title: Analysis of single nucleotide polymorphisms implicate mTOR signalling in the development of new-onset diabetes after transplantation.
abstract: BACKGROUND
  Despite excellent first year outcomes in kidney transplantation, there remain significant long-term complications related to new-onset diabetes after transplantation (NODAT). The purpose of this study was to validate the findings of previous investigations of candidate gene variants in patients undergoing a protocolised, contemporary immunosuppression regimen, using detailed serial biochemical testing to identify NODAT development.
  
  
  METHODS
  One hundred twelve live and deceased donor renal transplant recipients were prospectively followed-up for NODAT onset, biochemical testing at days 7, 90, and 365 after transplantation. Sixty-eight patients were included after exclusion for non-white ethnicity and pre-transplant diabetes. Literature review to identify candidate gene variants was undertaken as described previously.
  
  
  RESULTS
  Over 25% of patients developed NODAT. In an adjusted model for age, sex, BMI, and BMI change over 12 months, five out of the studied 37 single nucleotide polymorphisms (SNPs) were significantly associated with NODAT: rs16936667:PRDM14 OR 10.57;95% CI 1.8-63.0;p = 0.01, rs1801282:PPARG OR 8.5; 95% CI 1.4-52.7; p = 0.02, rs8192678:PPARGC1A OR 0.26; 95% CI 0.08-0.91; p = 0.03, rs2144908:HNF4A OR 7.0; 95% CI 1.1-45.0;p = 0.04 and rs2340721:ATF6 OR 0.21; 95%CI 0.04-1.0; p = 0.05.
  
  
  CONCLUSIONS
  This study represents a replication study of candidate SNPs associated with developing NODAT and implicates mTOR as the central regulator via altered insulin sensitivity, pancreatic β cell, and mitochondrial survival and dysfunction as evidenced by the five SNPs.
  
  
  CONCLUSIONS
  1)Highlights the importance of careful biochemical phenotyping with oral glucose tolerance tests to diagnose NODAT in reducing time to diagnosis and missed cases.2)This alters potential genotype:phenotype association.3)The replication study generates the hypothesis that mTOR signalling pathway may be involved in NODAT development.
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Chand
authors.affiliation: Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland.
authors.forename: A J
authors.initials: AJ
authors.lastname: McKnight
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Shabir
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom.
authors.forename: W
authors.initials: W
authors.lastname: Chan
authors.affiliation: Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland.
authors.forename: J A
authors.initials: JA
authors.lastname: McCaughan
authors.affiliation: Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, Northern Ireland.
authors.forename: A P
authors.initials: AP
authors.lastname: Maxwell
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Harper
authors.affiliation: Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital, Birmingham B15 2WB, United Kingdom; Centre for Translational Inflammation Research, University of Birmingham, Birmingham B15 2WB, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Borrows
keywords: ATF6, Activated transcription factor; BMI, Body mass index; GWAS, Genome-wide association study; HLA, Human leucocyte antigen; HNF4, Hepatocyte nuclear factor 4; NODAT, New-onset diabetes after transplantation; New-onset diabetes after transplantation; PI3, Phospho-inositide 3-kinase; PPARGC1α, Peroxisome proliferator-activated receptor gamma co-activator 1 alpha; PPARy, Peroxisome proliferator-activated receptor gamma; PRDM14, PR domain zinc protein 14; SNP, Single nucleotide polymorphism; mTOR; mTOR, Mammalian target of rapamycin; single nucleotide polymorphisms