Association testing of previously reported variants in a large case-control meta-analysis of diabetic nephropathy

Winfred W. Williams, Rany M. Salem, Amy Jayne McKnight, Niina Sandholm, Carol Forsblom, Andrew Taylor, Candace Guiducci, Jarred B. McAteer, Gareth J. McKay, Tamara Isakova, Eoin P. Brennan, Denise M. Sadlier, Cameron D. Palmer, Jenny Söderlund, Emma Fagerholm, Valma Harjutsalo, Raija Lithovius, Daniel Gordin, Kustaa Hietala, Janne KytöMaija Parkkonen, Milla Rosengård-Bärlund, Lena Thorn, Anna Syreeni, Nina Tolonen, Markku Saraheimo, Johan Wadén, Janne Pitkäniemi, Cinzia Sarti, Jaakko Tuomilehto, Karl Tryggvason, Anne May Österholm, Bing He, Steve Bain, Finian Martin, Catherine Godson, Joel N. Hirschhorn, Alexander P. Maxwell, Per-Henrik Groop, Jose C. Florez*

*Corresponding author for this work

    Research output: Contribution to journalArticleScientificpeer-review

    60 Citations (Scopus)

    Abstract

    We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10 -9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genomewide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

    Original languageEnglish
    Pages (from-to)2187-2194
    Number of pages8
    JournalDIABETES
    Volume61
    Issue number8
    DOIs
    Publication statusPublished - Aug 2012
    MoE publication typeA1 Journal article-refereed

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