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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 results for the chromosome 7p, 9q, 11p, and 13q loci. A: Genome-wide association scan and imputed data for the chromosome 7p locus. rs39059 (solid red triangle) is located at position IVS1 + 21350 relative to exon 1 of CHN2 isoform 2 and is in tight linkage disequilibrium with rs39075 (r2 = 0.96), located at position IVS1 + 42572. rs39059 and rs39075 reside −69,318 and −90,540 kb, respectively, upstream of CPVL isoforms 1 and 2. A third alternate transcript (isoform 3) is predicted for CPVL and contains an exon that extends to intron 1 of CHN2. rs39059 and rs39075 are located at positions −20579 and −41801, respectively, relative to this transcript. ▲, SNPs genotyped on the Affymetrix array (n = 163); △, imputed SNPs (n = 694). *Imputed SNP rs39075 was genotyped in the GoKinD samples to confirm the imputation. B: Genome-wide association scan and imputed data for the chromosome 9q locus. A total of 100 genotyped SNPs from the Affymetrix array data and 450 imputed SNPs are shown. rs10868025 (solid red triangle) is located at position −10829 relative to FRMD3's transcription start site. rs10868025 is in complete linkage disequilibrium (r2 = 1.0) and only 253 bp from imputed SNP rs13289150 (△ superimposed on rs10868025). rs1888747, located at position −2204, is in partial linkage disequilibrium (r2 = 0.81) with rs10868025. *Imputed SNP rs1888747 was genotyped in the GoKinD samples to confirm the imputation. C: Genome-wide association scan and imputed data for the chromosome 11p locus. A total of 33 genotyped SNPs from the Affymetrix array data and 190 imputed SNPs are shown. rs739401 and rs451041 (solid red triangles) are in strong linkage disequilibrium (r2 = 0.97). rs739401 is located in intron 16 (isoforms a and c)/17 (isoforms b and d) of the CARS gene (position IVS16 + 687/IVS17 + 687). rs451041 is located in intron 4 (isoforms a and c)/5 (isoforms b and d), position IVS4 − 203/IVS5 − 203). D: Genome-wide association scan and imputed data for the chromosome 13q locus. A total of 68 genotyped SNPs from the Affymetrix array data and 268 imputed SNPs are shown. Seven lead SNPs (rs1041466, rs1411766, rs17412858, rs6492208, rs2391777, rs7989848, and rs9521445) from this region are indicated in red. rs1411766 and rs17412858 are in complete linkage disequilibrium (r2 = 1.0). Similarly, rs6492208 and rs2391777 are in complete linkage disequilibrium (r2 = 1.0). rs7989848 and rs9521445 are in strong linkage disequilibrium (r2 = 0.87), whereas only modest linkage disequilibrium exists between all other SNP pairs (r2 = 0.30–0.65). The two nearest genes are MYO16 and IRS2, located ∼384 kb centromeric and 120 kb telomeric of this region, respectively.
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Figure 2: Summary of genome-wide association results for the chromosome 7p, 9q, 11p, and 13q loci. A: Genome-wide association scan and imputed data for the chromosome 7p locus. rs39059 (solid red triangle) is located at position IVS1 + 21350 relative to exon 1 of CHN2 isoform 2 and is in tight linkage disequilibrium with rs39075 (r2 = 0.96), located at position IVS1 + 42572. rs39059 and rs39075 reside −69,318 and −90,540 kb, respectively, upstream of CPVL isoforms 1 and 2. A third alternate transcript (isoform 3) is predicted for CPVL and contains an exon that extends to intron 1 of CHN2. rs39059 and rs39075 are located at positions −20579 and −41801, respectively, relative to this transcript. ▲, SNPs genotyped on the Affymetrix array (n = 163); △, imputed SNPs (n = 694). *Imputed SNP rs39075 was genotyped in the GoKinD samples to confirm the imputation. B: Genome-wide association scan and imputed data for the chromosome 9q locus. A total of 100 genotyped SNPs from the Affymetrix array data and 450 imputed SNPs are shown. rs10868025 (solid red triangle) is located at position −10829 relative to FRMD3's transcription start site. rs10868025 is in complete linkage disequilibrium (r2 = 1.0) and only 253 bp from imputed SNP rs13289150 (△ superimposed on rs10868025). rs1888747, located at position −2204, is in partial linkage disequilibrium (r2 = 0.81) with rs10868025. *Imputed SNP rs1888747 was genotyped in the GoKinD samples to confirm the imputation. C: Genome-wide association scan and imputed data for the chromosome 11p locus. A total of 33 genotyped SNPs from the Affymetrix array data and 190 imputed SNPs are shown. rs739401 and rs451041 (solid red triangles) are in strong linkage disequilibrium (r2 = 0.97). rs739401 is located in intron 16 (isoforms a and c)/17 (isoforms b and d) of the CARS gene (position IVS16 + 687/IVS17 + 687). rs451041 is located in intron 4 (isoforms a and c)/5 (isoforms b and d), position IVS4 − 203/IVS5 − 203). D: Genome-wide association scan and imputed data for the chromosome 13q locus. A total of 68 genotyped SNPs from the Affymetrix array data and 268 imputed SNPs are shown. Seven lead SNPs (rs1041466, rs1411766, rs17412858, rs6492208, rs2391777, rs7989848, and rs9521445) from this region are indicated in red. rs1411766 and rs17412858 are in complete linkage disequilibrium (r2 = 1.0). Similarly, rs6492208 and rs2391777 are in complete linkage disequilibrium (r2 = 1.0). rs7989848 and rs9521445 are in strong linkage disequilibrium (r2 = 0.87), whereas only modest linkage disequilibrium exists between all other SNP pairs (r2 = 0.30–0.65). The two nearest genes are MYO16 and IRS2, located ∼384 kb centromeric and 120 kb telomeric of this region, respectively.

Mentions: Analyses of the imputed SNPs in our lead loci identified 11 additional SNPs that were highly correlated withthe original associations (P < 1 × 10−5). Of these, two were more strongly associated with diabetic nephropathy than our lead genotyped SNPs. Imputed SNP rs1888747 (chromosome 9q), which is in partial linkage disequilibrium (r2 = 0.81) with rs10868025, was more strongly associated with diabetic nephropathy than the original SNP (P = 4.7 × 10−7) (Fig. 2B). Similarly, two imputed SNPs in the 7p region (rs39075 and rs39076) were also more strongly associated than the original SNP in that region (rs39059) (Fig. 2A). Both imputed SNPs were genotyped in the GoKinD samples, and the associations with the imputed data were confirmed (rs39075, P = 6.5 × 10−7; and rs1888747, P = 6.3 × 10−7) (Table 2).


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 results for the chromosome 7p, 9q, 11p, and 13q loci. A: Genome-wide association scan and imputed data for the chromosome 7p locus. rs39059 (solid red triangle) is located at position IVS1 + 21350 relative to exon 1 of CHN2 isoform 2 and is in tight linkage disequilibrium with rs39075 (r2 = 0.96), located at position IVS1 + 42572. rs39059 and rs39075 reside −69,318 and −90,540 kb, respectively, upstream of CPVL isoforms 1 and 2. A third alternate transcript (isoform 3) is predicted for CPVL and contains an exon that extends to intron 1 of CHN2. rs39059 and rs39075 are located at positions −20579 and −41801, respectively, relative to this transcript. ▲, SNPs genotyped on the Affymetrix array (n = 163); △, imputed SNPs (n = 694). *Imputed SNP rs39075 was genotyped in the GoKinD samples to confirm the imputation. B: Genome-wide association scan and imputed data for the chromosome 9q locus. A total of 100 genotyped SNPs from the Affymetrix array data and 450 imputed SNPs are shown. rs10868025 (solid red triangle) is located at position −10829 relative to FRMD3's transcription start site. rs10868025 is in complete linkage disequilibrium (r2 = 1.0) and only 253 bp from imputed SNP rs13289150 (△ superimposed on rs10868025). rs1888747, located at position −2204, is in partial linkage disequilibrium (r2 = 0.81) with rs10868025. *Imputed SNP rs1888747 was genotyped in the GoKinD samples to confirm the imputation. C: Genome-wide association scan and imputed data for the chromosome 11p locus. A total of 33 genotyped SNPs from the Affymetrix array data and 190 imputed SNPs are shown. rs739401 and rs451041 (solid red triangles) are in strong linkage disequilibrium (r2 = 0.97). rs739401 is located in intron 16 (isoforms a and c)/17 (isoforms b and d) of the CARS gene (position IVS16 + 687/IVS17 + 687). rs451041 is located in intron 4 (isoforms a and c)/5 (isoforms b and d), position IVS4 − 203/IVS5 − 203). D: Genome-wide association scan and imputed data for the chromosome 13q locus. A total of 68 genotyped SNPs from the Affymetrix array data and 268 imputed SNPs are shown. Seven lead SNPs (rs1041466, rs1411766, rs17412858, rs6492208, rs2391777, rs7989848, and rs9521445) from this region are indicated in red. rs1411766 and rs17412858 are in complete linkage disequilibrium (r2 = 1.0). Similarly, rs6492208 and rs2391777 are in complete linkage disequilibrium (r2 = 1.0). rs7989848 and rs9521445 are in strong linkage disequilibrium (r2 = 0.87), whereas only modest linkage disequilibrium exists between all other SNP pairs (r2 = 0.30–0.65). The two nearest genes are MYO16 and IRS2, located ∼384 kb centromeric and 120 kb telomeric of this region, respectively.
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Related In: Results  -  Collection

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Figure 2: Summary of genome-wide association results for the chromosome 7p, 9q, 11p, and 13q loci. A: Genome-wide association scan and imputed data for the chromosome 7p locus. rs39059 (solid red triangle) is located at position IVS1 + 21350 relative to exon 1 of CHN2 isoform 2 and is in tight linkage disequilibrium with rs39075 (r2 = 0.96), located at position IVS1 + 42572. rs39059 and rs39075 reside −69,318 and −90,540 kb, respectively, upstream of CPVL isoforms 1 and 2. A third alternate transcript (isoform 3) is predicted for CPVL and contains an exon that extends to intron 1 of CHN2. rs39059 and rs39075 are located at positions −20579 and −41801, respectively, relative to this transcript. ▲, SNPs genotyped on the Affymetrix array (n = 163); △, imputed SNPs (n = 694). *Imputed SNP rs39075 was genotyped in the GoKinD samples to confirm the imputation. B: Genome-wide association scan and imputed data for the chromosome 9q locus. A total of 100 genotyped SNPs from the Affymetrix array data and 450 imputed SNPs are shown. rs10868025 (solid red triangle) is located at position −10829 relative to FRMD3's transcription start site. rs10868025 is in complete linkage disequilibrium (r2 = 1.0) and only 253 bp from imputed SNP rs13289150 (△ superimposed on rs10868025). rs1888747, located at position −2204, is in partial linkage disequilibrium (r2 = 0.81) with rs10868025. *Imputed SNP rs1888747 was genotyped in the GoKinD samples to confirm the imputation. C: Genome-wide association scan and imputed data for the chromosome 11p locus. A total of 33 genotyped SNPs from the Affymetrix array data and 190 imputed SNPs are shown. rs739401 and rs451041 (solid red triangles) are in strong linkage disequilibrium (r2 = 0.97). rs739401 is located in intron 16 (isoforms a and c)/17 (isoforms b and d) of the CARS gene (position IVS16 + 687/IVS17 + 687). rs451041 is located in intron 4 (isoforms a and c)/5 (isoforms b and d), position IVS4 − 203/IVS5 − 203). D: Genome-wide association scan and imputed data for the chromosome 13q locus. A total of 68 genotyped SNPs from the Affymetrix array data and 268 imputed SNPs are shown. Seven lead SNPs (rs1041466, rs1411766, rs17412858, rs6492208, rs2391777, rs7989848, and rs9521445) from this region are indicated in red. rs1411766 and rs17412858 are in complete linkage disequilibrium (r2 = 1.0). Similarly, rs6492208 and rs2391777 are in complete linkage disequilibrium (r2 = 1.0). rs7989848 and rs9521445 are in strong linkage disequilibrium (r2 = 0.87), whereas only modest linkage disequilibrium exists between all other SNP pairs (r2 = 0.30–0.65). The two nearest genes are MYO16 and IRS2, located ∼384 kb centromeric and 120 kb telomeric of this region, respectively.
Mentions: Analyses of the imputed SNPs in our lead loci identified 11 additional SNPs that were highly correlated withthe original associations (P < 1 × 10−5). Of these, two were more strongly associated with diabetic nephropathy than our lead genotyped SNPs. Imputed SNP rs1888747 (chromosome 9q), which is in partial linkage disequilibrium (r2 = 0.81) with rs10868025, was more strongly associated with diabetic nephropathy than the original SNP (P = 4.7 × 10−7) (Fig. 2B). Similarly, two imputed SNPs in the 7p region (rs39075 and rs39076) were also more strongly associated than the original SNP in that region (rs39059) (Fig. 2A). Both imputed SNPs were genotyped in the GoKinD samples, and the associations with the imputed data were confirmed (rs39075, P = 6.5 × 10−7; and rs1888747, P = 6.3 × 10−7) (Table 2).

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