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 Makinen; 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 Heikkila; Kustaa Hietala; Janne Kyto; Paivi Lahermo; Markku Lehto; Raija Lithovius; Anne-May Osterholm; Maija Parkkonen; Janne Pitkaniemi; Milla Rosengard-Barlund; Markku Saraheimo; Cinzia Sarti; Jenny Soderlund; Aino Soro-Paavonen; Anna Syreeni; Lena M. Thorn; Heikki Tikkanen; Nina Tolonen; Karl Tryggvason; Jaakko Tuomilehto; Johan Waden; Geoffrey V. Gill; Sarah Prior; Candace Guiducci; Daniel B. Mirel; Andrew Taylor; S. Mohsen Hosseini; Hans-Henrik Parving; Peter Rossing; Lise Tarnow; Claes Ladenvall; Francois Alhenc-Gelas; Pierre Lefebvre; Vincent Rigalleau; Ronan Roussel; David-Alexandre Tregouet; Anna Maestroni; Silvia Maestroni; Henrik Falhammar; Tianwei Gu; Anna Mollsten; 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

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 Makinen, 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 Heikkila, Kustaa Hietala, Janne Kyto, Paivi Lahermo, Markku Lehto, Raija Lithovius, Anne-May Osterholm, Maija Parkkonen, Janne Pitkaniemi, Milla Rosengard-Barlund, Markku Saraheimo, Cinzia Sarti, Jenny Soderlund, Aino Soro-Paavonen, Anna Syreeni, Lena M. Thorn, Heikki Tikkanen, Nina Tolonen, Karl Tryggvason, Jaakko Tuomilehto, Johan Waden, Geoffrey V. Gill, Sarah Prior, Candace Guiducci, Daniel B. Mirel, Andrew Taylor, S. Mohsen Hosseini, Hans-Henrik Parving, Peter Rossing, Lise Tarnow, Claes Ladenvall, Francois Alhenc-Gelas, Pierre Lefebvre, Vincent Rigalleau, Ronan Roussel, David-Alexandre Tregouet, Anna Maestroni, Silvia Maestroni, Henrik Falhammar, Tianwei Gu, Anna Mollsten, 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

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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 genomewide association studies (GWAS) of T1D DN comprising similar to 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 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 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 x 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
DOIs	https://doi.org/10.1371/journal.pgen.1002921
Publication status	Published - 2012

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Endocrinology and Diabetes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., Makinen, 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., ... Maxwell, A. P. (2012). New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics, 8(9). https://doi.org/10.1371/journal.pgen.1002921

@article{9c6c7f5b618f456ab6ea604c25bb3e92,

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 genomewide association studies (GWAS) of T1D DN comprising similar to 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 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 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 x 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 Ville-Petteri Makinen 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 Heikkila and Kustaa Hietala and Janne Kyto and Paivi Lahermo and Markku Lehto and Raija Lithovius and Anne-May Osterholm and Maija Parkkonen and Janne Pitkaniemi and Milla Rosengard-Barlund and Markku Saraheimo and Cinzia Sarti and Jenny Soderlund 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 Waden and Gill, {Geoffrey V.} and Sarah Prior and Candace Guiducci and Mirel, {Daniel B.} and Andrew Taylor and Hosseini, {S. Mohsen} 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 Silvia Maestroni and Henrik Falhammar and Tianwei Gu and Anna Mollsten 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 Per-Henrik Groop and Maxwell, {Alexander P.}",

year = "2012",

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

language = "English",

volume = "8",

journal = "PLoS Genetics",

issn = "1553-7404",

publisher = "Public Library of Science (PLoS)",

number = "9",

}

Sandholm, N, Salem, RM, McKnight, AJ, Brennan, EP, Forsblom, C, Isakova, T, McKay, GJ, Williams, WW, Sadlier, DM, Makinen, V-P, Swan, EJ, Palmer, C, Boright, AP, Ahlqvist, E, Deshmukh, HA, Keller, BJ, Huang, H, Ahola, AJ, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkila, O, Hietala, K, Kyto, J, Lahermo, P, Lehto, M, Lithovius, R, Osterholm, A-M, Parkkonen, M, Pitkaniemi, J, Rosengard-Barlund, M, Saraheimo, M, Sarti, C, Soderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, LM, Tikkanen, H, Tolonen, N, Tryggvason, K, Tuomilehto, J, Waden, J, Gill, GV, Prior, S, Guiducci, C, Mirel, DB, Taylor, A, Hosseini, SM, Parving, H-H, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc-Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Tregouet, D-A, Maestroni, A, Maestroni, S, Falhammar, H, Gu, T, Mollsten, 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, P-H & Maxwell, AP 2012, 'New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes', PLoS Genetics, vol. 8, no. 9. 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 - Makinen, 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 - Heikkila, Outi

AU - Hietala, Kustaa

AU - Kyto, Janne

AU - Lahermo, Paivi

AU - Lehto, Markku

AU - Lithovius, Raija

AU - Osterholm, Anne-May

AU - Parkkonen, Maija

AU - Pitkaniemi, Janne

AU - Rosengard-Barlund, Milla

AU - Saraheimo, Markku

AU - Sarti, Cinzia

AU - Soderlund, 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 - Waden, 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, Francois

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 - Mollsten, 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.

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 genomewide association studies (GWAS) of T1D DN comprising similar to 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 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 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 x 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 genomewide association studies (GWAS) of T1D DN comprising similar to 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 x 10(-8)) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 x 10(-9)). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-beta 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 x 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.

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

C2 - 23028342

SN - 1553-7404

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

ER -

New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

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