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; Helen M. Colhoun; Andrew D. Paterson; DCCT-EDIC Res Grp

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, Helen M. Colhoun, Andrew D. Paterson, DCCT-EDIC Res Grp

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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
Article number	e1002921
Number of pages	13
Journal	PLoS Genetics
Volume	8
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1002921
Publication status	Published - 20 Sept 2012

Keywords

GENE
RISK
NATURAL-HISTORY
GENOME-WIDE ASSOCIATION
COLLAGEN CHAINS
GROWTH-FACTOR
RENAL-FUNCTION
EXPRESSION
NEPHROPATHY
AF4/FMR2 FAMILY

UN SDGs

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

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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., 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., ... DCCT-EDIC Res Grp (2012). New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genetics, 8(9), Article e1002921. https://doi.org/10.1371/journal.pgen.1002921

@article{dbfc2ea44f8a44f9bc1173742253c7d9,

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.",

keywords = "GENE, RISK, NATURAL-HISTORY, GENOME-WIDE ASSOCIATION, COLLAGEN CHAINS, GROWTH-FACTOR, RENAL-FUNCTION, EXPRESSION, NEPHROPATHY, AF4/FMR2 FAMILY",

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 Colhoun, {Helen M.} and Paterson, {Andrew D.} and {DCCT-EDIC Res Grp}",

year = "2012",

month = sep,

day = "20",

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

language = "English",

volume = "8",

journal = "PLoS Genetics",

issn = "1553-7404",

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, 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, Colhoun, HM, Paterson, AD & DCCT-EDIC Res Grp 2012, 'New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes', PLoS Genetics, vol. 8, no. 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 - 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 - Colhoun, Helen M.

AU - Paterson, Andrew D.

AU - DCCT-EDIC Res Grp

PY - 2012/9/20

Y1 - 2012/9/20

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.

KW - GENE

KW - RISK

KW - NATURAL-HISTORY

KW - GENOME-WIDE ASSOCIATION

KW - COLLAGEN CHAINS

KW - GROWTH-FACTOR

KW - RENAL-FUNCTION

KW - EXPRESSION

KW - NEPHROPATHY

KW - AF4/FMR2 FAMILY

U2 - 10.1371/journal.pgen.1002921

DO - 10.1371/journal.pgen.1002921

M3 - Article

SN - 1553-7404

VL - 8

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

M1 - e1002921

ER -

New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

Abstract

Keywords

UN SDGs

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