, Samy Hadjadj33,34,35, Andrzej Krolewski16, Andrew D Paterson15, Jose C Florez13,36, Joel N Hirschhorn12,13,14, Alexander P Maxwell23,37, David Dunger19, Claudio Cobelli10, Helen M Colhoun8, Leif Groop7, Mark I McCarthy4,5,38, Per-Henrik Groop39,2,3,40.
Abstract
Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.Entities:
Keywords: diabetic kidney disease; genetics and development; genome-wide association study; whole exome sequencing
Mesh：
Year: 2016 PMID： 27647854 PMCID： PMC5280020 DOI： 10.1681/ASN.2016020231
Source DB: PubMed Journal: J Am Soc Nephrol ISSN： 1046-6673 Impact factor: 10.121