Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

APOL1 variants and kidney disease in people of recent African ancestry

Nature Reviews Nephrology volume 9, pages 240–244 (2013)Cite this article

Subjects

Abstract

Coding variants within the APOL1 gene have been associated with kidney disease, explaining an association that was previously attributed to variants within the neighbouring MYH9 gene. To better define the role of APOL1 in causing kidney disease in individuals of African ancestry, we performed an extensive survey of the common variation in the region surrounding the APOL1 gene, as seen through the lens of the 1000 Genomes Project. Arguing by exclusion, it is reasonable to conclude that the putative APOL1 causal variants are not proxies for any other variants with more direct roles in kidney disease. Our statistical argument is in part made possible by the exceptionally young age of the APOL1 coding variants coupled with the unusually high rate of genetic recombination surrounding this gene. Although no biological evidence currently exists for the causality of APOL1 variants with kidney disease, our statistical reasoning provides a strong case for causality, and a region to target in future functional studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Illustration of the recombination landscape in the region near the APOL1 gene.
Figure 2: Linkage disequilibrium plot for rs73885319.

Similar content being viewed by others

References

  1. Byrne, C., Nedelman, J., & Luke, R. G. Race, socioeconomic status, and the development of end-stage renal disease. Am. J. Kidney Dis. 23, 16 (1994).

    Article  CAS  Google Scholar 

  2. U. S. Renal Data System, USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (2012).

  3. Kopp, J. B. et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 40, 1175–1184 (2008).

    Article  CAS  Google Scholar 

  4. Kao, W. H. et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat. Genet. 40, 1185–1192 (2008).

    Article  CAS  Google Scholar 

  5. Arrondel, C. et al. Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndromes. J. Am. Soc. Nephrol. 13, 65–74 (2002).

    CAS  PubMed  Google Scholar 

  6. Freedman, B. I. et al. Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney Int. 75, 736–745 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Freedman, B. I. et al. Non-muscle myosin heavy chain 9 gene MYH9 associations in African Americans with clinically diagnosed type 2 diabetes mellitus-associated ESRD. Nephrol. Dial. Transplant. 24, 3366–3371 (2009).

    Article  CAS  Google Scholar 

  8. Freedman, B. I. et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with albuminuria in hypertensive African Americans: the HyperGEN Study. Am. J. Nephrol. 29, 626–632 (2009).

    Article  CAS  Google Scholar 

  9. Behar, D. M. et al. African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans. Hum. Mol. Genet. 19, 1816–1827 (2010).

    Article  CAS  Google Scholar 

  10. Nelson, G. W. et al. Dense mapping of MYH9 localizes the strongest kidney disease associations to the region of introns 13 to 15. Hum. Mol. Genet. 19, 1805–1815 (2010).

    Article  CAS  Google Scholar 

  11. Franceschini, N. et al. The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study. Hum. Genet. 127, 295–301 (2010).

    Article  CAS  Google Scholar 

  12. The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  13. Hinds, D. A. et al. Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079 (2005).

    Article  CAS  Google Scholar 

  14. Collins, F. S., Brooks, L. D. & Chakravarti, A. A DNA polymorphism discovery resource for research on human genetic variation. Genome Res. 8, 1229–1231 (1998).

    Article  CAS  Google Scholar 

  15. Clark, A. G., Hubisz, M. J., Bustamante, C. D., Williamson, S. H. & Nielsen, R. Ascertainment bias in studies of human genome-wide polymorphism. Genome Res. 15, 1496–1502 (2005).

    Article  CAS  Google Scholar 

  16. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  17. Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).

    Article  CAS  Google Scholar 

  18. Tzur, S. et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum. Genet. 128, 345–350 (2010).

    Article  CAS  Google Scholar 

  19. Reeves-Daniel, A. M. et al. The APOL1 gene and allograft survival after kidney transplantation. Am. J. Transplant. 11, 1025–1030 (2011).

    Article  CAS  Google Scholar 

  20. Papeta, N. et al. APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. J. Am. Soc. Nephrol. 22, 1991–1996 (2011).

    Article  CAS  Google Scholar 

  21. Kanji, Z. et al. Genetic variation in APOL1 associates with younger age at hemodialysis initiation. J. Am. Soc. Nephrol. 22, 2091–2097 (2011).

    Article  CAS  Google Scholar 

  22. Friedman, D. J., Kozlitina, J., Genovese, G., Jog, P. & Pollak, M. R. Population-based risk assessment of APOL1 on renal disease. J. Am. Soc. Nephrol. 22, 2098–2105 (2011).

    Article  CAS  Google Scholar 

  23. Madhavan, S. M. et al. APOL1 localization in normal kidney and nondiabetic kidney disease. J. Am. Soc. Nephrol. 22, 2119–2128 (2011).

    Article  CAS  Google Scholar 

  24. Kopp, J. B. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J. Am. Soc. Nephrol. 22, 2129–2137 (2011).

    Article  CAS  Google Scholar 

  25. Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat. Genet. 40, 1124–1129 (2008).

    Article  CAS  Google Scholar 

  26. Reich, D. et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 5, e1000360 (2009).

    Article  Google Scholar 

  27. Johnson, A. D. et al. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938–2939 (2008).

    Article  CAS  Google Scholar 

  28. Thorvaldsdóttir, H., Robinson, J. T., Mesirov, J. P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. http://dx.doi.org/10.1093/bib/bbs017.

  29. Handsaker, R. E., Korn, J. M., Nemesh, J. & McCarroll, S. A. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale. Nat. Genet. 43, 269–276 (2011).

    Article  CAS  Google Scholar 

  30. Smith, M. W. et al. A high-density admixture map for disease gene discovery in African Americans. Am. J. Hum. Genet. 74, 1001–1013 (2004).

    Article  CAS  Google Scholar 

  31. Genovese, G. et al. A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. Kidney Int. 78, 698–704 (2010).

    Article  Google Scholar 

  32. Fine, D. M. et al. APOL1 risk variants predict histopathology and progression to ESRD in HIV-related kidney disease. J. Am. Soc. Nephrol. 23, 343–350 (2012).

    Article  CAS  Google Scholar 

  33. Ashley-Koch, A. E. et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br. J. Haematol. 155, 386–394 (2011).

    Article  CAS  Google Scholar 

  34. Behar, D. M. et al. Absence of APOL1 risk variants protects against HIV-associated nephropathy in the Ethiopian population. Am. J. Nephrol. 34, 452–459 (2011).

    Article  CAS  Google Scholar 

  35. Bockenhauer, D., Medlar, A. J., Ashton, E., Kleta, R. & Lench, N. Genetic testing in renal disease. Pediatr. Nephrol. 27, 873–883 (2012).

    Article  Google Scholar 

  36. Rosset, S., Tzur, S., Behar, D. M., Wasser, W. G. & Skorecki, K. The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus. Nat. Rev. Nephrol. 7, 313–326 (2011).

    Article  CAS  Google Scholar 

  37. Freedman, B. I. & Langefeld, C. D. The new era of APOL1-associated glomerulosclerosis. Nephrol. Dial. Transplant. 27, 1288–1291 (2012).

    Article  CAS  Google Scholar 

  38. NHLBI Exome Sequencing Project. Exome Variant Server [online], (2011).

  39. Bostrom, M. A. et al. Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy. Am. J. Kidney Dis. 59, 210–221 (2012).

    Article  CAS  Google Scholar 

  40. Tzur, S., Rosset, S., Skorecki, K. & Wasser, W. G. APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease. Nephrol. Dial. Transplant. 27, 1498–1505 (2012).

    Article  CAS  Google Scholar 

  41. Cheng, W. et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese. Nephrol. Dial. Transplant. 26, 2544–2549 (2011).

    Article  CAS  Google Scholar 

  42. O'Seaghdha, C. M. et al. The MYH9/APOL1 region and chronic kidney disease in European-Americans. Hum. Mol. Genet. 20, 2450–2456 (2011).

    Article  CAS  Google Scholar 

  43. Cooke, J. N. et al. Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans. Nephrol. Dial. Transplant. 27, 1505–1511 (2011).

    Article  Google Scholar 

  44. Freedman, B. I. et al. Differential effects of MYH9 and APOL1 risk variants on FRMD3 association with diabetic ESRD in African Americans. PLoS Genet. 7, e1002150 (2011).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Stanley Center, Broad Institute, Cambridge, 02142, MA, USA

    Giulio Genovese

  2. Beth Israel Deaconess Medical Center, Boston, 02215, MA, USA

    David J. Friedman & Martin R. Pollak

Authors
  1. Giulio Genovese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin R. Pollak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Martin R. Pollak.

Ethics declarations

Competing interests

G. Genovese, D. J. Friedman and M. R. Pollak have filed a patent in relation to this topic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Genovese, G., Friedman, D. & Pollak, M. APOL1 variants and kidney disease in people of recent African ancestry. Nat Rev Nephrol 9, 240–244 (2013). https://doi.org/10.1038/nrneph.2013.34

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2013.34

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing