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Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA.

ABSTRACT: African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA pools were genotyped in duplicate on the Illumina HumanHap550-Duo BeadChip. Normalization methods were developed and applied to array intensity values to reduce inter-array variance. Allele frequencies were calculated from normalized channel intensities and compared between case and control pools. Three SNPs had p values of <1.0E-6: rs4462445 (ch 13), rs4821469 (ch 22) and rs8077346 (ch 17). After normalization, top scoring SNPs (n = 65) were genotyped individually in 464 of the original cases and 478 of the controls, with replication in 336 non-DM ESRD cases and 363 non-nephropathy controls. Sixteen SNPs were associated with non-DM ESRD (p < 7.7E-4, Bonferroni corrected). Twelve of these SNPs are in or near the MYH9 gene. The four non-MYH9 SNPs that were associated with non-DM ESRD in the pooled samples were not associated in the replication set. Five SNPs that were modestly associated in the pooled samples were more strongly associated in the replication and/or combined samples. This is the first GWAS for non-DM ESRD in African Americans using pooled DNA. We demonstrate strong association between non-DM ESRD in African Americans with MYH9, and have identified additional candidate loci.

SUBMITTER: Bostrom MA

PROVIDER: S-EPMC3144421 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA.

Bostrom Meredith A MA Lu Lingyi L Chou Jeff J Hicks Pamela J PJ Xu Jianzhao J Langefeld Carl D CD Bowden Donald W DW Freedman Barry I BI

Human genetics 20100608 2

African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA poo ...[more]

PMID: 20532800

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Project description:Non-diabetic forms of nephropathy commonly lead to end-stage renal disease (non-DM ESRD). Previous studies have demonstrated that African Americans are more susceptible to non-DM ESRD compared to other ethnic groups, and this risk has a strong genetic component. A genome-wide scan for ESRD in African American families enriched for non-DM ESRD showed evidence for linkage in chromosome 13q33.3, and a candidate gene in this region, klotho, was selected for a detailed analysis in a follow-up case-control association study.Thirty-four single-nucleotide polymorphisms (SNPs) in the klotho gene were genotyped in 317 unrelated African American non-DM ESRD cases and 354 non-nephropathy controls, including 12 SNPs identified by re-sequencing a region around exon 4.Two SNPs demonstrated modest admixture-adjusted evidence of association with non-DM ESRD, rs650439 (P = 0.013, recessive model) and rs643780 (P = 0.017, recessive model), while rs17643698 approached significance (P = 0.0953, two degrees of freedom test). Eight of the most significant SNPs were tested for replication in a second case-control collection (557 African American non-DM ESRD cases and 187 controls), and there was no evidence of association in replicate cases and controls; nor when the samples were combined for a total of 874 non-DM cases and 541 controls. Cox proportional hazards models were computed to test for association between polymorphisms in klotho and age at onset of ESRD. A three-SNP haplotype, rs526906, rs525014 and rs571118 (T/T/A), was associated with age of onset of ESRD [P = 0.007, recessive model; hazard ratio (HR) = 0.70]. Subjects homozygous for this haplotype had a mean 4 years later onset of ESRD, suggesting a slower disease progression. HapMap subjects homozygous for this haplotype had increased expression of klotho, further supporting a protective role of this variant in ESRD.We conclude that three SNPs in intron 1 of the klotho gene are associated with delayed age at onset of non-DM ESRD in African Americans.

Project description:Background and objectivesGenetic variation in the cubilin (CUBN) gene is associated with albuminuria and CKD. Common and rare coding variants in CUBN and the gene encoding its transport partner megalin (LRP2) were assessed for association with ESRD in blacks.Design, setting, participants, & measurementsSixty-six CUBN and LRP2 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this multistage study. Exome sequencing data from 529 blacks with type 2 diabetes (T2D) -associated ESRD and 535 controls lacking T2D or nephropathy (the Type 2 Diabetes Genes [T2D-GENES] Consortium) were first evaluated, focusing on coding variants in CUBN and LRP2; 15 potentially associated SNPs identified from the T2D-GENES Consortium as well as 51 other selected SNPs were then assessed in an independent T2D-ESRD sample set of blacks (the Affymetrix Axiom Biobank Genotyping Array [AXIOM]; 2041 patients with T2D-ESRD, 627 patients with T2D without nephropathy, and 1140 nondiabetic, non-nephropathy controls). A meta-analysis combining the T2D-GENES Consortium and the AXIOM data was performed for 18 overlapping SNPs. Additionally, all 66 SNPs were genotyped in the Wake Forest School of Medicine samples of blacks with nondiabetic ESRD (885 patients with nondiabetic ESRD and 721 controls). Association testing with ESRD was performed in models including age, sex, African ancestry proportion, and apolipoprotein L1 gene renal-risk variants.ResultsCUBN SNP rs1801239 (I2984V), previously associated with albuminuria, was significantly associated with T2D-ESRD in blacks (the T2D-GENES Consortium and the AXIOM meta-analysis, P=0.03; odds ratio, 1.31; 95% confidence interval, 1.03 to 1.67; minor allele frequency =0.028). A novel LRP2 missense variant, rs17848169 (N2632D), was also significantly protective from T2D-ESRD (the T2D-GENES Consortium and the AXIOM, P<0.002; odds ratio, 0.47; 95% confidence interval, 0.29 to 0.75; meta-analysis minor allele frequency =0.007). Neither SNP was associated with T2D when contrasting patients with T2D with controls lacking diabetes. CUBN and LRP2 SNPs were not associated with nondiabetic etiologies of ESRD.ConclusionsEvidence for genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESRD in populations with recent African ancestry.

Project description:BackgroundUsing data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.Methods and resultsAmong 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.ConclusionsIn the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

Dataset Information

Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA.

Publications

Candidate genes for non-diabetic ESRD in African Americans: a genome-wide association study using pooled DNA.

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