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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. and Makinen, Ville-Petteri, et al. (2012) In PLoS Genetics 8(9).
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... (More)
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. (Less)
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1553-7404
DOI
10.1371/journal.pgen.1002921
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English
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@article{9c6c7f5b-618f-456a-b6ea-604c25bb3e92,
  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       = {Sandholm, Niina and Salem, Rany M. and McKnight, Amy Jayne and Brennan, Eoin P. and Forsblom, Carol and Isakova, Tamara and McKay, Gareth J. and Williams, Winfred W. and Sadlier, Denise M. and Makinen, Ville-Petteri and Swan, Elizabeth J. and Palmer, Cameron and Boright, Andrew P. and Ahlqvist, Emma and Deshmukh, Harshal A. and Keller, Benjamin J. and Huang, Huateng and Ahola, Aila J. and Fagerholm, Emma and Gordin, Daniel and Harjutsalo, Valma and He, Bing and Heikkila, Outi and Hietala, Kustaa and Kyto, Janne and Lahermo, Paivi and Lehto, Markku and Lithovius, Raija and Osterholm, Anne-May and Parkkonen, Maija and Pitkaniemi, Janne and Rosengard-Barlund, Milla and Saraheimo, Markku and Sarti, Cinzia and Soderlund, Jenny and Soro-Paavonen, Aino and Syreeni, Anna and Thorn, Lena M. and Tikkanen, Heikki and Tolonen, Nina and Tryggvason, Karl and Tuomilehto, Jaakko and Waden, Johan and Gill, Geoffrey V. and Prior, Sarah and Guiducci, Candace and Mirel, Daniel B. and Taylor, Andrew and Hosseini, S. Mohsen and Parving, Hans-Henrik and Rossing, Peter and Tarnow, Lise and Ladenvall, Claes and Alhenc-Gelas, Francois and Lefebvre, Pierre and Rigalleau, Vincent and Roussel, Ronan and Tregouet, David-Alexandre and Maestroni, Anna and Maestroni, Silvia and Falhammar, Henrik and Gu, Tianwei and Mollsten, Anna and Cimponeriu, Danut and Ioana, Mihai and Mota, Maria and Mota, Eugen and Serafinceanu, Cristian and Stavarachi, Monica and Hanson, Robert L. and Nelson, Robert G. and Kretzler, Matthias and Colhoun, Helen M. and Panduru, Nicolae Mircea and Gu, Harvest F. and Brismar, Kerstin and Zerbini, Gianpaolo and Hadjadj, Samy and Marre, Michel and Groop, Leif and Lajer, Maria and Bull, Shelley B. and Waggott, Daryl and Paterson, Andrew D. and Savage, David A. and Bain, Stephen C. and Martin, Finian and Hirschhorn, Joel N. and Godson, Catherine and Florez, Jose C. and Groop, Per-Henrik and Maxwell, Alexander P.},
  issn         = {1553-7404},
  language     = {eng},
  number       = {9},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002921},
  volume       = {8},
  year         = {2012},
}