Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy
- Winfred W. Williams1,2,3,4,
- Rany M. Salem2,5,
- Amy Jayne McKnight6,
- Niina Sandholm7,8,9,
- Carol Forsblom7,8,
- Andrew Taylor1,2,10,
- Candace Guiducci2,
- Jarred B. McAteer1,2,10,
- Gareth J. McKay6,
- Tamara Isakova11,
- Eoin P. Brennan12,13,
- Denise M. Sadlier12,13,14,
- Cameron Palmer2,5,
- Jenny Söderlund7,8,
- Emma Fagerholm7,8,
- Valma Harjutsalo7,8,15,
- Raija Lithovius7,8,
- Daniel Gordin7,8,
- Kustaa Hietala7,16,
- Janne Kytö7,16,
- Maija Parkkonen7,8,
- Milla Rosengård-Bärlund7,8,
- Lena Thorn7,8,
- Anna Syreeni7,8,
- Nina Tolonen7,8,
- Markku Saraheimo7,8,
- Johan Wadén7,8,
- Janne Pitkäniemi17,
- Cinzia Sarti17,
- Jaakko Tuomilehto15,17,18,
- Karl Tryggvason19,
- Anne-May Österholm19,
- Bing He19,
- Steve Bain20,
- Finian Martin12,21,
- Catherine Godson12,13,
- Joel N. Hirschhorn2,5,
- Alexander P. Maxwell6,
- Per-Henrik Groop7,8,
- Jose C. Florez1,2,4,10⇓ and
- for the GENIE Consortium
- 1Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
- 2Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
- 3Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 5Endocrine Research Unit, Department of Endocrinology, Children’s Hospital, Boston, Massachusetts
- 6Nephrology Research, Centre for Public Health, Queen’s University of Belfast, Belfast, U.K.
- 7Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- 8Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
- 9Department of Biomedical Engineering and Computational Science, Aalto University, Helsinki, Finland
- 10Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- 11Division of Nephrology, University of Miami, Miller School of Medicine, Miami, Florida
- 12UCD Diabetes Research Centre, Conway Institute, University College Dublin, Belfield, Dublin, Ireland
- 13School of Medicine, University College Dublin, Belfield, Dublin, Ireland
- 14Mater University Hospital, Dublin, Ireland
- 15Department of Chronic Disease Prevention, Welfare and Health Promotion Division, National Institute for Health and Welfare, Helsinki, Finland
- 16Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
- 17Department of Public Health, University of Helsinki, Helsinki, Finland
- 18South Ostrobothnia Central Hospital, Seinäjoki, Finland
- 19Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
- 20Institute of Life Sciences, Swansea University, Swansea, U.K.
- 21School of Biomolecular and Biomedical Sciences, University College Dublin, Belfield, Dublin, Ireland
- Corresponding author: Jose C. Florez, .
W.W.W., R.M.S., A.J.M., and N.S. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0751/-/DC1
See accompanying commentary, p. 1923.
- Received June 1, 2011.
- Accepted April 5, 2012.
- © 2012 by the American Diabetes Association.
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