New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

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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.

Details

Authors
  • 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
  • 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
  • S. Mohsen Hosseini
  • Hans-Henrik Parving
  • Peter Rossing
  • Lise Tarnow
  • Claes Ladenvall
  • Francois Alhenc-Gelas
  • Pierre Lefebvre
  • Vincent Rigalleau
  • Ronan Roussel
  • David-Alexandre Tregouet
  • Anna Maestroni
  • Silvia Maestroni
  • Henrik Falhammar
  • Tianwei Gu
  • Anna Mollsten
  • Danut Cimponeriu
  • Mihai Ioana
  • Maria Mota
  • Eugen Mota
  • Cristian Serafinceanu
  • Monica Stavarachi
  • Robert L. Hanson
  • Robert G. Nelson
  • Matthias Kretzler
  • Helen M. Colhoun
  • Nicolae Mircea Panduru
  • Harvest F. Gu
  • Kerstin Brismar
  • Gianpaolo Zerbini
  • Samy Hadjadj
  • Michel Marre
  • Maria Lajer
  • Shelley B. Bull
  • Daryl Waggott
  • Andrew D. Paterson
  • David A. Savage
  • Stephen C. Bain
  • Finian Martin
  • Joel N. Hirschhorn
  • Catherine Godson
  • Jose C. Florez
  • Per-Henrik Groop
  • Alexander P. Maxwell
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
JournalPLoS Genetics
Volume8
Issue number9
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

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