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 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 journalArticlepeer-review

60 Scopus citations

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 (US)
Pages (from-to)2187-2194
Number of pages8
JournalDiabetes
Volume61
Issue number8
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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