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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Aug;63(2):498–505. doi: 10.1086/301967

Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33.

P Rihet 1, Y Traoré 1, L Abel 1, C Aucan 1, T Traoré-Leroux 1, F Fumoux 1
PMCID: PMC1377308  PMID: 9683598

Abstract

Plasmodium falciparum malaria remains a major cause of morbidity and mortality in many tropical countries, especially those in sub-Saharan Africa. Human genetic control of malaria infection is poorly understood; in particular, genes controlling P. falciparum blood infection levels remain to be identified. We recently evidenced the existence of complex genetic factors controlling blood infection levels in an urban population living in Burkina Faso. We performed, on 153 sibs from 34 families, sib-pair linkage analyses between blood infection levels and chromosome 5q31-q33, which contains numerous candidate genes encoding immunological molecules. Our results, obtained by means of the two-point Haseman-Elston (HE) method and a nonparametric (NP) approach, show linkage of parasitemia to D5S393 (P=.002) and D5S658 (P=.0004). Multipoint analyses confirmed linkage, with a peak close to D5S658 (P=.0013 and P=.0007 with the HE and NP methods, respectively). The heritability of the locus was .48, according to the two-point results, and .43, according to the multipoint results; this indicates that its variation accounted for approximately 45% of the variance of blood infection levels and that the locus plays a central role in the control of parasitemia. The identification of the gene is, therefore, of major interest in understanding the mechanisms controlling P. falciparum parasitemia.

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Selected References

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  1. Abbas A. K., Murphy K. M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Abel L., Cot M., Mulder L., Carnevale P., Feingold J. Segregation analysis detects a major gene controlling blood infection levels in human malaria. Am J Hum Genet. 1992 Jun;50(6):1308–1317. [PMC free article] [PubMed] [Google Scholar]
  3. Bouharoun-Tayoun H., Oeuvray C., Lunel F., Druilhe P. Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. J Exp Med. 1995 Aug 1;182(2):409–418. doi: 10.1084/jem.182.2.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Butler D., Maurice J., O'Brien C. Time to put malaria control on the global agenda. Nature. 1997 Apr 10;386(6625):535–536. doi: 10.1038/386535a0. [DOI] [PubMed] [Google Scholar]
  5. Chandrasekharappa S. C., Rebelsky M. S., Firak T. A., Le Beau M. M., Westbrook C. A. A long-range restriction map of the interleukin-4 and interleukin-5 linkage group on chromosome 5. Genomics. 1990 Jan;6(1):94–99. doi: 10.1016/0888-7543(90)90452-z. [DOI] [PubMed] [Google Scholar]
  6. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  7. Ferrante A., Kumaratilake L., Rzepczyk C. M., Dayer J. M. Killing of Plasmodium falciparum by cytokine activated effector cells (neutrophils and macrophages). Immunol Lett. 1990 Aug;25(1-3):179–187. doi: 10.1016/0165-2478(90)90112-4. [DOI] [PubMed] [Google Scholar]
  8. Foote S. J., Burt R. A., Baldwin T. M., Presente A., Roberts A. W., Laural Y. L., Lew A. M., Marshall V. M. Mouse loci for malaria-induced mortality and the control of parasitaemia. Nat Genet. 1997 Dec;17(4):380–381. doi: 10.1038/ng1297-380. [DOI] [PubMed] [Google Scholar]
  9. Fortin A., Belouchi A., Tam M. F., Cardon L., Skamene E., Stevenson M. M., Gros P. Genetic control of blood parasitaemia in mouse malaria maps to chromosome 8. Nat Genet. 1997 Dec;17(4):382–383. doi: 10.1038/ng1297-382. [DOI] [PubMed] [Google Scholar]
  10. Garcia A., Cot M., Chippaux J. P., Ranque S., Feingold J., Demenais F., Abel L. Genetic control of blood infection levels in human malaria: evidence for a complex genetic model. Am J Trop Med Hyg. 1998 Apr;58(4):480–488. doi: 10.4269/ajtmh.1998.58.480. [DOI] [PubMed] [Google Scholar]
  11. Haseman J. K., Elston R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav Genet. 1972 Mar;2(1):3–19. doi: 10.1007/BF01066731. [DOI] [PubMed] [Google Scholar]
  12. Hill A. V., Allsopp C. E., Kwiatkowski D., Anstey N. M., Twumasi P., Rowe P. A., Bennett S., Brewster D., McMichael A. J., Greenwood B. M. Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991 Aug 15;352(6336):595–600. doi: 10.1038/352595a0. [DOI] [PubMed] [Google Scholar]
  13. Hill A. V. Genetic susceptibility to malaria and other infectious diseases: from the MHC to the whole genome. Parasitology. 1996;112 (Suppl):S75–S84. doi: 10.1017/s003118200007668x. [DOI] [PubMed] [Google Scholar]
  14. Hoffman S. L., Crutcher J. M., Puri S. K., Ansari A. A., Villinger F., Franke E. D., Singh P. P., Finkelman F., Gately M. K., Dutta G. P. Sterile protection of monkeys against malaria after administration of interleukin-12. Nat Med. 1997 Jan;3(1):80–83. doi: 10.1038/nm0197-80. [DOI] [PubMed] [Google Scholar]
  15. Jepson A., Banya W., Sisay-Joof F., Hassan-King M., Nunes C., Bennett S., Whittle H. Quantification of the relative contribution of major histocompatibility complex (MHC) and non-MHC genes to human immune responses to foreign antigens. Infect Immun. 1997 Mar;65(3):872–876. doi: 10.1128/iai.65.3.872-876.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jepson A., Sisay-Joof F., Banya W., Hassan-King M., Frodsham A., Bennett S., Hill A. V., Whittle H. Genetic linkage of mild malaria to the major histocompatibility complex in Gambian children: study of affected sibling pairs. BMJ. 1997 Jul 12;315(7100):96–97. doi: 10.1136/bmj.315.7100.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996 Jun;58(6):1347–1363. [PMC free article] [PubMed] [Google Scholar]
  18. Kruglyak L., Lander E. S. High-resolution genetic mapping of complex traits. Am J Hum Genet. 1995 May;56(5):1212–1223. [PMC free article] [PubMed] [Google Scholar]
  19. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  20. Marquet S., Abel L., Hillaire D., Dessein H., Kalil J., Feingold J., Weissenbach J., Dessein A. J. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat Genet. 1996 Oct;14(2):181–184. doi: 10.1038/ng1096-181. [DOI] [PubMed] [Google Scholar]
  21. Marsh D. G., Neely J. D., Breazeale D. R., Ghosh B., Freidhoff L. R., Ehrlich-Kautzky E., Schou C., Krishnaswamy G., Beaty T. H. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994 May 20;264(5162):1152–1156. doi: 10.1126/science.8178175. [DOI] [PubMed] [Google Scholar]
  22. McGuire W., Hill A. V., Allsopp C. E., Greenwood B. M., Kwiatkowski D. Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994 Oct 6;371(6497):508–510. doi: 10.1038/371508a0. [DOI] [PubMed] [Google Scholar]
  23. Metcalf D. Control of granulocytes and macrophages: molecular, cellular, and clinical aspects. Science. 1991 Oct 25;254(5031):529–533. doi: 10.1126/science.1948028. [DOI] [PubMed] [Google Scholar]
  24. Meyers D. A., Postma D. S., Panhuysen C. I., Xu J., Amelung P. J., Levitt R. C., Bleecker E. R. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics. 1994 Sep 15;23(2):464–470. doi: 10.1006/geno.1994.1524. [DOI] [PubMed] [Google Scholar]
  25. Miller L. H., Good M. F., Milon G. Malaria pathogenesis. Science. 1994 Jun 24;264(5167):1878–1883. doi: 10.1126/science.8009217. [DOI] [PubMed] [Google Scholar]
  26. Miller L. H. Malaria. Protective selective pressure. Nature. 1996 Oct 10;383(6600):480–481. doi: 10.1038/383480a0. [DOI] [PubMed] [Google Scholar]
  27. Müller-Myhsok B., Stelma F. F., Guissé-Sow F., Muntau B., Thye T., Burchard G. D., Gryseels B., Horstmann R. D. Further evidence suggesting the presence of a locus, on human chromosome 5q31-q33, influencing the intensity of infection with Schistosoma mansoni. Am J Hum Genet. 1997 Aug;61(2):452–454. doi: 10.1016/S0002-9297(07)64073-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Naotunne T. S., Karunaweera N. D., Del Giudice G., Kularatne M. U., Grau G. E., Carter R., Mendis K. N. Cytokines kill malaria parasites during infection crisis: extracellular complementary factors are essential. J Exp Med. 1991 Mar 1;173(3):523–529. doi: 10.1084/jem.173.3.523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nicolaides N. C., Holroyd K. J., Ewart S. L., Eleff S. M., Kiser M. B., Dragwa C. R., Sullivan C. D., Grasso L., Zhang L. Y., Messler C. J. Interleukin 9: a candidate gene for asthma. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13175–13180. doi: 10.1073/pnas.94.24.13175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Postma D. S., Bleecker E. R., Amelung P. J., Holroyd K. J., Xu J., Panhuysen C. I., Meyers D. A., Levitt R. C. Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med. 1995 Oct 5;333(14):894–900. doi: 10.1056/NEJM199510053331402. [DOI] [PubMed] [Google Scholar]
  31. Ramer-Quinn D. S., Baker R. A., Sanders V. M. Activated T helper 1 and T helper 2 cells differentially express the beta-2-adrenergic receptor: a mechanism for selective modulation of T helper 1 cell cytokine production. J Immunol. 1997 Nov 15;159(10):4857–4867. [PubMed] [Google Scholar]
  32. Ruwende C., Khoo S. C., Snow R. W., Yates S. N., Kwiatkowski D., Gupta S., Warn P., Allsopp C. E., Gilbert S. C., Peschu N. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995 Jul 20;376(6537):246–249. doi: 10.1038/376246a0. [DOI] [PubMed] [Google Scholar]
  33. Saltman D. L., Dolganov G. M., Warrington J. A., Wasmuth J. J., Lovett M. A physical map of 15 loci on human chromosome 5q23-q33 by two-color fluorescence in situ hybridization. Genomics. 1993 Jun;16(3):726–732. doi: 10.1006/geno.1993.1254. [DOI] [PubMed] [Google Scholar]
  34. Sjöberg K., Lepers J. P., Raharimalala L., Larsson A., Olerup O., Marbiah N. T., Troye-Blomberg M., Perlmann P. Genetic regulation of human anti-malarial antibodies in twins. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2101–2104. doi: 10.1073/pnas.89.6.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stevenson M. M., Lyanga J. J., Skamene E. Murine malaria: genetic control of resistance to Plasmodium chabaudi. Infect Immun. 1982 Oct;38(1):80–88. doi: 10.1128/iai.38.1.80-88.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Troye-Blomberg M., Berzins K., Perlmann P. T-cell control of immunity to the asexual blood stages of the malaria parasite. Crit Rev Immunol. 1994;14(2):131–155. doi: 10.1615/critrevimmunol.v14.i2.20. [DOI] [PubMed] [Google Scholar]
  37. Troye-Blomberg M., Riley E. M., Kabilan L., Holmberg M., Perlmann H., Andersson U., Heusser C. H., Perlmann P. Production by activated human T cells of interleukin 4 but not interferon-gamma is associated with elevated levels of serum antibodies to activating malaria antigens. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5484–5488. doi: 10.1073/pnas.87.14.5484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Warrington J. A., Bailey S. K., Armstrong E., Aprelikova O., Alitalo K., Dolganov G. M., Wilcox A. S., Sikela J. M., Wolfe S. F., Lovett M. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics. 1992 Jul;13(3):803–808. doi: 10.1016/0888-7543(92)90156-m. [DOI] [PubMed] [Google Scholar]
  39. de Vries J. E. Molecular and biological characteristics of interleukin-13. Chem Immunol. 1996;63:204–218. [PubMed] [Google Scholar]

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