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The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans

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Abstract

Four genome wide linkage scans for diabetic nephropathy have mapped susceptibility loci to chromosome 18q22.3-23 in the region of the carnosinase genes, CNDP1 and CNDP2. CNDP1 has been associated with diabetic nephropathy in Europeans and European Americans, but not African-Americans. Individuals homozygous for a five tri-nucleotide repeat allele (5L; D18S880) are protected from diabetic nephropathy. We identified 64 variants after sequencing the exons, promoter, and 3′ UTR of CNDP1 and CNDP2 in African-American and European American DNA samples. After scanning 44 of these variants, extensive genotyping of 12 SNPs and D18S880 was performed in 1,025 African-American cases with type 2 diabetes (DM)-associated end-stage renal disease (ESRD) and 1,064 African-American non-diabetic non-nephropathy controls to assess whether the carnosinase genes influence risk for DM-ESRD in African-Americans. Evidence of association with DM-ESRD was seen with 2 SNPs: rs6566810 and rs4892247; 3 two-marker haplotypes: rs6566810 and rs17089362, rs17089362 and rs890336, and rs890334 and rs12717111 (global empirical P = 0.0034, 0.0275, and 0.0002, respectively) and 3 three-marker haplotypes: rs6566810, rs17089362, and rs890336; rs890335, rs890334, and rs12717111; and rs890334, rs12717111, and D18S880 (global empirical P = 0.0074, 1.5E-05, and 0.0032, respectively). The risk haplotypes (rs6566810, rs17089362 [A,T] and rs6566810, rs17089362, rs890336 [A,T,C]) were most strongly associated with DM-ESRD among African-Americans in the non 5L–5L group. Variants in the carnosinase genes appear to contribute to diabetic nephropathy susceptibility in African-Americans. Protection from diabetic nephropathy afforded by 5L–5L homozygosity in CNDP1 may be masked by the effects of additional risk haplotypes in CNDP1 and CNDP2.

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Acknowledgments

This research was supported in part by NIH grants RO1 DK066358 (DWB), R01 DK053591 (DWB), RO1 KD070941 (BIF), and in part by the General Clinical Research Center of the Wake Forest University School of Medicine grant M01 RR07122.

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Authors and Affiliations

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

    Caitrin W. McDonough, Pamela J. Hicks & Donald W. Bowden

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

    Caitrin W. McDonough, Pamela J. Hicks & Donald W. Bowden

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

    Pamela J. Hicks & Donald W. Bowden

  4. Graduate Program in Molecular Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Caitrin W. McDonough

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

    Barry I. Freedman & Donald W. Bowden

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

    Lingyi Lu & Carl D. Langefeld

Authors
  1. Caitrin W. McDonough
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  2. Pamela J. Hicks
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  3. Lingyi Lu
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  4. Carl D. Langefeld
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  5. Barry I. Freedman
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  6. Donald W. Bowden
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Correspondence to Donald W. Bowden.

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McDonough, C.W., Hicks, P.J., Lu, L. et al. The influence of carnosinase gene polymorphisms on diabetic nephropathy risk in African-Americans. Hum Genet 126, 265–275 (2009). https://doi.org/10.1007/s00439-009-0667-0

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  • DOI: https://doi.org/10.1007/s00439-009-0667-0

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