Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

Francesco Sambo, Alberto Malovini, Niina Sandholm, Monica Stavarachi, Carol Forsblom, Ville Petteri Mäkinen, Valma Harjutsalo, Raija Lithovius, Daniel Gordin, Maija Parkkonen, Markku Saraheimo, Lena M. Thorn, Nina Tolonen, Johan Wadén, Bing He, Anne May Österholm, Jaako Tuomilehto, Maria Lajer, Rany M. Salem, Amy Jayne McKnightLise Tarnow, Nicolae M. Panduru, Nicola Barbarini, Barbara Di Camillo, Gianna M. Toffolo, Karl Tryggvason, Riccardo Bellazzi, Claudio Cobelli, Per Henrik Groop

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    19 Citations (Scopus)


    Aims/hypothesis: Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. Methods: We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). Results: Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p<0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. Conclusions/interpretation: This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

    Original languageEnglish
    Pages (from-to)1611-1622
    Number of pages12
    Issue number8
    Publication statusPublished or Issued - Aug 2014


    • Bag of Naive Bayes
    • Diabetic nephropathy
    • End-stage renal disease
    • Susceptibility loci

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

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