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Hum Genet. 2016 Nov;135(11):1251-1262. Epub 2016 Jul 26.

Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans.

Author information

1
Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
2
Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
3
Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
4
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
5
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
6
Center for Genomics and Personalized Medicine Research, Medical Center Boulevard, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA. mng@wakehealth.edu.
7
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. mng@wakehealth.edu.

Abstract

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.

PMID:
27461219
PMCID:
PMC5053912
DOI:
10.1007/s00439-016-1714-2
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare that they have no conflict of interest.

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