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 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.
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Brennan
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Tamara
authors.initials: T
authors.lastname: Isakova
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: McKay
authors.forename: Winfred W
authors.initials: WW
authors.lastname: Williams
authors.forename: Denise M
authors.initials: DM
authors.lastname: Sadlier
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Swan
authors.forename: Cameron
authors.initials: C
authors.lastname: Palmer
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Boright
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: Harshal A
authors.initials: HA
authors.lastname: Deshmukh
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Keller
authors.forename: Huateng
authors.initials: H
authors.lastname: Huang
authors.forename: Aila J
authors.initials: AJ
authors.lastname: Ahola
authors.forename: Emma
authors.initials: E
authors.lastname: Fagerholm
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Outi
authors.initials: O
authors.lastname: Heikkilä
authors.forename: Kustaa
authors.initials: K
authors.lastname: Hietala
authors.forename: Janne
authors.initials: J
authors.lastname: Kytö
authors.forename: Päivi
authors.initials: P
authors.lastname: Lahermo
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.forename: Raija
authors.initials: R
authors.lastname: Lithovius
authors.forename: Anne-May
authors.initials: AM
authors.lastname: Osterholm
authors.forename: Maija
authors.initials: M
authors.lastname: Parkkonen
authors.forename: Janne
authors.initials: J
authors.lastname: Pitkäniemi
authors.forename: Milla
authors.initials: M
authors.lastname: Rosengård-Bärlund
authors.forename: Markku
authors.initials: M
authors.lastname: Saraheimo
authors.forename: Cinzia
authors.initials: C
authors.lastname: Sarti
authors.forename: Jenny
authors.initials: J
authors.lastname: Söderlund
authors.forename: Aino
authors.initials: A
authors.lastname: Soro-Paavonen
authors.forename: Anna
authors.initials: A
authors.lastname: Syreeni
authors.forename: Lena M
authors.initials: LM
authors.lastname: Thorn
authors.forename: Heikki
authors.initials: H
authors.lastname: Tikkanen
authors.forename: Nina
authors.initials: N
authors.lastname: Tolonen
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Johan
authors.initials: J
authors.lastname: Wadén
authors.forename: Geoffrey V
authors.initials: GV
authors.lastname: Gill
authors.forename: Sarah
authors.initials: S
authors.lastname: Prior
authors.forename: Candace
authors.initials: C
authors.lastname: Guiducci
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Mirel
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.forename: S Mohsen
authors.initials: SM
authors.lastname: Hosseini
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: François
authors.initials: F
authors.lastname: Alhenc-Gelas
authors.forename: Pierre
authors.initials: P
authors.lastname: Lefebvre
authors.forename: Vincent
authors.initials: V
authors.lastname: Rigalleau
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Tregouet
authors.forename: Anna
authors.initials: A
authors.lastname: Maestroni
authors.forename: Silvia
authors.initials: S
authors.lastname: Maestroni
authors.forename: Henrik
authors.initials: H
authors.lastname: Falhammar
authors.forename: Tianwei
authors.initials: T
authors.lastname: Gu
authors.forename: Anna
authors.initials: A
authors.lastname: Möllsten
authors.forename: Danut
authors.initials: D
authors.lastname: Cimponeriu
authors.forename: Mihai
authors.initials: M
authors.lastname: Ioana
authors.forename: Maria
authors.initials: M
authors.lastname: Mota
authors.forename: Eugen
authors.initials: E
authors.lastname: Mota
authors.forename: Cristian
authors.initials: C
authors.lastname: Serafinceanu
authors.forename: Monica
authors.initials: M
authors.lastname: Stavarachi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
authors.forename: Nicolae Mircea
authors.initials: NM
authors.lastname: Panduru
authors.forename: Harvest F
authors.initials: HF
authors.lastname: Gu
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Zerbini
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
authors.forename: Daryl
authors.initials: D
authors.lastname: Waggott
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.forename: David A
authors.initials: DA
authors.lastname: Savage
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Bain
authors.forename: Finian
authors.initials: F
authors.lastname: Martin
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Maxwell
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D066247:Receptor, ErbB-4; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: C097738:AFF3 protein, human; D009687:Nuclear Proteins; D053773:Transforming Growth Factor beta1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4