title: Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Information Engineering, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sambo
authors.forename: Alberto
authors.initials: A
authors.lastname: Malovini
authors.forename: Niina
authors.initials: N
authors.lastname: Sandholm
authors.forename: Monica
authors.initials: M
authors.lastname: Stavarachi
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.forename: Ville-Petteri
authors.initials: VP
authors.lastname: Mäkinen
authors.forename: Valma
authors.initials: V
authors.lastname: Harjutsalo
authors.forename: Raija
authors.initials: R
authors.lastname: Lithovius
authors.forename: Daniel
authors.initials: D
authors.lastname: Gordin
authors.forename: Maija
authors.initials: M
authors.lastname: Parkkonen
authors.forename: Markku
authors.initials: M
authors.lastname: Saraheimo
authors.forename: Lena M
authors.initials: LM
authors.lastname: Thorn
authors.forename: Nina
authors.initials: N
authors.lastname: Tolonen
authors.forename: Johan
authors.initials: J
authors.lastname: Wadén
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Anne-May
authors.initials: AM
authors.lastname: Osterholm
authors.forename: Jaako
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Amy Jayne
authors.initials: AJ
authors.lastname: McKnight
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.forename: Nicolae M
authors.initials: NM
authors.lastname: Panduru
authors.forename: Nicola
authors.initials: N
authors.lastname: Barbarini
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Camillo
authors.forename: Gianna M
authors.initials: GM
authors.lastname: Toffolo
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bellazzi
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics