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Genetic analysis of diabetic nephropathy on chromosome 18 in African Americans: linkage analysis and dense SNP mapping

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Abstract

Genetic studies in Turkish, Native American, European American, and African American (AA) families have linked chromosome 18q21.1–23 to susceptibility for diabetes-associated nephropathy. In this study, we have carried out fine linkage mapping in the 18q region previously linked to diabetic nephropathy in AAs by genotyping both microsatellite and single nucleotide polymorphisms (SNPs) for linkage analysis in an expanded set of 223 AA families multiplexed for type 2 diabetes associated ESRD (T2DM-ESRD). Several approaches were used to evaluate evidence of linkage with the strongest evidence for linkage in ordered subset analysis with an earlier age of T2DM diagnosis compared to the remaining pedigrees (LOD 3.9 at 90.1 cM, ∆P = 0.0161, NPL P value = 0.00002). Overall, the maximum LODs and LOD-1 intervals vary in magnitude and location depending upon analysis. The linkage mapping was followed up by performing a dense SNP map, genotyping 2,814 SNPs in the refined LOD-1 region in 1,029 AA T2DM-ESRD cases and 1,027 AA controls. Of the top 25 most associated SNPs, 10 resided within genic regions. Two candidate genes stood out: NEDD4L and SERPINB7. SNP rs512099, located in intron 1 of NEDD4L, was associated under a dominant model of inheritance [P value = 0.0006; Odds ratio (95% Confidence Interval) OR (95% CI) = 0.70 (0.57–0.86)]. SNP rs1720843, located in intron 2 of SERPINB7, was associated under a recessive model of inheritance [P value = 0.0017; OR (95% CI) = 0.65 (0.50–0.85)]. Collectively, these results suggest that multiple genes in this region may influence diabetic nephropathy susceptibility in AAs.

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Abbreviations

cM:

centiMorgan

ESRD:

End-stage renal disease

LOD:

Log of the odds

DN:

Diabetic nephropathy

OSA:

Ordered subsets analysis

NPL:

Nonparametric linkage

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Acknowledgments

We wish to thank the patients, their relatives, and staff of the Southeastern Kidney Council, Inc./ESRD Network 6 for their participation. This work was supported by NIH grants RO1 DK066358 (DWB), R01 DK053591 (DWB), R01 HL56266 (BIF), R01 KD070941 (BIF) and in part by the General Clinical Research Center of the Wake Forest University School of Medicine grant M01 RR07122. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University; contract number N01-HG-65403.

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Authors and Affiliations

  1. Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Caitrin W. McDonough, Meredith A. Bostrom, Pamela J. Hicks & Donald W. Bowden

  2. Program in Molecular Medicine and Translational Science, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Caitrin W. McDonough

  3. Center for Diabetes Research, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Meredith A. Bostrom, Pamela J. Hicks & Donald W. Bowden

  4. Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Meredith A. Bostrom, Pamela J. Hicks & Donald W. Bowden

  5. Department of Public Health Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Lingyi Lu, Carl D. Langefeld & Jasmin Divers

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

    Josyf C. Mychaleckyj

  7. Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Barry I. Freedman & Donald W. Bowden

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  1. Caitrin W. McDonough
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  2. Meredith A. Bostrom
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Correspondence to Donald W. Bowden.

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McDonough, C.W., Bostrom, M.A., Lu, L. et al. Genetic analysis of diabetic nephropathy on chromosome 18 in African Americans: linkage analysis and dense SNP mapping. Hum Genet 126, 805–817 (2009). https://doi.org/10.1007/s00439-009-0732-8

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