To identify genetic variants contributing to end-stage renal disease (ESRD) in type 2 diabetes, we performed a genome-wide analysis of 115,352 single nucleotide polymorphisms (SNPs) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for >10 years without macroalbuminuria. Using a sliding window statistic of ranked SNPs, we identified a 200-kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools. These SNPs were genotyped in individuals comprising each pool, and strong evidence for association was found with rs2720709 (P ‫؍‬ 0.000021; odds ratio 2.57 [95% CI 1.66 -3.96]), which is located in the plasmacytoma variant translocation gene PVT1. We sequenced all exons, exon-intron boundaries, and the promoter of PVT1 and identified 47 variants, 11 of which represented nonredundant markers with minor allele frequency >0.05. We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319-kb flanking rs2720709 (ϳ1 SNP/3.5 kb); 23 markers were associated with ESRD at P < 0.01. The strongest evidence for association was found for rs2648875 (P ‫؍‬ 0.0000018; 2.97 [1.90 -4.65]), which maps to intron 8 of PVT1. Together, these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes. Diabetes 56: [975][976][977][978][979][980][981][982][983] 2007

OBJECTIVE-End-stage renal disease (ESRD) attributed to diabetes is strongly dependent on genetic factors. We previously reported association between variants in the plasmacytoma variant translocation gene (PVT1) and ESRD attributed to type 2 diabetes in Pima Indians. The objective of this study was to evaluate the extent to which these variants mediate susceptibility in other populations. RESEARCH DESIGN AND METHODS-We genotyped 24markers showing the strongest evidence for association in Pima Indians in unrelated Caucasians with type 1 diabetes from the Genetics of Kidneys in Diabetes (GoKinD) study. The study sample was comprised of 531 case subjects with ESRD and 564 control subjects with diabetes duration Ͼ20 years and a maximum urinary albumin-to-creatinine ratio Ͻ150 mg/g. RESULTS-Markers rs13447075 (odds ratio [OR]1.47 [95% CI 1.14 -1.89] per copy of A allele; P ϭ 0.003) and rs2648862 (2.66 [1.19 -5.92] per copy of C allele; P ϭ 0.008) were strongly associated with ESRD in analyses adjusting for age 2 , age 3 , duration of diabetes, and smoking status. We further identified a common haplotype containing the C allele at rs10808565 and the A allele at rs13447075 that was associated with ESRD (P ϭ 0.003). PVT1 gene expression yields several isoforms, and rs13447075 is located within the coding region of one of these transcript variants. We identified expression of this isoform in four major human kidney cell types, including mesangial, cortical epithelial, epithelial, and proximal tubule cells. CONCLUSIONS-These results are the first to provide confirmatory evidence supporting a role for PVT1 in mediating susceptibility to ESRD attributable to diabetes. Diabetes 56:3027-3032, 2007

Variants in the engulfment and cell motility 1 gene, ELMO1, have previously been associated with kidney disease attributed to type 2 diabetes. The Pima Indians of Arizona have high rates of diabetic nephropathy, which is strongly dependent on genetic determinants; thus, we sought to investigate the role of ELMO1 polymorphisms in mediating susceptibility to this disease in this population. Genotype distributions were compared among 141 individuals with nephropathy and 416 individuals without heavy proteinuria in a family study of 257 sibships, and 107 cases with diabetic ESRD and 108 controls with long duration diabetes and no nephropathy. We sequenced 17.4 kb of ELMO1 and identified 19 variants. We genotyped 12 markers, excluding those in 100% genotypic concordance with other variants or with a minor allele frequency <0.05, plus 21 additional markers showing association with ESRD in earlier studies. In the family study, the strongest evidence for association was with rs1345365 (odds ratio [OR]=2.42 per copy of A allele [1.35-4.32]; P=0.001) and rs10951509 (OR=2.42 per copy of A allele [1.31-4.48]; P=0.002), both of which are located in intron 13 and are in strong pairwise linkage disequilibrium (r(2)=0.97). These associations were in the opposite direction from those observed in African Americans, which suggests that the relationship between diabetic kidney disease and ELMO1 variation may involve as yet undiscovered functional variants or complex interactions with other biological variables.

These findings identify several novel loci which may contribute to ESRD susceptibility in individuals with Type 1 diabetes.

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.