Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

OBJECTIVE—Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS—We genotyped 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes- associated complications. RESULTS—A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P1105. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR]1.45, P5.0107). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR 1.36, P3.1106). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR]1.33, P0.02, and HR1.32, P 0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney. CONCLUSIONS—We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes

New polymorphism of ENPP1 (PC-1) is associated with increased risk of type 2 diabetes among obese individuals

The K121Q polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is associated with type 2 diabetes and obesity. The possibility of other ENPP1 polymorphisms influencing these phenotypes has received little attention. Our aim was to examine the associations of tagging single nucleotide polymorphisms (SNPs) and haplotypes of the linkage disequilibrium (LD) block containing K121Q polymorphism with type 2 diabetes in a Polish population, controlling for any effect of obesity. We genotyped 426 type 2 diabetic case and 370 control subjects for seven SNPs in ENPP1. In the total group, neither type 2 diabetes nor obesity was significantly associated with any SNP. However, in obese subjects, two SNPs were significantly associated with type 2 diabetes: the Q allele of K121Q (odds ratio 1.6 [95% CI 1.003-2.6]) and T allele of rs997509 (4.7 [1.6-13.9]). In the LD block, four SNPs plus the K121Q polymorphism distinguished six haplotypes, three of which carried the Q allele. Interestingly, the T allele of rs997509 sufficed to distinguish a 121Q-carrying haplotype that was significantly more associated with type 2 diabetes than the other two (4.2 [1.3-13.5]). These other two 121Q-carrying haplotypes were not associated with type 2 diabetes. In conclusion, we found a new SNP, rs997509, in intron 1 that is strongly associated with risk of type 2 diabetes in obese individuals. The molecular mechanisms underlying this association are unknow