New susceptibility loci associated with kidney disease in type 1 diabetes

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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 , Mäkinen , V-P , Swan , E J , Palmer , C , Boright , A P , Ahlqvist , E , Deshmukh , H A , Keller , B J , Huang , H , Ahola , A , Dahlström , E H , Gordin , T D , Harjutsalo , V , He , B , Heikkilä , O , Hietala , K , Kytö , J , Lahermo , P , Lehto , M , Lithovius , R , Österholm , A-M , Parkkonen , M , Pitkäniemi , J M , Rosengård-Bärlund , M , Saraheimo , M , Sarti , C , Söderlun , J , Soro-Paavonen , A , Syreeni , A , Thorn , L , Tikkanen , H O , Tolonen , N E , Tryggvason , K , Tuomilehto , J , Waden , J , Gill , G V , Prior , S , Guiducci , C , Mirel , D B , Taylor , A , Hosseini , S M , EDIC Research Group , DCCT , Parving , H-H , Rossing , P , Tarnow , L , Ladenvall , C , Alhenc-Gelas , F , Lefebvre , P , Rigalleau , V , Roussel , R , Tregouet , D-A , Maestroni , A , Falhammar , H , Gu , T , Möllsten , A , Cimponeriu , D , Ioana , M , Mota , M , Mota , E , Serafinceanu , C , Stavarachi , M , Hanson , R L , Nelson , R G , Kretzler , M , Colhoun , H M , Panduru , N M , Gu , H F , Brismar , K , Zerbini , G , Hadjadj , S , Marre , M , Groop , L , Lajer , M , Bull , S B , Waggott , D , Paterson , A D , Savage , D A , Bain , S C , Martin , F , Hirschhorn , J N , Godson , C , Florez , J C , Groop , P H , Maxwell , A P & Panduru , N M 2012 , ' New susceptibility loci associated with kidney disease in type 1 diabetes ' , PLoS Genetics , vol. 8 , no. 9 , pp. e1002921 . https://doi.org/10.1371/journal.pgen.1002921

Title: New susceptibility loci associated with kidney disease in type 1 diabetes
Author: 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; Dahlström, Emma Helena; Gordin, Ted Daniel; Harjutsalo, Valma; He, Bing; Heikkilä, Outi; Hietala, Kustaa; Kytö, Janne; Lahermo, Päivi; Lehto, Markku; Lithovius, Raija; Österholm, Anne-May; Parkkonen, Maija; Pitkäniemi, Janne Mikael; Rosengård-Bärlund, Milla; Saraheimo, Markku; Sarti, Cinzia; Söderlun, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena; Tikkanen, Heikki Olavi; Tolonen, Nina Emilia; Tryggvason, Karl; Tuomilehto, Jaakko; Waden, Johan; Gill, Geoffrey V.; Prior, Sarah; Guiducci, Candace; Mirel, Daniel B.; Taylor, Andrew; Hosseini, S. Mohsen; EDIC Research Group, DCCT/; Parving, Hans-Henrik; Rossing, Peter; Tarnow, Lise; Ladenvall, Claes; Alhenc-Gelas, Francois; Lefebvre, Pierre; Rigalleau, Vincent; Roussel, Ronan; Tregouet, David-Alexandre; Maestroni, Anna; Falhammar, Henrik; Gu, Tianwei; Möllsten, Anna; Cimponeriu, Danut; Ioana, Mihai; Mota, Maria; Mota, Eugen; Serafinceanu, Cristian; Stavarachi, Monica; Hanson, Robert L.; Nelson, Robert G.; Kretzler, Matthias; Colhoun, Helen M.; Panduru, Nicolae Mircea; Gu, Harvest F.; Brismar, Kerstin; Zerbini, Gianpaolo; Hadjadj, Samy; Marre, Michel; Groop, Leif; Lajer, Maria; Bull, Shelley B.; Waggott, Daryl; Paterson, Andrew D.; Savage, David A.; Bain, Stephen C.; Martin, Finian; Hirschhorn, Joel N.; Godson, Catherine; Florez, Jose C.; Groop, Per Henrik; Maxwell, Alexander P.; Panduru, Nicolae Mircea
Contributor: University of Helsinki, Department of Medicine
University of Helsinki, Nefrologian yksikkö
University of Helsinki, Nefrologian yksikkö
University of Helsinki, Nefrologian yksikkö
University of Helsinki, Department of Medicine
University of Helsinki, Department of Medicine
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Ophthalmology and Otorhinolaryngology
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Nefrologian yksikkö
University of Helsinki, Hjelt Institute (-2014)
University of Helsinki, Department of Medicine
University of Helsinki, Department of Public Health
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Nefrologian yksikkö
University of Helsinki, Clinicum
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medicine
University of Helsinki, University of Medicine and Pharmacy "Carol Davila"
Date: 2012
Language: eng
Number of pages: 24
Belongs to series: PLoS Genetics
ISSN: 1553-7390
URI: http://hdl.handle.net/10138/162537
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.
Subject: 3142 Public health care science, environmental and occupational health
type 1 diabetes
kideny disease
3121 General medicine, internal medicine and other clinical medicine
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