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; Bing He; 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; 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; 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; Carsten A. Böger

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 J. Ahola, Emma Fagerholm, Daniel GordinValma Harjutsalo, Bing He, 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, 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, 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, Carsten A. Böger

Publikation: Bidrag til tidsskrift › Artikel › Forskning › 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.

Originalsprog	Engelsk
Artikelnummer	e1002921
Tidsskrift	PLoS Genetics
Vol/bind	8
Udgave nummer	9
DOI	https://doi.org/10.1371/journal.pgen.1002921
Status	Udgivet - 1 sep. 2012

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10.1371/journal.pgen.1002921

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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. J., Fagerholm, E., ... Böger, C. A. (2012). New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics, 8(9), Artikel e1002921. https://doi.org/10.1371/journal.pgen.1002921

@article{4be1b0ae824f45acb65999386101a7d5,

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.",

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 M{\"a}kinen, {Ville Petteri} 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 Ahola, {Aila J.} and Emma Fagerholm and Daniel Gordin 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 {\"O}sterholm, {Anne May} and Maija Parkkonen and Janne Pitk{\"a}niemi and Milla Roseng{\aa}rd-B{\"a}rlund and Markku Saraheimo and Cinzia Sarti and Jenny S{\"o}derlund and Aino Soro-Paavonen and Anna Syreeni and Thorn, {Lena M.} and Heikki Tikkanen and Nina Tolonen and Karl Tryggvason and Jaakko Tuomilehto and Johan Wad{\'e}n and Gill, {Geoffrey V.} and Sarah Prior and Candace Guiducci and Mirel, {Daniel B.} and Andrew Taylor and Hosseini, {S. Mohsen} and Parving, {Hans Henrik} and Peter Rossing and Lise Tarnow and Claes Ladenvall and Fran{\c c}ois Alhenc-Gelas and Pierre Lefebvre and Vincent Rigalleau and Ronan Roussel and Tregouet, {David Alexandre} and Anna Maestroni and Silvia 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 B{\"o}ger, {Carsten A.}",

year = "2012",

month = sep,

day = "1",

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

language = "English",

volume = "8",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

Sandholm, N, Salem, RM, McKnight, AJ, Brennan, EP, Forsblom, C, Isakova, T, McKay, GJ, Williams, WW, Sadlier, DM, Mäkinen, VP, Swan, EJ, Palmer, C, Boright, AP, Ahlqvist, E, Deshmukh, HA, Keller, BJ, Huang, H, Ahola, AJ, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkilä, O, Hietala, K, Kytö, J, Lahermo, P, Lehto, M, Lithovius, R, Österholm, AM, Parkkonen, M, Pitkäniemi, J, Rosengård-Bärlund, M, Saraheimo, M, Sarti, C, Söderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, LM, Tikkanen, H, Tolonen, N, Tryggvason, K, Tuomilehto, J, Wadén, J, Gill, GV, Prior, S, Guiducci, C, Mirel, DB, Taylor, A, Hosseini, SM, Parving, HH, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc-Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Tregouet, DA, Maestroni, A, Maestroni, S, 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 & Böger, CA 2012, 'New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes', PLoS Genetics, bind 8, nr. 9, 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 J.

AU - Fagerholm, Emma

AU - Gordin, 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

AU - Rosengård-Bärlund, Milla

AU - Saraheimo, Markku

AU - Sarti, Cinzia

AU - Söderlund, Jenny

AU - Soro-Paavonen, Aino

AU - Syreeni, Anna

AU - Thorn, Lena M.

AU - Tikkanen, Heikki

AU - Tolonen, Nina

AU - Tryggvason, Karl

AU - Tuomilehto, Jaakko

AU - Wadén, Johan

AU - Gill, Geoffrey V.

AU - Prior, Sarah

AU - Guiducci, Candace

AU - Mirel, Daniel B.

AU - Taylor, Andrew

AU - Hosseini, S. Mohsen

AU - Parving, Hans Henrik

AU - Rossing, Peter

AU - Tarnow, Lise

AU - Ladenvall, Claes

AU - Alhenc-Gelas, François

AU - Lefebvre, Pierre

AU - Rigalleau, Vincent

AU - Roussel, Ronan

AU - Tregouet, David Alexandre

AU - Maestroni, Anna

AU - Maestroni, Silvia

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 - Böger, Carsten A.

PY - 2012/9/1

Y1 - 2012/9/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84866889255&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

C2 - 23028342

AN - SCOPUS:84866889255

SN - 1553-7390

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

M1 - e1002921

ER -

New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

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