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Comparative Study
. 2008 Aug;124(1):63-71.
doi: 10.1007/s00439-008-0523-7. Epub 2008 Jun 17.

Evaluation of a SNP map of 6q24-27 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population

Tennille S Leak  1 , Josyf C Mychaleckyj, Shelly G Smith, Keith L Keene, Candace J Gordon, Pamela J Hicks, Barry I Freedman, Donald W Bowden, Michèle M Sale
Affiliations
Comparative Study

Evaluation of a SNP map of 6q24-27 confirms diabetic nephropathy loci and identifies novel associations in type 2 diabetes patients with nephropathy from an African-American population

Tennille S Leak et al. Hum Genet. 2008 Aug.

Abstract

Previously, we performed a genome scan for type 2 diabetes (T2DM) using 638 African-American (AA) affected sibling pairs from 247 families; non-parametric linkage analysis suggested evidence of linkage at 6q24-27 (LOD 2.26). To comprehensively evaluate this region, we performed a two-stage association study by first constructing a SNP map of 754 SNPs selected from HapMap on the basis of linkage disequilibrium (LD) in 300 AAT2DM end-stage renal disease (ESRD) subjects, 311 AA controls, 43 European American controls and 45 Yoruba Nigerian samples (Set 1). Replication analyses were conducted in an independent population of 283 AA T2DM-ESRD subjects and 282 AA controls (Set 2). In addition, we adjusted for the impact of admixture on association results by using ancestry informative markers (AIMs). In Stage 1, 137 (18.2%) SNPs showed nominal evidence of association (P < 0.05) in one or more of tests of association: allelic (n = 33), dominant (n = 36), additive (n = 29), or recessive (n = 34) genotypic models, and 2- (n = 47) and 3-SNP (n = 43) haplotypic analyses. These SNPs were selected for follow-up genotyping. Stage 2 analyses confirmed association with a predicted 2-SNP "risk" haplotype in the PARK2 gene. Also, two intergenic SNPs showed consistent genotypic association with T2DM-ESRD: rs12197043 and rs4897081. Combined analysis of all subjects from both stages revealed nominal associations with 17 SNPs within genes, including suggestive associations in ESR1 and PARK2. This study confirms known diabetic nephropathy loci and identifies potentially novel susceptibility variants located within 6q24-27 in AA.

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Figures

Figure 1
Figure 1. Single SNP genotypic association results for 754 SNPs in Set 1
X axis: Marker positions in kb; Y-axis: -log10(global P-value). The P<0.05 nominal level of significance is indicated by the dashed line.
Figure 2
Figure 2. Single SNP genotypic association results for 137 SNPs in Set 2
X axis: Marker positions in kb; Y-axis: -log10(global P-value). The P<0.05 nominal level of significance is indicated by the dashed line. Replicated SNPs (rs12197043 and rs4897081) are represented by enlarged data points.
Figure 3
Figure 3. Single SNP genotypic association results for 137 SNPs in Set 1 and Set 2 combined
X axis: Marker positions in kb; Y-axis: -log10(global P-value). The P<0.05 nominal level of significance is indicated by the dashed line. Replicated SNPs (rs12197043 and rs4897081) are represented by enlarged data points.
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