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, Andrew Taylor, David A Savage, Alexander P Maxwell, DCCT/EDIC Research Group

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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 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-ß1) 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 languageEnglish
Article numbere1002921
Pages (from-to)e1002921
JournalPLoS Genetics
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 2012

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diabetic nephropathy
insulin-dependent diabetes mellitus
diabetes
Kidney Diseases
Diabetic Nephropathies
kidney diseases
Type 1 Diabetes Mellitus
polymorphism
loci
gene
single nucleotide polymorphism
meta-analysis
Single Nucleotide Polymorphism
transplantation
Genes
quality of life
genes
phenotype
chromosome
Chronic Kidney Failure

Bibliographical note

NS, RS, AJM & EPB are joint first authors as all contributed equally

Cite this

Sandholm, N., Salem, R. M., McKnight, A. J., Brennan, E. P., Forsblom, C., Isakova, T., ... DCCT/EDIC Research Group (2012). New susceptibility Loci associated with kidney disease in type 1 diabetes. PLoS Genetics, 8(9), e1002921. [e1002921]. https://doi.org/10.1371/journal.pgen.1002921
Sandholm, Niina ; Salem, Rany M ; McKnight, Amy Jayne ; Brennan, Eoin P ; Forsblom, Carol ; Isakova, Tamara ; McKay, Gareth J ; Williams, Winfred W ; Sadlier, Denise M ; Mäkinen, Ville-Petteri ; Swan, Elizabeth J ; Palmer, Cameron ; Boright, Andrew P ; Ahlqvist, Emma ; Deshmukh, Harshal A ; Keller, Benjamin J ; Huang, Huateng ; Ahola, Aila J ; Fagerholm, Emma ; Gordin, Daniel ; Harjutsalo, Valma ; He, Bing ; Heikkilä, Outi ; Hietala, Kustaa ; Kytö, Janne ; Lahermo, Päivi ; Lehto, Markku ; Lithovius, Raija ; Osterholm, Anne-May ; Parkkonen, Maija ; Pitkäniemi, Janne ; Rosengård-Bärlund, Milla ; Saraheimo, Markku ; Sarti, Cinzia ; Söderlund, Jenny ; Soro-Paavonen, Aino ; Syreeni, Anna ; Thorn, Lena M ; Tikkanen, Heikki ; Tolonen, Nina ; Tryggvason, Karl ; Tuomilehto, Jaakko ; Wadén, Johan ; Gill, Geoffrey V ; Prior, Sarah ; Guiducci, Candace ; Mirel, Daniel B ; Taylor, Andrew ; Savage, David A ; Maxwell, Alexander P ; DCCT/EDIC Research Group. / New susceptibility Loci associated with kidney disease in type 1 diabetes. In: PLoS Genetics. 2012 ; Vol. 8, No. 9. pp. e1002921.
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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 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-{\ss}1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P?=?2.1×10(-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.",
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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, 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, Taylor, A, Savage, DA, Maxwell, AP & DCCT/EDIC Research Group 2012, 'New susceptibility Loci associated with kidney disease in type 1 diabetes', PLoS Genetics, vol. 8, no. 9, e1002921, pp. e1002921. https://doi.org/10.1371/journal.pgen.1002921

New susceptibility Loci associated with kidney disease in type 1 diabetes. / Sandholm, Niina; Salem, Rany M; McKnight, Amy Jayne; Brennan, Eoin P; Forsblom, Carol; Isakova, Tamara; McKay, Gareth J; Williams, Winfred W; Sadlier, Denise M; Mäkinen, Ville-Petteri; Swan, Elizabeth J; Palmer, Cameron; Boright, Andrew P; Ahlqvist, Emma; Deshmukh, Harshal A; Keller, Benjamin J; Huang, Huateng; Ahola, Aila J; Fagerholm, Emma; Gordin, Daniel; Harjutsalo, Valma; He, Bing; Heikkilä, Outi; Hietala, Kustaa; Kytö, Janne; Lahermo, Päivi; Lehto, Markku; Lithovius, Raija; Osterholm, Anne-May; Parkkonen, Maija; Pitkäniemi, Janne; Rosengård-Bärlund, Milla; Saraheimo, Markku; Sarti, Cinzia; Söderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M; Tikkanen, Heikki; Tolonen, Nina; Tryggvason, Karl; Tuomilehto, Jaakko; Wadén, Johan; Gill, Geoffrey V; Prior, Sarah; Guiducci, Candace; Mirel, Daniel B; Taylor, Andrew; Savage, David A; Maxwell, Alexander P; DCCT/EDIC Research Group.

In: PLoS Genetics, Vol. 8, No. 9, e1002921, 09.2012, p. e1002921.

Research output: Contribution to journalArticle

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 - Taylor, Andrew

AU - Savage, David A

AU - Maxwell, Alexander P

AU - DCCT/EDIC Research Group

N1 - NS, RS, AJM & EPB are joint first authors as all contributed equally

PY - 2012/9

Y1 - 2012/9

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-ß1) 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-ß1) 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.

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

C2 - 23028342

VL - 8

SP - e1002921

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 9

M1 - e1002921

ER -

Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T et al. New susceptibility Loci associated with kidney disease in type 1 diabetes. PLoS Genetics. 2012 Sep;8(9):e1002921. e1002921. https://doi.org/10.1371/journal.pgen.1002921