The Genetic Landscape of Renal Complications in Type 1 Diabetes
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The Genetic Landscape of Renal Complications in Type 1 Diabetes. / Sandholm, Niina; Van Zuydam, Natalie; Ahlqvist, Emma; Juliusdottir, Thorhildur; Deshmukh, Harshal A; Rayner, N William; Di Camillo, Barbara; Forsblom, Carol; Fadista, Joao; Ziemek, Daniel; Salem, Rany M; Hiraki, Linda T; Pezzolesi, Marcus; Trégouët, David; Dahlström, Emma; Valo, Erkka; Oskolkov, Nikolay; Ladenvall, Claes; Marcovecchio, M Loredana; Cooper, Jason; Sambo, Francesco; Malovini, Alberto; Manfrini, Marco; McKnight, Amy Jayne; Lajer, Maria; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; FinnDiane Study Group; Tuomilehto, Jaakko; Lyssenko, Valeriya; McKeigue, Paul M; Rich, Stephen S; Brosnan, Mary Julia; Fauman, Eric; Bellazzi, Riccardo; Rossing, Peter; Hadjadj, Samy; Krolewski, Andrzej; Paterson, Andrew D; The DCCT/EDIC Study Group; Florez, Jose C; Hirschhorn, Joel N; Maxwell, Alexander P; GENIE Consortium; Dunger, David; Cobelli, Claudio; Colhoun, Helen M; Groop, Leif; McCarthy, Mark I; Groop, Per-Henrik; on behalf of The SUMMIT Consortium.
In: Journal of the American Society of Nephrology, Vol. 28, No. 2, 2017, p. 557-574.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Genetic Landscape of Renal Complications in Type 1 Diabetes
AU - Sandholm, Niina
AU - Van Zuydam, Natalie
AU - Ahlqvist, Emma
AU - Juliusdottir, Thorhildur
AU - Deshmukh, Harshal A
AU - Rayner, N William
AU - Di Camillo, Barbara
AU - Forsblom, Carol
AU - Fadista, Joao
AU - Ziemek, Daniel
AU - Salem, Rany M
AU - Hiraki, Linda T
AU - Pezzolesi, Marcus
AU - Trégouët, David
AU - Dahlström, Emma
AU - Valo, Erkka
AU - Oskolkov, Nikolay
AU - Ladenvall, Claes
AU - Marcovecchio, M Loredana
AU - Cooper, Jason
AU - Sambo, Francesco
AU - Malovini, Alberto
AU - Manfrini, Marco
AU - McKnight, Amy Jayne
AU - Lajer, Maria
AU - Harjutsalo, Valma
AU - Gordin, Daniel
AU - Parkkonen, Maija
AU - FinnDiane Study Group
AU - Tuomilehto, Jaakko
AU - Lyssenko, Valeriya
AU - McKeigue, Paul M
AU - Rich, Stephen S
AU - Brosnan, Mary Julia
AU - Fauman, Eric
AU - Bellazzi, Riccardo
AU - Rossing, Peter
AU - Hadjadj, Samy
AU - Krolewski, Andrzej
AU - Paterson, Andrew D
AU - The DCCT/EDIC Study Group
AU - Florez, Jose C
AU - Hirschhorn, Joel N
AU - Maxwell, Alexander P
AU - GENIE Consortium
AU - Dunger, David
AU - Cobelli, Claudio
AU - Colhoun, Helen M
AU - Groop, Leif
AU - McCarthy, Mark I
AU - Groop, Per-Henrik
AU - on behalf of The SUMMIT Consortium
N1 - Copyright © 2016 by the American Society of Nephrology.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1681/ASN.2016020231
DO - 10.1681/ASN.2016020231
M3 - Journal article
C2 - 27647854
VL - 28
SP - 557
EP - 574
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
SN - 1046-6673
IS - 2
ER -
ID: 166505585