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 Cooper; Francesco Sambo; Alberto Malovini; Marco Manfrini; Amy Jayne McKnight; Maria Lajer; Valma Harjutsalo; Daniel Gordin; Maija Parkkonen; FinnDiane Study Group; Jaakko Tuomilehto; Valeriya Lyssenko; Paul M McKeigue; Stephen S Rich; Mary Julia Brosnan; Eric Fauman; Riccardo Bellazzi; Peter Rossing; Samy Hadjadj; Andrzej Krolewski; Andrew D Paterson; The DCCT/EDIC Study Group; Jose C Florez; Joel N Hirschhorn; Alexander P Maxwell; GENIE Consortium; David Dunger; Claudio Cobelli; Helen M Colhoun; Leif Groop; Mark I McCarthy; Per-Henrik Groop; on behalf of The SUMMIT Consortium

doi:10.1681/asn.2016020231

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, FinnDiane Study Group, Jaakko Tuomilehto, Valeriya Lyssenko, Paul M McKeigue, Stephen S Rich, Mary Julia Brosnan, Eric Fauman, Riccardo Bellazzi, Peter Rossing, Samy Hadjadj, Andrzej Krolewski, Andrew D Paterson, The DCCT/EDIC Study Group, Jose C Florez, Joel N Hirschhorn, Alexander P Maxwell, GENIE Consortium, David Dunger, Claudio Cobelli, Helen M Colhoun, Leif Groop, Mark I McCarthy, Per-Henrik Groop, on behalf of The SUMMIT Consortium

Institut for Klinisk Medicin

54 Citationer (Scopus)

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 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.

Originalsprog	Engelsk
Tidsskrift	Journal of the American Society of Nephrology
Vol/bind	28
Udgave nummer	2
Sider (fra-til)	557-574
ISSN	1046-6673
DOI	https://doi.org/10.1681/asn.2016020231
Status	Udgivet - feb. 2017

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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., ... on behalf of The SUMMIT Consortium (2017). The Genetic Landscape of Renal Complications in Type 1 Diabetes. Journal of the American Society of Nephrology, 28(2), 557-574. https://doi.org/10.1681/asn.2016020231

Sandholm, N, Van Zuydam, N, Ahlqvist, E, Juliusdottir, T, Deshmukh, HA, Rayner, NW, Di Camillo, B, Forsblom, C, Fadista, J, Ziemek, D, Salem, RM, Hiraki, LT, Pezzolesi, M, Trégouët, D, Dahlström, E, Valo, E, Oskolkov, N, Ladenvall, C, Marcovecchio, ML, Cooper, J, Sambo, F, Malovini, A, Manfrini, M, McKnight, AJ, Lajer, M, Harjutsalo, V, Gordin, D, Parkkonen, M, FinnDiane Study Group, Tuomilehto, J, Lyssenko, V, McKeigue, PM, Rich, SS, Brosnan, MJ, Fauman, E, Bellazzi, R, Rossing, P, Hadjadj, S, Krolewski, A, Paterson, AD, The DCCT/EDIC Study Group, Florez, JC, Hirschhorn, JN, Maxwell, AP, GENIE Consortium, Dunger, D, Cobelli, C, Colhoun, HM, Groop, L, McCarthy, MI, Groop, P-H & on behalf of The SUMMIT Consortium 2017, 'The Genetic Landscape of Renal Complications in Type 1 Diabetes', Journal of the American Society of Nephrology, bind 28, nr. 2, s. 557-574. https://doi.org/10.1681/asn.2016020231

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title = "The Genetic Landscape of Renal Complications in Type 1 Diabetes",

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 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.",

author = "Niina Sandholm and {Van Zuydam}, Natalie and Emma Ahlqvist and Thorhildur Juliusdottir and Deshmukh, {Harshal A} and Rayner, {N William} and {Di Camillo}, Barbara and Carol Forsblom and Joao Fadista and Daniel Ziemek and Salem, {Rany M} and Hiraki, {Linda T} and Marcus Pezzolesi and David Tr{\'e}gou{\"e}t and Emma Dahlstr{\"o}m and Erkka Valo and Nikolay Oskolkov and Claes Ladenvall and Marcovecchio, {M Loredana} and Jason Cooper and Francesco Sambo and Alberto Malovini and Marco Manfrini and McKnight, {Amy Jayne} and Maria Lajer and Valma Harjutsalo and Daniel Gordin and Maija Parkkonen and {FinnDiane Study Group} and Jaakko Tuomilehto and Valeriya Lyssenko and McKeigue, {Paul M} and Rich, {Stephen S} and Brosnan, {Mary Julia} and Eric Fauman and Riccardo Bellazzi and Peter Rossing and Samy Hadjadj and Andrzej Krolewski and Paterson, {Andrew D} and {The DCCT/EDIC Study Group} and Florez, {Jose C} and Hirschhorn, {Joel N} and Maxwell, {Alexander P} and {GENIE Consortium} and David Dunger and Claudio Cobelli and Colhoun, {Helen M} and Leif Groop and McCarthy, {Mark I} and Per-Henrik Groop and {on behalf of The SUMMIT Consortium}",

note = "Copyright {\textcopyright} 2016 by the American Society of Nephrology.",

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doi = "10.1681/asn.2016020231",

language = "English",

volume = "28",

pages = "557--574",

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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

PY - 2017/2

Y1 - 2017/2

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=6.4310-3). 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.

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=6.4310-3). 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.

U2 - 10.1681/asn.2016020231

DO - 10.1681/asn.2016020231

M3 - Journal article

C2 - 27647854

SN - 1046-6673

VL - 28

SP - 557

EP - 574

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

IS - 2

ER -

The Genetic Landscape of Renal Complications in Type 1 Diabetes

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