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New susceptibility loci associated with kidney disease in Type 1 diabetes

Niina Sandholm, Rany M Salem, Amy Jayne McKnight, Eoin P Brennan, Carol Forsblom, Tamara Isakova, Gareth J McKay, Winfred W Williams, Denise M Sadlier, Ville-Petteri Mäkinen, Elizabeth J Swan, Cameron Palmer, Andrew P Boright, Emma Ahlqvist, Harshal A Deshmukh, Benjamin J Keller, Huateng Huang, Aila J Ahola, Emma Fagerholm, Daniel Gordin, Valma Harjutsalo, He Bing, Outi Heikkilä, Kustaa Hietala, Janne Kytö, Päivi Lahermo, Markku Lehto, Raija Lithovius, Anne-May Österholm, Maija Parkkonen, Janne Pitkäniemi, Milla Rosengård-Bärlund, Markku Saraheimo, Cinzia Sarti, Jenny Söderlund, Aino Soro-Paavonen, Anna Syreeni, Lena M Thorn, Heikki Tikkanen, Nina Tolonen, Karl Tryggvason, Jaakko Tuomilehto, Johan Wadén, Geoffrey V Gill, Sarah Prior Orcid Logo, Candace Guiducci, Daniel B Mirel, Andrew Taylor, S. Mohsen Hosseini, DCCT/EDIC Research Group, Hans-Henrik Parving, Peter Rossing, Lise Tarnow, Claes Ladenvall, François Alhenc-Gelas, Pierre Lefebvre, Vincent Rigalleau, Ronan Roussel, David-Alexandre Tregouet, Anna Maestroni, Silvia Maestroni, Henrik Falhammar, Gu Tianwei, Anna Möllsten, Danut Cimponeriu, Mihai Ioana, Maria Mota, Eugen Mota, Cristian Serafinceanu, Monica Stavarachi, Robert L Hanson, Robert G Nelson, Matthias Kretzler, Helen M Colhoun, Nicolae Mircea Panduru, Gu Harvest F, Kerstin Brismar, Gianpaolo Zerbini, Samy Hadjadj, Michel Marre, Leif Groop, Maria Lajer, Shelley B Bull, Daryl Waggott, Andrew D Paterson, David A Savage, Stephen C Bain, Finian Martin, Joel N Hirschhorn, Catherine Godson, Jose C Florez, Per-Henrik Groop, Alexander P Maxwell

PLOS Genetics, Volume: 8

Swansea University Author: Sarah Prior Orcid Logo

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DOI (Published version): 10.1371/journal.pgen.1002921

Abstract

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the...

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Published in: PLOS Genetics
Published: 2012
URI: https://cronfa.swan.ac.uk/Record/cronfa12818
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Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2&#xD7;10&#x2212;8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0&#xD7;10&#x2212;9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-&#x3B2;1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1&#xD7;10&#x2212;7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. 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spelling 2014-12-05T15:13:31.2475803 v2 12818 2012-09-25 New susceptibility loci associated with kidney disease in Type 1 diabetes cdda101035997acfaa6fdf17097f52b2 0000-0001-8703-8092 Sarah Prior Sarah Prior true false 2012-09-25 MEDS Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN. Journal Article PLOS Genetics 8 31 12 2012 2012-12-31 10.1371/journal.pgen.1002921 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2014-12-05T15:13:31.2475803 2012-09-25T14:37:02.7195150 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Niina Sandholm 1 Rany M Salem 2 Amy Jayne McKnight 3 Eoin P Brennan 4 Carol Forsblom 5 Tamara Isakova 6 Gareth J McKay 7 Winfred W Williams 8 Denise M Sadlier 9 Ville-Petteri Mäkinen 10 Elizabeth J Swan 11 Cameron Palmer 12 Andrew P Boright 13 Emma Ahlqvist 14 Harshal A Deshmukh 15 Benjamin J Keller 16 Huateng Huang 17 Aila J Ahola 18 Emma Fagerholm 19 Daniel Gordin 20 Valma Harjutsalo 21 He Bing 22 Outi Heikkilä 23 Kustaa Hietala 24 Janne Kytö 25 Päivi Lahermo 26 Markku Lehto 27 Raija Lithovius 28 Anne-May Österholm 29 Maija Parkkonen 30 Janne Pitkäniemi 31 Milla Rosengård-Bärlund 32 Markku Saraheimo 33 Cinzia Sarti 34 Jenny Söderlund 35 Aino Soro-Paavonen 36 Anna Syreeni 37 Lena M Thorn 38 Heikki Tikkanen 39 Nina Tolonen 40 Karl Tryggvason 41 Jaakko Tuomilehto 42 Johan Wadén 43 Geoffrey V Gill 44 Sarah Prior 0000-0001-8703-8092 45 Candace Guiducci 46 Daniel B Mirel 47 Andrew Taylor 48 S. Mohsen Hosseini 49 DCCT/EDIC Research Group 50 Hans-Henrik Parving 51 Peter Rossing 52 Lise Tarnow 53 Claes Ladenvall 54 François Alhenc-Gelas 55 Pierre Lefebvre 56 Vincent Rigalleau 57 Ronan Roussel 58 David-Alexandre Tregouet 59 Anna Maestroni 60 Silvia Maestroni 61 Henrik Falhammar 62 Gu Tianwei 63 Anna Möllsten 64 Danut Cimponeriu 65 Mihai Ioana 66 Maria Mota 67 Eugen Mota 68 Cristian Serafinceanu 69 Monica Stavarachi 70 Robert L Hanson 71 Robert G Nelson 72 Matthias Kretzler 73 Helen M Colhoun 74 Nicolae Mircea Panduru 75 Gu Harvest F 76 Kerstin Brismar 77 Gianpaolo Zerbini 78 Samy Hadjadj 79 Michel Marre 80 Leif Groop 81 Maria Lajer 82 Shelley B Bull 83 Daryl Waggott 84 Andrew D Paterson 85 David A Savage 86 Stephen C Bain 87 Finian Martin 88 Joel N Hirschhorn 89 Catherine Godson 90 Jose C Florez 91 Per-Henrik Groop 92 Alexander P Maxwell 93
title New susceptibility loci associated with kidney disease in Type 1 diabetes
spellingShingle New susceptibility loci associated with kidney disease in Type 1 diabetes
Sarah Prior
title_short New susceptibility loci associated with kidney disease in Type 1 diabetes
title_full New susceptibility loci associated with kidney disease in Type 1 diabetes
title_fullStr New susceptibility loci associated with kidney disease in Type 1 diabetes
title_full_unstemmed New susceptibility loci associated with kidney disease in Type 1 diabetes
title_sort New susceptibility loci associated with kidney disease in Type 1 diabetes
author_id_str_mv cdda101035997acfaa6fdf17097f52b2
author_id_fullname_str_mv cdda101035997acfaa6fdf17097f52b2_***_Sarah Prior
author Sarah Prior
author2 Niina Sandholm
Rany M Salem
Amy Jayne McKnight
Eoin P Brennan
Carol Forsblom
Tamara Isakova
Gareth J McKay
Winfred W Williams
Denise M Sadlier
Ville-Petteri Mäkinen
Elizabeth J Swan
Cameron Palmer
Andrew P Boright
Emma Ahlqvist
Harshal A Deshmukh
Benjamin J Keller
Huateng Huang
Aila J Ahola
Emma Fagerholm
Daniel Gordin
Valma Harjutsalo
He Bing
Outi Heikkilä
Kustaa Hietala
Janne Kytö
Päivi Lahermo
Markku Lehto
Raija Lithovius
Anne-May Österholm
Maija Parkkonen
Janne Pitkäniemi
Milla Rosengård-Bärlund
Markku Saraheimo
Cinzia Sarti
Jenny Söderlund
Aino Soro-Paavonen
Anna Syreeni
Lena M Thorn
Heikki Tikkanen
Nina Tolonen
Karl Tryggvason
Jaakko Tuomilehto
Johan Wadén
Geoffrey V Gill
Sarah Prior
Candace Guiducci
Daniel B Mirel
Andrew Taylor
S. Mohsen Hosseini
DCCT/EDIC Research Group
Hans-Henrik Parving
Peter Rossing
Lise Tarnow
Claes Ladenvall
François Alhenc-Gelas
Pierre Lefebvre
Vincent Rigalleau
Ronan Roussel
David-Alexandre Tregouet
Anna Maestroni
Silvia Maestroni
Henrik Falhammar
Gu Tianwei
Anna Möllsten
Danut Cimponeriu
Mihai Ioana
Maria Mota
Eugen Mota
Cristian Serafinceanu
Monica Stavarachi
Robert L Hanson
Robert G Nelson
Matthias Kretzler
Helen M Colhoun
Nicolae Mircea Panduru
Gu Harvest F
Kerstin Brismar
Gianpaolo Zerbini
Samy Hadjadj
Michel Marre
Leif Groop
Maria Lajer
Shelley B Bull
Daryl Waggott
Andrew D Paterson
David A Savage
Stephen C Bain
Finian Martin
Joel N Hirschhorn
Catherine Godson
Jose C Florez
Per-Henrik Groop
Alexander P Maxwell
format Journal article
container_title PLOS Genetics
container_volume 8
publishDate 2012
institution Swansea University
doi_str_mv 10.1371/journal.pgen.1002921
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.
published_date 2012-12-31T06:21:07Z
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