Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

  1. for the GENIE Consortium
  1. 1Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  2. 2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  3. 3Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
  5. 5Endocrine Research Unit, Department of Endocrinology, Children’s Hospital, Boston, Massachusetts
  6. 6Nephrology Research, Centre for Public Health, Queen’s University of Belfast, Belfast, U.K.
  7. 7Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
  8. 8Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
  9. 9Department of Biomedical Engineering and Computational Science, Aalto University, Helsinki, Finland
  10. 10Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
  11. 11Division of Nephrology, University of Miami, Miller School of Medicine, Miami, Florida
  12. 12UCD Diabetes Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland
  13. 13School of Medicine, University College Dublin, Belfield, Dublin, Ireland
  14. 14Mater University Hospital, Dublin, Ireland
  15. 15Department of Chronic Disease Prevention, Welfare and Health Promotion Division, National Institute for Health and Welfare, Helsinki, Finland
  16. 16Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
  17. 17Department of Public Health, University of Helsinki, Helsinki, Finland
  18. 18South Ostrobothnia Central Hospital, Seinäjoki, Finland
  19. 19Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  20. 20Institute of Life Sciences, Swansea University, Swansea, U.K.
  21. 21School of Biomolecular and Biomedical Sciences, University College Dublin, Belfield, Dublin, Ireland
  1. Corresponding author: Jose C. Florez, jcflorez{at}partners.org.
  1. W.W.W., R.M.S., A.J.M., and N.S. contributed equally to this work.

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 genome-wide 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.

Footnotes

  • Received June 1, 2011.
  • Accepted April 5, 2012.

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  1. Diabetes vol. 61 no. 8 2187-2194
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