Journal
DIABETIC MEDICINE
Volume 26, Issue 11, Pages 1090-1098Publisher
WILEY
DOI: 10.1111/j.1464-5491.2009.02846.x
Keywords
Carnosinase 1; end-stage renal disease; genome-wide association study; GoKinD study; microvascular complications; Type 1 diabetes
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Funding
- Juvenile Diabetes Research Foundation
- United States Centers for DiseaseControl and Prevention
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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 < 0.0006). Conclusions These findings identify several novel loci which may contribute to ESRD susceptibility in individuals with Type 1 diabetes.
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