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The genetic landscape of renal complications in type 1 diabetes

Sandholm, Niina ; Van Zuydam, Natalie ; Ahlqvist, Emma LU ; Juliusdottir, Thorhildur ; Deshmukh, Harshal A. ; Rayner, N. William ; Di Camillo, Barbara ; Forsblom, Carol ; Fadista, Joao LU and Ziemek, Daniel , et al. (2017) In Journal of the American Society of Nephrology 28(2). p.557-574
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=6.4310-3). 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... (More)

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=6.4310-3). 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 associatedvariants.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=2.2310-5) and the risk of type 2 diabetes (P=6.1310-4) associated with the risk of diabetic kidney disease.Wealso found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1310-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0310-6), and pentose and glucuronate interconversions (P=3.0310-6) 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.

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Journal of the American Society of Nephrology
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28
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18 pages
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American Society of Nephrology
external identifiers
  • scopus:85021404855
  • pmid:27647854
ISSN
1046-6673
DOI
10.1681/ASN.2016020231
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English
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yes
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bc31c369-d619-4c8e-baef-a6302c5e25a5
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2020-04-23 12:08:56
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2020-07-12 06:08:06
@article{bc31c369-d619-4c8e-baef-a6302c5e25a5,
  abstract     = {<p>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=6.4310<sup>-3</sup>). 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 associatedvariants.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=2.2310<sup>-5</sup>) and the risk of type 2 diabetes (P=6.1310<sup>-4</sup>) associated with the risk of diabetic kidney disease.Wealso found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1310<sup>-4</sup>). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0310<sup>-6</sup>), and pentose and glucuronate interconversions (P=3.0310<sup>-6</sup>) 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.</p>},
  author       = {Sandholm, Niina and Van Zuydam, Natalie and Ahlqvist, Emma and Juliusdottir, Thorhildur and Deshmukh, Harshal A. and Rayner, N. William and Di Camillo, Barbara and Forsblom, Carol and Fadista, Joao and Ziemek, Daniel and Salem, Rany M. and Hiraki, Linda T. and Pezzolesi, Marcus and Trégouët, David and Dahlström, Emma and Valo, Erkka and Oskolkov, Nikolay and Ladenvall, Claes and Marcovecchio, M. Loredana and Cooper, Jason and Sambo, Francesco and Malovini, Alberto and Manfrini, Marco and McKnight, Amy Jayne and Lajer, Maria and Harjutsalo, Valma and Gordin, Daniel and Parkkonen, Maija and Tuomilehto, Jaakko and Lyssenko, Valeriya and McKeigue, Paul M. and Rich, Stephen S. and Brosnan, Mary Julia and Fauman, Eric and Bellazzi, Riccardo and Rossing, Peter and Hadjadj, Samy and Krolewski, Andrzej and Paterson, Andrew D. and Florez, Jose C. and Hirschhorn, Joel N. and Maxwell, Alexander P. and Dunger, David and Cobelli, Claudio and Colhoun, Helen M. and Groop, Leif and McCarthy, Mark I. and Groop, Per Henrik},
  issn         = {1046-6673},
  language     = {eng},
  number       = {2},
  pages        = {557--574},
  publisher    = {American Society of Nephrology},
  series       = {Journal of the American Society of Nephrology},
  title        = {The genetic landscape of renal complications in type 1 diabetes},
  url          = {http://dx.doi.org/10.1681/ASN.2016020231},
  doi          = {10.1681/ASN.2016020231},
  volume       = {28},
  year         = {2017},
}