Pilot study: association of traditional and genetic risk factors and new-onset diabetes mellitus following kidney transplantation.

INTRODUCTION: New-onset diabetes mellitus, which occurs after kidney transplant and type 2 diabetes mellitus (T2DM), shares common risk factors and antecedents in impaired insulin secretion and action. Several genetic polymorphisms have been shown to be associated with T2DM. We hypothesized that transplant recipients who carry risk alleles for T2DM are "tipped over" to develop diabetes mellitus in the posttransplant milieu. METHODS: We investigated the association of genetic and traditional risk factors present before transplantation and the development of new-onset diabetes mellitus after kidney transplantation (NODAT). Markers in 8 known T2DM-linked genes were genotyped using either the iPLEX assay or allelic discrimination (AD)-PCR in the study cohort testing for association with NODAT. We used univariate and multivariate logistic regression models for the association of pretransplant nongenetic and genetic variables with the development of NODAT. RESULTS: The study cohort included 91 kidney transplant recipients with at least 1 year posttransplant follow-up, including 22 who developed NODAT. We observed that increased age, family history of T2DM, pretransplant obesity, and triglyceridemia were associated with NODAT development. In addition, we observed positive trends, although statistically not significant, for association between T2DM-associated genes and NODAT. CONCLUSIONS: These findings demonstrated an increased NODAT risk among patient with a positive family history for T2DM, which, in conjunction with the observed positive predictive trends of known T2DM-associated genetic polymorphisms with NODAT, was suggestive of a genetic predisposition to NODAT.

Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to Type 1 diabetes.

AIMS: Genetic factors play a major role in the progression of kidney disease in diabetes. To identify candidate single nucleotide polymorphisms (SNPs) with potential effects on susceptibility to end-stage renal disease (ESRD), we performed a whole genome association scan using pooled DNA from Caucasian individuals with Type 1 diabetes. METHODS: We utilized the Illumina Infinium II HumanHap 550 beadchip platform to genotype 555 352 SNPs in DNA pools comprised of 547 cases with ESRD and 549 control subjects with Type 1 diabetes duration > 20 years and no ESRD. Pooled probe intensity was used to predict mean allele frequency (MAF) for each locus. Individual genotyping was performed using the iPLEX assay in conjunction with the MassARRAY platform (Sequenom). RESULTS: We identified 2870 markers showing substantial differences in MAF (5.0-10.7%) between pools. To initiate validation of these findings, we genotyped 22 high-ranking markers in 462 individuals with ESRD and 470 unaffected control subjects selected from the genome-wide SNP genotyping study sample. We observed the strongest evidence for association between ESRD and rs1749824, located in the ZMIZ1 gene [OR = 1.47 (1.21-1.78) per copy of T allele; P = 8.1 x 10(-5)] and rs9298190, located in the musculin gene [OR = 1.56 (1.28-1.91) per copy of C allele; P = 1.6 x 10(-5)]. Evidence for nominal association with markers in or near the IRS2, TMPO, BID, KLRA1, ELMO1 and CNDP1 genes was also observed (P < or = 0.0006). CONCLUSIONS: These findings identify several novel loci which may contribute to ESRD susceptibility in individuals with Type 1 diabetes.