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Comprehensive evaluation of the estrogen receptor α gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population

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Abstract

We previously investigated the estrogen receptor α gene (ESR1) as a positional candidate for type 2 diabetes (T2DM), and found evidence for association between the intron 1-intron 2 region of this gene and T2DM and/or nephropathy in an African American (AA) population. Our objective was to comprehensively evaluate variants across the entire ESR1 gene for association in AA with T2DM and end stage renal disease (T2DM–ESRD). One hundred fifty SNPs in ESR1, spanning 476 kb, were genotyped in 577 AA individuals with T2DM–ESRD and 596 AA controls. Genotypic association tests for dominant, additive, and recessive models, and haplotypic association, were calculated using a χ2 statistic and corresponding P value. Thirty-one SNPs showed nominal evidence for association (P < 0.05) with T2DM–ESRD in one or more genotypic model. After correcting for multiple tests, promoter SNP rs11964281 (nominal P = 0.000291, adjusted P = 0.0289), and intron 4 SNPs rs1569788 (nominal P = 0.000754, adjusted P = 0.0278) and rs9340969 (nominal P = 0.00109, adjusted P = 0.0467) remained significant at experimentwise error rate (EER) P ≤ 0.05 for the dominant class of tests. Twenty-three of the thirty-one associated SNPs cluster within the intron 4–intron 6 regions. Gender stratification revealed nominal evidence for association with 35 SNPs in females (352 cases; 306 controls) and seven SNPs in males (225 cases; 290 controls). We have identified a novel region of the ESR1 gene that may contain important functional polymorphisms in relation to susceptibility to T2DM and/or diabetic nephropathy.

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Acknowledgments

We thank the patients and staff of the Southeastern Kidney Council/ESRD Network 6 and individuals recruited as controls for their participation. Thanks also to recruiters Joyce Byers and Mitzie Spainhour, technician Candace Gordon, programmer Matt Stiegert, and Mark Hansen and colleagues at Illumina Inc. This work was supported by grants DK066358, DK072550, the 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

    Keith L. Keene, Shelly G. Smith, Tennille S. Leak, Donald W. Bowden & Michèle M. Sale

  2. Center for Public Health Genomics, University of Virginia, P.O. Box 800717, Charlottesville, VA, 22908, USA

    Josyf C. Mychaleckyj, Stephen S. Rich & Michèle M. Sale

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

    Josyf C. Mychaleckyj & Stephen S. Rich

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

    Peter S. Perlegas & Donald W. Bowden

  5. Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Carl D. Langefeld

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

    David M. Herrington, Barry I. Freedman, Donald W. Bowden & Michèle M. Sale

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

    Stephen S. Rich & Michèle M. Sale

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

    Michèle M. Sale

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  1. Keith L. Keene
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  2. Josyf C. Mychaleckyj
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  3. Shelly G. Smith
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  6. Carl D. Langefeld
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  9. Stephen S. Rich
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  10. Donald W. Bowden
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  11. Michèle M. Sale
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Correspondence to Michèle M. Sale.

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Keene, K.L., Mychaleckyj, J.C., Smith, S.G. et al. Comprehensive evaluation of the estrogen receptor α gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population. Hum Genet 123, 333–341 (2008). https://doi.org/10.1007/s00439-008-0482-z

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  • DOI: https://doi.org/10.1007/s00439-008-0482-z

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