AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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/ INTERPRETATION: 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: Mariana Murea; Jun-Ki Park; Shuchita Sharma; Hideki Kato; Antje Gruenwald; Thiruvur Niranjan; Han Si; David B Thomas; James M Pullman; Michal L Melamed; Katalin Susztak Journal: Kidney Int Date: 2010-06-09 Impact factor: 10.612
Authors: Shaun Purcell; Benjamin Neale; Kathe Todd-Brown; Lori Thomas; Manuel A R Ferreira; David Bender; Julian Maller; Pamela Sklar; Paul I W de Bakker; Mark J Daly; Pak C Sham Journal: Am J Hum Genet Date: 2007-07-25 Impact factor: 11.025
Authors: Amy Jayne McKnight; Christopher C Patterson; Kerry A Pettigrew; David A Savage; Jill Kilner; Madeline Murphy; Denise Sadlier; Alexander P Maxwell Journal: J Am Soc Nephrol Date: 2010-02-11 Impact factor: 10.121
Authors: David W Walsh; Sarah A Roxburgh; Paul McGettigan; Celine C Berthier; Desmond G Higgins; Matthias Kretzler; Clemens D Cohen; Sergio Mezzano; Derek P Brazil; Finian Martin Journal: Biochim Biophys Acta Date: 2007-10-11
Authors: Thiruvur Niranjan; Bernhard Bielesz; Antje Gruenwald; Manish P Ponda; Jeffrey B Kopp; David B Thomas; Katalin Susztak Journal: Nat Med Date: 2008-03-02 Impact factor: 53.440
Authors: David H Kavanagh; David A Savage; Christopher C Patterson; Amy Jayne McKnight; John K Crean; Alexander P Maxwell; Gareth J McKay Journal: PLoS One Date: 2011-08-18 Impact factor: 3.240
Authors: David H Kavanagh; David A Savage; Christopher C Patterson; Amy Jayne McKnight; John K Crean; Alexander P Maxwell; Gareth J McKay Journal: BMC Nephrol Date: 2013-06-18 Impact factor: 2.388
Authors: Gareth J McKay; David A Savage; Christopher C Patterson; Gareth Lewis; Amy Jayne McKnight; Alexander P Maxwell Journal: PLoS One Date: 2013-03-26 Impact factor: 3.240