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 Mäkinen, 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 Heikkilä, Kustaa Hietala, Janne Kytö, Päivi Lahermo, Markku Lehto, Raija Lithovius, Anne-May Osterholm, Maija Parkkonen, Janne Pitkäniemi, Milla Rosengård-Bärlund, Markku Saraheimo, Cinzia Sarti, Jenny Söderlund, Aino Soro-Paavonen, Anna Syreeni, Lena M Thorn, Heikki Tikkanen, Nina Tolonen, Karl Tryggvason, Jaakko Tuomilehto, Johan Wadén, Geoffrey V Gill, Sarah Prior, Candace Guiducci, Daniel B Mirel, Hans-Henrik Parving, Peter Rossing, Lise Tarnow, DCCT/EDIC Research Group

    192 Citationer (Scopus)

    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.
    OriginalsprogEngelsk
    TidsskriftP L o S Genetics
    Vol/bind8
    Udgave nummer9
    Sider (fra-til)e1002921
    ISSN1553-7390
    DOI
    StatusUdgivet - 2012

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