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.

Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

Abstract

GLUCOSES-PHOSPHATE dehydrogeiiase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people1. The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria2,3. However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results4‡-8. Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females1,5‡-11. Furthermore, how much protection may be afforded is unknown. Here we report that, in two large case-control studies of over 2,000 African children, the common African form of G6PD deficiency (G6PD A‡-) is associated with a 46‡-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

References

  1. Beutler, E. Semin. Haemat. 27, 137–164 (1990).

    CAS  Google Scholar 

  2. Allison, A. C. Nature 186, 531–532 (1960).

    Article  ADS  CAS  Google Scholar 

  3. Motulsky, A. G. Hum. Biol. 32, 28–62 (1960).

    CAS  PubMed  Google Scholar 

  4. Gilles, H. M. et al. Lancet I, 138–140 (1967).

    Article  CAS  Google Scholar 

  5. Bienzle, U., Ayeni, O., Lucas, A. O. & Luzzato, L. Lancet I, 107–110 (1972).

    Article  Google Scholar 

  6. Martin, S. K., Miller, L. H. & Alling, D. Lancet I, 524–526 (1979).

    Article  Google Scholar 

  7. Luzzatto, L. & Bienzle, U. Lancet I, 1183–1184 (1979).

    Article  Google Scholar 

  8. Miller, L. H. in Malaria. Principles and Practice of Malariology (eds Wernsdorfer, W. H. & McGregor, I. A.) 493–494 (Churchill Livingstone, Edinburgh, 1988).

    Google Scholar 

  9. Luzzatto, L. & Battistuzzi, U. Adv. med. Genet. 14, 217–329 (1985).

    CAS  Google Scholar 

  10. Greene, L. Yb. phys. Anthrop. 36, 153–178 (1993).

    Article  Google Scholar 

  11. Martin, S. K. Parasit. Today 7, 251–252 (1994).

    Article  Google Scholar 

  12. Hirono, A. & Beutler, E. Proc. natn. Acad. Sci. U.S.A. 85, 3951–3954 (1988).

    Article  ADS  CAS  Google Scholar 

  13. Vulliamy, T. et al. Proc. natn. Acad. Sci. U.S.A. 88, 8568–8571 (1991).

    Article  ADS  CAS  Google Scholar 

  14. Beutler, E. et al. Blood 7, 2550–2555 (1989).

    Google Scholar 

  15. Luzzatto, L. & Mehta, A. in The Metabolic Basis of Inherited Diseases (eds Scriver, C. R., Baudet, A. L., Sly, W. S. & Valle, D.) 2237–2265 (McGraw-Hill, 1989).

    Google Scholar 

  16. Usanga, E. A. & Luzzatto, L. Nature 313, 793–795 (1985).

    Article  ADS  CAS  Google Scholar 

  17. Ling, I. T. & Wilson, R. J. M. Molec. Biochem. Parasit. 31, 47–56 (1988).

    Article  CAS  Google Scholar 

  18. Kurdi-Haidar, B. & Luzzatto, L. Molec. Biochem. Parasit. 41, 83–92 (1990).

    Article  CAS  Google Scholar 

  19. Greenwood, B. M., Marsh, K. & Snow, R. W. Parasit. Today 7, 277–281 (1991).

    Article  CAS  Google Scholar 

  20. Marsh, K. Parasitology 104, S53–S59 (1992).

    Article  Google Scholar 

  21. Hill, A. V. S. et al. Nature 352, 595–560 (1991).

    Article  ADS  CAS  Google Scholar 

  22. McGuire, W., Hill, A. V. S., Allsopp, C. E. M., Greenwood, B. M. & Kwiatkowski, O. Nature 371, 508–511 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Hill, A. V. S. Trans. R. Soc. trop. Med. Hyg. 86, 225–232 (1992).

    Article  CAS  Google Scholar 

  24. Roth, E. F., Raventos-Suarez, C., Rinaldi, A. & Nagel, R. L. Proc. natn. Acad. Sci. U.S.A. 80, 298–292 (1983).

    Article  ADS  CAS  Google Scholar 

  25. Greenwood, B. M. et al. Trans. R. Soc. trop. Med. Hyg. 81, 478–486 (1987).

    Article  CAS  Google Scholar 

  26. Bruce-Chwatt, L. J. in Malaria. Principles and Practice of Malariology (eds Wernsdorfer, W. H. & McGregor, I. A.) 1–60 (Churchill Livingstone, Edinburgh, 1988).

    Google Scholar 

  27. Livingstone, F. B. Frequencies of Hemoglobin Variants (Oxford Univ. Press, 1985).

    Google Scholar 

  28. Motulsky, A. G. Lancet I, 1168–1169 (1961).

    Article  Google Scholar 

  29. Heller, P., Best, W. R., Nelson, R. B. & Becktel, J. New Engl. J. Med. 300, 1001–1008 (1979).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruwende, C., Khoo, S., Snow, R. et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376, 246–249 (1995). https://doi.org/10.1038/376246a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/376246a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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