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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

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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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Acknowledgments

We thank patients and staff of the Southeastern Kidney Council/ESRD Network 6 and individuals recruited as controls for their participation, Joyce Byers, Mitzie Spainhour, Matt Stiegert, and Mark Hansen and colleagues at Illumina, Inc. This work was supported by grants DK066358, DK072550, Wake Forest University General Clinical Research Center M01 RR07122, and a Career Development Award from the American Diabetes Association (MMS).

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Authors and Affiliations

  1. Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Tennille S. Leak, Shelly G. Smith, Keith L. Keene, Candace J. Gordon, Pamela J. Hicks, Donald W. Bowden & Michèle M. Sale

  2. Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Josyf C. Mychaleckyj, Barry I. Freedman, Donald W. Bowden & Michèle M. Sale

  3. Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Pamela J. Hicks & Donald W. Bowden

  4. Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, USA

    Josyf C. Mychaleckyj & Michèle M. Sale

  5. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    Josyf C. Mychaleckyj

  6. Department of Medicine, University of Virginia, Charlottesville, VA, USA

    Michèle M. Sale

  7. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA

    Michèle M. Sale

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  1. Tennille S. Leak
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Correspondence to Michèle M. Sale.

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Leak, T.S., Mychaleckyj, J.C., Smith, S.G. et al. 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. Hum Genet 124, 63–71 (2008). https://doi.org/10.1007/s00439-008-0523-7

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