The Genetic Landscape of Renal Complications in Type 1 Diabetes

Niina Sandholm, Natalie Van Zuydam, Emma Ahlqvist, Thorhildur Juliusdottir, Harshal A Deshmukh, N William Rayner, Barbara Di Camillo, Carol Forsblom, Joao Fadista, Daniel Ziemek, Rany M Salem, Linda T Hiraki, Marcus Pezzolesi, David Trégouët, Emma Dahlström, Erkka Valo, Nikolay Oskolkov, Claes Ladenvall, M Loredana Marcovecchio, Jason CooperFrancesco Sambo, Alberto Malovini, Marco Manfrini, Amy Jayne McKnight, Maria Lajer, Valma Harjutsalo, Daniel Gordin, Maija Parkkonen, Valeriya Lyssenko, Paul M McKeigue, Stephen S Rich, Mary Julia Brosnan, Eric Fauman, Riccardo Bellazzi, Peter Rossing, Samy Hadjadj, Andrzej Krolewski, Andrew D Paterson, Joel N Hirschhorn, Alexander P Maxwell, Claudio Cobelli, Helen M Colhoun, Leif Groop, Mark I McCarthy, Per-Henrik Groop, FinnDiane Study Group, Jaakko Tuomilehto

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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.

Original languageEnglish
Pages (from-to)557-574
Number of pages18
JournalJournal of the American Society of Nephrology : JASN
Volume28
Issue number2
DOIs
Publication statusPublished - Feb 2017

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Keywords

  • Adolescent
  • Adult
  • Diabetes Mellitus, Type 1
  • Diabetic Nephropathies
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Young Adult
  • Journal Article

Cite this

Sandholm, N., Van Zuydam, N., Ahlqvist, E., Juliusdottir, T., Deshmukh, H. A., Rayner, N. W., Di Camillo, B., Forsblom, C., Fadista, J., Ziemek, D., Salem, R. M., Hiraki, L. T., Pezzolesi, M., Trégouët, D., Dahlström, E., Valo, E., Oskolkov, N., Ladenvall, C., Marcovecchio, M. L., ... FinnDiane Study Group, Jaakko Tuomilehto (2017). The Genetic Landscape of Renal Complications in Type 1 Diabetes. Journal of the American Society of Nephrology : JASN, 28(2), 557-574. https://doi.org/10.1681/ASN.2016020231