African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania

English version České info

Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects red blood cells from oxidative damage. Numerous genetic variants of G6PD, residing in the X chromosome, are found among African populations: mutations causing A- deficiency can lead to serious clinical outcomes (including hemolytic anemia) but also confer protection against severe malaria. Epidemiological studies have used some of the genetic markers that cause A- deficiency to establish who is protected from severe malaria, with differing results. Whether females, with one or two copies of mutant genes, males with one copy, or both genders are protected is uncertain. This uncertainty is due to G6PD and malaria phenotypic complexity and misclassification, and to genetic differences between populations and the limited numbers of genetic markers (usually 2) considered. In this study we analysed more than 30 G6PD genetic markers in 506 Tanzanian children with severe malaria and 477 without malaria. We found that only females with one normal and one mutant copy of the gene (heterozygotes) were protected from severe malaria. Further, we established that the G6PD gene is under evolutionary pressure with the likely mechanism being selection by malaria. Our work demonstrates that studies of severe malaria and G6PD enzymatic function across African populations require, in addition to complete and accurate G6PD phenotypic classification, the identification and analysis of the full repertoire of G6PD genetic markers.

Vyšlo v časopise: African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania. PLoS Genet 11(2): e32767. doi:10.1371/journal.pgen.1004960
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004960

Souhrn

Zdroje

1. Minucci A, Moradkhani K, Hwang MJ, Zuppi C, Giardina B, Capoluongo E (2012). Glucose-6-phosphate dehydrogenase (G6PD) mutations database: review of the "old" and update of the new mutations. Blood Cells Mol Dis. 15;48(3):154–65. doi: 10.1016/j.bcmd.2012.01.001 22293322

2. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria (1998). J Mol Med 76: 581–588. 9694435

3. Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G et al (2001). Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science. 293(5529):455–62. 11423617

4. Eziefula AC, Pett H, Grignard L, Opus S, Kiggundu M et al (2014). Glucose-6-Phosphate Dehydrogenase Status and Risk of Hemolysis in Plasmodium falciparum-Infected African Children Receiving Single-Dose Primaquine. Antimicrob Agents Chemother. 58(8):4971–3. doi: 10.1128/AAC.02889-14 24913169

5. Shah SS, Diakite SA, Traore K, Diakite M, Kwiatkowski DP et al (2012). A novel cytofluorometric assay for the detection and quantification of glucose-6-phosphate dehydrogenase deficiency. Sci Rep 2:299. doi: 10.1038/srep00299 22393475

6. Hayden MS, Ghosh S (2004). Signaling to NF-kappaB. Genes Dev. 18:2195–224. 15371334

7. Fusco F, Paciolla M, Napolitano F, Pescatore A, D'Addario I et al (2012). Genomic architecture at the incontinentia pigmenti locus favours de novo pathological alleles through different mechanisms. Hum. Molec. Genet. 21: 1260–1271. doi: 10.1093/hmg/ddr556 22121116

8. Clark TG, Fry AE, Auburn S, Campino S, Diakite M et al (2009). Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility. Eur J Hum Genetics 17:1080–5. doi: 10.1038/ejhg.2009.8 19223928

9. Maiga B, Dolo A, Campino S, Sepulveda N, Corran P et al (2014). Glucose-6-phosphate dehydrogenase polymorphisms and mild malaria susceptibility in Dogon and Fulani, Mali. Malaria J 13(1):270.

10. Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT (1989). Molecular heterogeneity of glucose-6-phosphate dehydrogenase A. Blood 74: 2550–2555. 2572288

11. Sirugo G, Predazzi IM, Bartlett J, Tacconelli A, Walther M et al (2014). G6PD A- deficiency and severe malaria in The Gambia: heterozygote advantage and possible homozygote disadvantage. Am J Trop Med Hyg 90(5):856–9. doi: 10.4269/ajtmh.13-0622 24615128

12. Guindo A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA (2007). X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med 4: e66. 1. 17355169

13. Santana MS, Monteiro WM, Siqueira AM, Costa MF, Sampaio V et al (2013). Glucose-6-phosphate dehydrogenase deficient variants are associated with reduced susceptibility to malaria in the Brazilian Amazon. Trans R Soc Trop Med Hyg 107:301–6. doi: 10.1093/trstmh/trt015 23479361

14. Ruwende C, Khoo SC, Snow RW, Yates SN, Kwiatkowski D et al (1995). Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376: 246–249. 7617034

15. Toure O, Konate S, Sissoko S, Niangaly A, Barry A et al (2012). Candidate polymorphisms and severe malaria in a Malian population. PLoS One. 27(9):e43987.

16. De Araujo C, Migot-Nabias F, Guitard J, Pelleau S, Vulliamy Tet al (2006). The role of the G6PD AEth376G/968C allele in glucose-6-phosphate dehydrogenase deficiency in the Seerer population of Senegal. Haematologica 91: 262–263. 16461316

17. Manjurano AM, Clark TG, Nadjm B, Mtove G, Wangai H et al (2012). Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. PLoS One. 7(10):e47463. doi: 10.1371/journal.pone.0047463 23144702

18. Bienzle U, Ayeni O, Lucas AO, Luzzatto L (1972). Glucose-6-phosphate dehydrogenase and malaria. Greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant. Lancet 1: 107–110. 4108978

19. MalariaGEN (2014). Reappraisal of known malaria resistance loci in a large multi-centre study. Nature Genetics, Sep 28. doi: 10.1038/ng.3107.

20. Town M, Bautista JM, Mason PJ, Luzzatto L (1992). Both mutations in G6PD A- are necessary to produce the G6PD deficient phenotype. Hum Mol Genet. 1992 Jun;1(3):171–4. 1303173

21. Garrigan D, Hammer MF (2006). Reconstructing human origins in the genomic era. Nature Reviews Genetics 7:669–680. 16921345

22. Luzzatto L (2012). G6PD deficiency and malaria selection. Heredity 108, 456; doi: 10.1038/hdy.2011.90 22009270

23. Leffler EM, Gao Z, Pfeifer S, Ségurel L, Auton A et al (2013). Multiple instances of ancient balancing selection shared between humans and chimpanzees. Science 339(6127):1578–82. doi: 10.1126/science.1234070 23413192

24. Luzzatto L, Usanga FA, Reddy S (1969). Glucose-6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science. 164(3881):839–42. 4889647

25. Cappadoro M, Giribaldi G, O'Brien E, Turrini F, Mannu F et al. (1998). Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 92: 2527–2534. 9746794

26. Sodeinde O, Clarke JL, Vulliamy TJ, Luzzatto L, Mason PJ (2003). Expression of Plasmodium falciparum G6PD-6PGL in laboratory parasites and inpatient isolates in G6PD-deficient and normal Nigerian children. Br. J. Haematol. 122:662–668. 12899722

27. Miller J, Golenser J, Spira DT, Kosower NS (1994). Plasmodium falciparum: thiol status and growth in normal and glucose-6-phosphate dehydrogenase deficient human erythrocytes. Exp Parasitol, 57:239–247.

28. Migeon BR, Kennedy JF (1975). Evidence for the inactivation of an X chromosome early in the development of the human female. Am J Hum Genet, 27:233–9; 1124767

29. Beutler E, Yeh M, Fairbanks VF (1962). The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A 48:9–16. 13868717

30. Battistuzzi G, Esan GJ, Fasuan FA, Modiano G, Luzzatto L (1977). Comparison of GdA and GdB activities in Nigerians. A study of the variation of the G6PD activity. Am J Hum Genet 29:31–36. 835573

31. LaRue N, Kahn M, Murray M, Leader BT, Bansil P et al (2014). Comparison of Quantitative and Qualitative Tests for Glucose-6-Phosphate Dehydrogenase Deficiency. Am J Trop Med Hygiene, in press.

32. Shah SS, Macharia A, Makale J, Uyoga S, Kivinen K et al (2014). Genetic determinants of glucose-6-phosphate dehydrogenase activity in Kenya. BMC Med Genet. Sep 9;15(1):93.

33. Ross P, Hall L, Smirnov I, Haff L (1998). High level multiplex genotyping by MALDI-TOF mass spectrometry. Nat Biotechnol 16:1347–1351. 9853617

34. Lake S, Lyon H, Silverman E, Weiss S, Laird N et al (2002). Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Human Heredity 55:56–65.

35. Clark TG, Campino SG, Teo YY, Small K, Auburn S et al (2010). A Bayesian approach to assess differences in linkage disequilibrium patterns in genomewide association studies. Bioinformatics 26:1999–2003. doi: 10.1093/bioinformatics/btq327 20554688

36. Tajima F (1989). The effect of change in population size on DNA polymorphism. Genetics 123:597–601. 2599369