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Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, Ng DP, Placha G, Canani LH, Bochenski J, Waggott D, Merchant ML, Krolewski B, Mirea L, Wanic K, Katavetin P, Kure M, Wolkow P, Dunn JS, Smiles A, Walker WH, Boright AP, Bull SB, DCCT/EDIC Research GroupDoria A, Rogus JJ, Rich SS, Warram JH, Krolewski AS - Diabetes (2009)

Bottom Line: We demonstratedexpression of both FRMD3 and CARS in human kidney.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.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT

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 approximately 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 P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression 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.

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Related in: MedlinePlus

Summary of genome-wide association scan results in the GoKinD collection. The –log10 P values calculated using the Cochran-Mantel-Haenszel method (adjusting for sex and GoKinD subcollection [JDC/GWU]) across the entire genome are shown for the combined GoKinD collection. The horizontal dashed line corresponds to a –log10 P value = 5.0 (P = 1 × 10−5). SNPs shown in green (n = 11) exceed this threshold (because of the resolution of this image, some of the SNPs located on chromosome 13 [n = 7] appear indistinguishable).
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Figure 1: Summary of genome-wide association scan results in the GoKinD collection. The –log10 P values calculated using the Cochran-Mantel-Haenszel method (adjusting for sex and GoKinD subcollection [JDC/GWU]) across the entire genome are shown for the combined GoKinD collection. The horizontal dashed line corresponds to a –log10 P value = 5.0 (P = 1 × 10−5). SNPs shown in green (n = 11) exceed this threshold (because of the resolution of this image, some of the SNPs located on chromosome 13 [n = 7] appear indistinguishable).

Mentions: Although no SNP achieved genome-wide significance (0.05/359,193 = 1.4 × 10−7), the primary association analysis identified 11 SNPs representing four distinct chromosomal regions with P < 1 × 10−5 (Fig. 1 and Table 2), which were considered for replication. The strongest association with diabetic nephropathy occurred on chromosome 9q with rs10868025 (OR = 1.45, P = 5.0 × 10−7). This SNP is located near the 5′ end of the 4.1 protein ezrin, radixin, moesin (FERM) domain–containing 3 (FRMD3) gene.


Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes.

Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, Ng DP, Placha G, Canani LH, Bochenski J, Waggott D, Merchant ML, Krolewski B, Mirea L, Wanic K, Katavetin P, Kure M, Wolkow P, Dunn JS, Smiles A, Walker WH, Boright AP, Bull SB, DCCT/EDIC Research GroupDoria A, Rogus JJ, Rich SS, Warram JH, Krolewski AS - Diabetes (2009)

Summary of genome-wide association scan results in the GoKinD collection. The –log10 P values calculated using the Cochran-Mantel-Haenszel method (adjusting for sex and GoKinD subcollection [JDC/GWU]) across the entire genome are shown for the combined GoKinD collection. The horizontal dashed line corresponds to a –log10 P value = 5.0 (P = 1 × 10−5). SNPs shown in green (n = 11) exceed this threshold (because of the resolution of this image, some of the SNPs located on chromosome 13 [n = 7] appear indistinguishable).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682673&req=5

Figure 1: Summary of genome-wide association scan results in the GoKinD collection. The –log10 P values calculated using the Cochran-Mantel-Haenszel method (adjusting for sex and GoKinD subcollection [JDC/GWU]) across the entire genome are shown for the combined GoKinD collection. The horizontal dashed line corresponds to a –log10 P value = 5.0 (P = 1 × 10−5). SNPs shown in green (n = 11) exceed this threshold (because of the resolution of this image, some of the SNPs located on chromosome 13 [n = 7] appear indistinguishable).
Mentions: Although no SNP achieved genome-wide significance (0.05/359,193 = 1.4 × 10−7), the primary association analysis identified 11 SNPs representing four distinct chromosomal regions with P < 1 × 10−5 (Fig. 1 and Table 2), which were considered for replication. The strongest association with diabetic nephropathy occurred on chromosome 9q with rs10868025 (OR = 1.45, P = 5.0 × 10−7). This SNP is located near the 5′ end of the 4.1 protein ezrin, radixin, moesin (FERM) domain–containing 3 (FRMD3) gene.

Bottom Line: We demonstratedexpression of both FRMD3 and CARS in human kidney.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.

View Article: PubMed Central - PubMed

Affiliation: Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT

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 approximately 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 P < 1 x 10(-5). The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 x 10(-7)). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 x 10(-6)). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression 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.

Show MeSH
Related in: MedlinePlus