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 Ahola; Emma Helena Dahlström; Ted Daniel Gordin; Valma Harjutsalo; Bing He; Outi Heikkilä; Kustaa  Hietala; Janne Kytö; Päivi Lahermo; Markku Lehto; Raija Lithovius; Anne-May Österholm; Maija Parkkonen; Janne Mikael Pitkäniemi; Milla Rosengård-Bärlund; Markku Saraheimo; Cinzia Sarti; Jenny Söderlun; Aino Soro-Paavonen; Anna Syreeni; Lena Thorn; Heikki Olavi Tikkanen; Nina Emilia Tolonen; Karl Tryggvason; Jaakko Tuomilehto; Johan Waden; 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; Francois Alhenc-Gelas; Pierre Lefebvre; Vincent Rigalleau; Ronan Roussel; David-Alexandre Tregouet; Anna Maestroni; Henrik Falhammar; Tianwei Gu; 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; Harvest F. Gu; 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; Nicolae Mircea Panduru

doi:10.1371/journal.pgen.1002921

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 Ahola, Emma Helena Dahlström, Ted Daniel GordinValma Harjutsalo, Bing He, Outi Heikkilä, Kustaa Hietala, Janne Kytö, Päivi Lahermo, Markku Lehto, Raija Lithovius, Anne-May Österholm, Maija Parkkonen, Janne Mikael Pitkäniemi, Milla Rosengård-Bärlund, Markku Saraheimo, Cinzia Sarti, Jenny Söderlun, Aino Soro-Paavonen, Anna Syreeni, Lena Thorn, Heikki Olavi Tikkanen, Nina Emilia Tolonen, Karl Tryggvason, Jaakko Tuomilehto, Johan Waden, 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, Francois Alhenc-Gelas, Pierre Lefebvre, Vincent Rigalleau, Ronan Roussel, David-Alexandre Tregouet, Anna Maestroni, Henrik Falhammar, Tianwei Gu, 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, Harvest F. Gu, 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, Nicolae Mircea Panduru

Research output: Contribution to journal › Article › Scientific › peer-review

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 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.

Original language	English
Journal	PLoS Genetics
Volume	8
Issue number	9
Pages (from-to)	e1002921
Number of pages	24
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1002921
Publication status	Published - 2012
MoE publication type	A1 Journal article-refereed

Fields of Science

3142 Public health care science, environmental and occupational health
type 1 diabetes
kideny disease
3121 General medicine, internal medicine and other clinical medicine

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10.1371/journal.pgen.1002921Licence: CC BY

New Susceptibility Loci Associated with Kidney DiseaseFinal published version, 557 KBLicence: CC BY

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Sandholm, N., Salem, R. M., McKnight, A. J., Brennan, E. P., Forsblom, C., Isakova, T., McKay, G. J., Williams, W. W., Sadlier, D. M., Mäkinen, V.-P., Swan, E. J., Palmer, C., Boright, A. P., Ahlqvist, E., Deshmukh, H. A., Keller, B. J., Huang, H., Ahola, A., Dahlström, E. H., ... Panduru, N. M. (2012). New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genetics, 8(9), e1002921. https://doi.org/10.1371/journal.pgen.1002921

@article{124dcde6a12a4c8ba81a39bdddb5b5b9,

title = "New susceptibility loci associated with kidney disease in type 1 diabetes",

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 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. ",

keywords = "3142 Public health care science, environmental and occupational health, type 1 diabetes, kideny disease, 3121 General medicine, internal medicine and other clinical medicine",

author = "Niina Sandholm and Salem, {Rany M.} and McKnight, {Amy Jayne} and Brennan, {Eoin P.} and Carol Forsblom and Tamara Isakova and McKay, {Gareth J.} and Williams, {Winfred W.} and Sadlier, {Denise M.} and Ville-Petteri M{\"a}kinen and Swan, {Elizabeth J.} and Cameron Palmer and Boright, {Andrew P.} and Emma Ahlqvist and Deshmukh, {Harshal A.} and Keller, {Benjamin J.} and Huateng Huang and Aila Ahola and Dahlstr{\"o}m, {Emma Helena} and Gordin, {Ted Daniel} and Valma Harjutsalo and Bing He and Outi Heikkil{\"a} and Kustaa Hietala and Janne Kyt{\"o} and P{\"a}ivi Lahermo and Markku Lehto and Raija Lithovius and Anne-May {\"O}sterholm and Maija Parkkonen and Pitk{\"a}niemi, {Janne Mikael} and Milla Roseng{\aa}rd-B{\"a}rlund and Markku Saraheimo and Cinzia Sarti and Jenny S{\"o}derlun and Aino Soro-Paavonen and Anna Syreeni and Lena Thorn and Tikkanen, {Heikki Olavi} and Tolonen, {Nina Emilia} and Karl Tryggvason and Jaakko Tuomilehto and Johan Waden and Gill, {Geoffrey V.} and Sarah Prior and Candace Guiducci and Mirel, {Daniel B.} and Andrew Taylor and Hosseini, {S. Mohsen} and {EDIC Research Group}, DCCT/ and Hans-Henrik Parving and Peter Rossing and Lise Tarnow and Claes Ladenvall and Francois Alhenc-Gelas and Pierre Lefebvre and Vincent Rigalleau and Ronan Roussel and David-Alexandre Tregouet and Anna Maestroni and Henrik Falhammar and Tianwei Gu and Anna M{\"o}llsten and Danut Cimponeriu and Mihai Ioana and Maria Mota and Eugen Mota and Cristian Serafinceanu and Monica Stavarachi and Hanson, {Robert L.} and Nelson, {Robert G.} and Matthias Kretzler and Colhoun, {Helen M.} and Panduru, {Nicolae Mircea} and Gu, {Harvest F.} and Kerstin Brismar and Gianpaolo Zerbini and Samy Hadjadj and Michel Marre and Leif Groop and Maria Lajer and Bull, {Shelley B.} and Daryl Waggott and Paterson, {Andrew D.} and Savage, {David A.} and Bain, {Stephen C.} and Finian Martin and Hirschhorn, {Joel N.} and Catherine Godson and Florez, {Jose C.} and Groop, {Per Henrik} and Maxwell, {Alexander P.} and Panduru, {Nicolae Mircea}",

note = "WOS:000309817900008 ",

year = "2012",

doi = "10.1371/journal.pgen.1002921",

language = "English",

volume = "8",

pages = "e1002921",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

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Sandholm, N, Salem, RM, McKnight, AJ, Brennan, EP, Forsblom, C, Isakova, T, McKay, GJ, Williams, WW, Sadlier, DM, Mäkinen, V-P, Swan, EJ, Palmer, C, Boright, AP, Ahlqvist, E, Deshmukh, HA, Keller, BJ, Huang, H, Ahola, A, Dahlström, EH , Gordin, TD, Harjutsalo, V, He, B, Heikkilä, O, Hietala, K, Kytö, J, Lahermo, P , Lehto, M, Lithovius, R, Österholm, A-M, Parkkonen, M, Pitkäniemi, JM, Rosengård-Bärlund, M, Saraheimo, M , Sarti, C, Söderlun, J, Soro-Paavonen, A, Syreeni, A, Thorn, L , Tikkanen, HO , Tolonen, NE, Tryggvason, K, Tuomilehto, J, Waden, J, Gill, GV, Prior, S, Guiducci, C, Mirel, DB, Taylor, A, Hosseini, SM, EDIC Research Group, DCCT, Parving, H-H, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc-Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Tregouet, D-A, Maestroni, A, Falhammar, H, Gu, T, Möllsten, A, Cimponeriu, D, Ioana, M, Mota, M, Mota, E, Serafinceanu, C, Stavarachi, M, Hanson, RL, Nelson, RG, Kretzler, M, Colhoun, HM, Panduru, NM, Gu, HF, Brismar, K, Zerbini, G, Hadjadj, S, Marre, M, Groop, L, Lajer, M, Bull, SB, Waggott, D, Paterson, AD, Savage, DA, Bain, SC, Martin, F, Hirschhorn, JN, Godson, C, Florez, JC, Groop, PH, Maxwell, AP & Panduru, NM 2012, 'New susceptibility loci associated with kidney disease in type 1 diabetes', PLoS Genetics, vol. 8, no. 9, pp. e1002921. https://doi.org/10.1371/journal.pgen.1002921

TY - JOUR

T1 - New susceptibility loci associated with kidney disease in type 1 diabetes

AU - Sandholm, Niina

AU - Salem, Rany M.

AU - McKnight, Amy Jayne

AU - Brennan, Eoin P.

AU - Forsblom, Carol

AU - Isakova, Tamara

AU - McKay, Gareth J.

AU - Williams, Winfred W.

AU - Sadlier, Denise M.

AU - Mäkinen, Ville-Petteri

AU - Swan, Elizabeth J.

AU - Palmer, Cameron

AU - Boright, Andrew P.

AU - Ahlqvist, Emma

AU - Deshmukh, Harshal A.

AU - Keller, Benjamin J.

AU - Huang, Huateng

AU - Ahola, Aila

AU - Dahlström, Emma Helena

AU - Gordin, Ted Daniel

AU - Harjutsalo, Valma

AU - He, Bing

AU - Heikkilä, Outi

AU - Hietala, Kustaa

AU - Kytö, Janne

AU - Lahermo, Päivi

AU - Lehto, Markku

AU - Lithovius, Raija

AU - Österholm, Anne-May

AU - Parkkonen, Maija

AU - Pitkäniemi, Janne Mikael

AU - Rosengård-Bärlund, Milla

AU - Saraheimo, Markku

AU - Sarti, Cinzia

AU - Söderlun, Jenny

AU - Soro-Paavonen, Aino

AU - Syreeni, Anna

AU - Thorn, Lena

AU - Tikkanen, Heikki Olavi

AU - Tolonen, Nina Emilia

AU - Tryggvason, Karl

AU - Tuomilehto, Jaakko

AU - Waden, Johan

AU - Gill, Geoffrey V.

AU - Prior, Sarah

AU - Guiducci, Candace

AU - Mirel, Daniel B.

AU - Taylor, Andrew

AU - Hosseini, S. Mohsen

AU - EDIC Research Group, DCCT/

AU - Parving, Hans-Henrik

AU - Rossing, Peter

AU - Tarnow, Lise

AU - Ladenvall, Claes

AU - Alhenc-Gelas, Francois

AU - Lefebvre, Pierre

AU - Rigalleau, Vincent

AU - Roussel, Ronan

AU - Tregouet, David-Alexandre

AU - Maestroni, Anna

AU - Falhammar, Henrik

AU - Gu, Tianwei

AU - Möllsten, Anna

AU - Cimponeriu, Danut

AU - Ioana, Mihai

AU - Mota, Maria

AU - Mota, Eugen

AU - Serafinceanu, Cristian

AU - Stavarachi, Monica

AU - Hanson, Robert L.

AU - Nelson, Robert G.

AU - Kretzler, Matthias

AU - Colhoun, Helen M.

AU - Panduru, Nicolae Mircea

AU - Gu, Harvest F.

AU - Brismar, Kerstin

AU - Zerbini, Gianpaolo

AU - Hadjadj, Samy

AU - Marre, Michel

AU - Groop, Leif

AU - Lajer, Maria

AU - Bull, Shelley B.

AU - Waggott, Daryl

AU - Paterson, Andrew D.

AU - Savage, David A.

AU - Bain, Stephen C.

AU - Martin, Finian

AU - Hirschhorn, Joel N.

AU - Godson, Catherine

AU - Florez, Jose C.

AU - Groop, Per Henrik

AU - Maxwell, Alexander P.

AU - Panduru, Nicolae Mircea

N1 - WOS:000309817900008

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - 3142 Public health care science, environmental and occupational health

KW - type 1 diabetes

KW - kideny disease

KW - 3121 General medicine, internal medicine and other clinical medicine

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

SN - 1553-7390

VL - 8

SP - e1002921

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

ER -

New susceptibility loci associated with kidney disease in type 1 diabetes

Abstract

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