title: Association analysis of Notch pathway signalling genes in diabetic nephropathy.
abstract: OBJECTIVE
  Several studies have provided compelling evidence implicating the Notch signalling pathway in diabetic nephropathy. Co-regulation of Notch signalling pathway genes with GREM1 has recently been demonstrated and several genes involved in the Notch pathway are differentially expressed in kidney biopsies from individuals with diabetic nephropathy. We assessed single-nucleotide polymorphisms (SNPs; n = 42) in four of these key genes (JAG1, HES1, NOTCH3 and ADAM10) for association with diabetic nephropathy using a case-control design.
  
  
  METHODS
  Tag SNPs and potentially functional SNPs were genotyped using Sequenom or Taqman technologies in a total of 1371 individuals with type 1 diabetes (668 patients with nephropathy and 703 controls without nephropathy). Patients and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK (http://pngu.mgh.harvard.edu/∼purcell/plink/) and haplotype frequencies in patients and controls were compared. Adjustment for multiple testing was performed by permutation testing.
  
  
  RESULTS
  In analyses stratified by centre, we identified six SNPs, rs8708 and rs11699674 (JAG1), rs10423702 and rs1548555 (NOTCH3), rs2054096 and rs8027998 (ADAM10) as being associated with diabetic nephropathy before, but not after, adjustment for multiple testing. Haplotype and subgroup analysis according to duration of diabetes also failed to find an association with diabetic nephropathy.
  
  
  CONCLUSIONS
  Our results suggest that common variants in JAG1, HES1, NOTCH3 and ADAM10 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes from involvement in the pathogenesis of diabetic nephropathy.
authors.affiliation: Nephrology Research Group, Centre for Public Health, Queen's University Belfast, Belfast, UK.
authors.forename: D
authors.initials: D
authors.lastname: Kavanagh
authors.forename: G J
authors.initials: GJ
authors.lastname: McKay
authors.forename: C C
authors.initials: CC
authors.lastname: Patterson
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.forename: D A
authors.initials: DA
authors.lastname: Savage
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000072197:ADAM10 Protein; D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000072056:Transcription Factor HES-1; D055815:Young Adult
chemical_list: D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C000606273:JAG1 protein, human; C499374:NOTCH3 protein, human; C078493:HES1 protein, human; C491236:ADAM10 protein, human