Skip to main content

Advertisement

Log in

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

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Download references

Acknowledgments

This work was supported by NIH Grants R01 DK53591 (DWB), DK070941, and DK084149 (BIF), and by the National Natural Science Foundation of China (No. 81200488). This work has also been made possible through an International Society of Nephrology Fellowship and Shanghai Jiaotong University K.C. Wong Medical Fellowship Fund (Jun Ma). We acknowledge the contributions of the study participants, coordinators, physicians, staff, and laboratory.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maggie C. Y. Ng.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

M. Guan and J. Ma were equal contributors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 44 kb)

Supplementary material 2 (XLSX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, M., Ma, J., Keaton, J.M. et al. Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum Genet 135, 1251–1262 (2016). https://doi.org/10.1007/s00439-016-1714-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-016-1714-2

Keywords

Navigation