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 Osterholm; 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; Hans-Henrik Parving; Peter Rossing; Lise Tarnow; DCCT/EDIC Research Group

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 Osterholm, 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, Hans-Henrik Parving, Peter Rossing, Lise Tarnow, DCCT/EDIC Research Group

201 Citationer (Scopus)

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
Tidsskrift	P L o S Genetics
Vol/bind	8
Udgave nummer	9
Sider (fra-til)	e1002921
ISSN	1553-7390
DOI	https://doi.org/10.1371/journal.pgen.1002921
Status	Udgivet - 2012

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10.1371/journal.pgen.1002921

Citationsformater

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., ... DCCT/EDIC Research Group (2012). New susceptibility loci associated with kidney disease in type 1 diabetes. P L o S Genetics, 8(9), e1002921. https://doi.org/10.1371/journal.pgen.1002921

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, AJ, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkilä, O, Hietala, K, Kytö, J, Lahermo, P, Lehto, M, Lithovius, R, Osterholm, A-M, 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, Parving, H-H , Rossing, P, Tarnow, L & DCCT/EDIC Research Group 2012, 'New susceptibility loci associated with kidney disease in type 1 diabetes', P L o S Genetics, bind 8, nr. 9, s. e1002921. https://doi.org/10.1371/journal.pgen.1002921

@article{4ca9c5c573ca45f9b22d3ccd6e0dc03f,

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 = "Diabetes Mellitus, Type 1, Diabetic Nephropathies, Fibrosis, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kidney Failure, Chronic, Kidney Tubules, Nuclear Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptor, Epidermal Growth Factor, Transforming Growth Factor beta1",

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 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 Anne-May Osterholm 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 Hans-Henrik Parving and Peter Rossing and Lise Tarnow and {DCCT/EDIC Research Group}",

year = "2012",

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

language = "English",

volume = "8",

pages = "e1002921",

journal = "P L o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

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 - Osterholm, 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 - Parving, Hans-Henrik

AU - Rossing, Peter

AU - Tarnow, Lise

AU - DCCT/EDIC Research Group

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 - Diabetes Mellitus, Type 1

KW - Diabetic Nephropathies

KW - Fibrosis

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Kidney Failure, Chronic

KW - Kidney Tubules

KW - Nuclear Proteins

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Receptor, Epidermal Growth Factor

KW - Transforming Growth Factor beta1

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Journal article

C2 - 23028342

SN - 1553-7390

VL - 8

SP - e1002921

JO - P L o S Genetics

JF - P L o S Genetics

IS - 9

ER -

New susceptibility loci associated with kidney disease in type 1 diabetes

Abstract

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