Location of Repository

Genetic Determination and Linkage Mapping of Plasmodium falciparum Malaria Related Traits in Senegal

By Anavaj Sakuntabhai, Rokhaya Ndiaye, Isabelle Casadémont, Chayanon Peerapittayamonkol, Christophe Rogier, Patricia Tortevoye, Adama Tall, Richard Paul, Chairat Turbpaiboon, Waraphon Phimpraphi, Jean-Francois Trape, André Spiegel, Simon Heath, Odile Mercereau-Puijalon, Alioune Dieye and Cécile Julier


Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2295258
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles



    1. (2007). A largescale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
    2. (2001). A major determinant quantitative-trait locus responsible for atopic dermatitis-like skin lesions in NC/Nga mice is located on Chromosome 9.
    3. (2002). A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production.
    4. (2000). A second-generation genomewide screen for asthma-susceptibility alleles in a founder population.
    5. (2007). Analysis of candidate genes on chromosomes 5q and 19p in celiac disease.
    6. (2006). Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no Linkage,
    7. (2000). Ascaris lumbricoides infection is associated with protection from cerebral malaria.
    8. (2007). Association of autism with polymorphisms in the paired-like homeodomain transcription factor 1 (PITX1) on chromosome 5q31: a candidate gene analysis.
    9. (2002). Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children.
    10. (2000). Bayesian analysis of an epidemiologic model of Plasmodium falciparum malaria infection in Ndiop,
    11. (2001). Chromosomal mapping of the host resistance locus to rodent malaria (Plasmodium yoelii) infection in mice.
    12. (1996). Combating malaria morbidity and mortality by reducing transmission.
    13. (1987). Common genetic disorders of the red cell and the ‘malaria hypothesis’.
    14. (1996). Different response to Plasmodium falciparum malaria in west African sympatric ethnic groups.
    15. (2005). Early life risk factors for atopic dermatitis in Ethiopian children.
    16. (2004). Elevated anti-malarial IgE in asymptomatic individuals is associated with reduced risk for subsequent clinical malaria.
    17. (1997). Elevated plasma levels of IgE in Plasmodium falciparum-primed individuals reflect an increased ratio of IL-4 to interferon-gamma (IFN-gamma)-producing cells.
    18. (1994). Evidence for a locus regulating total serum IgE levels mapping to chromosome
    19. (1996). Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations.
    20. (2006). Fine mapping and positional candidate studies on chromosome 5p13 identify multiple asthma susceptibility loci.
    21. (1997). Four years’ entomological study of the transmission of seasonal malaria
    22. (2004). Functional variants of OCTN cation transporter genes are associated with Crohn disease.
    23. (2005). Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis.
    24. (2007). Genes at human chromosome 5q31.1 regulate delayed-type hypersensitivity responses associated with Leishmania chagasi infection.
    25. (1996). Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31-q33.
    26. (1995). Genetic regulation of fever in Plasmodium falciparum malaria in Gambian twin children.
    27. (2005). Genetic study of ICAM1 in clinical malaria in Senegal.
    28. (2007). Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease.
    29. (2002). Genome-wide multilocus analysis for immune-mediated complex diseases.
    30. (2006). Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort.
    31. (2004). Genomewide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis.
    32. (2001). Genomewide screen and identification of gene-gene interactions for asthmasusceptibility loci in three U.S. populations: collaborative study on the genetics of asthma.
    33. (2001). Helminth infections are associated with protection from malariarelated acute renal failure and jaundice in Thailand.
    34. (1999). Heritability and segregation analysis of immune responses to specific malaria antigens in Papua New Guinea.
    35. (2005). Heritability of malaria in Africa.
    36. (1997). High annual and seasonal variations in malaria transmission by anophelines and vector species composition in Dielmo, a holoendemic area in Senegal.
    37. (1996). High incidence of malaria in alpha-thalassaemic children.
    38. (2000). Host factors affecting the delay of reappearance of Plasmodium falciparum after radical treatment among a semi-immune population exposed to intense perennial transmission.
    39. (2005). How malaria has affected the human genome and what human genetics can teach us about malaria.
    40. (2003). Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren.
    41. (1998). Human malaria: segregation analysis of blood infection levels in a suburban area and a rural area in Burkina Faso.
    42. (1999). IgE and tumor necrosis factor in malaria infection.
    43. (1997). Immunoglobulin E, a pathogenic factor in Plasmodium falciparum malaria.
    44. (2001). Improved evidence for linkage on 6p and 5p with retrospective pooling of data from three asthma genome screens.
    45. (2004). Increase of malaria attacks among children presenting concomitant infection by Schistosoma mansoni in Senegal.
    46. (2003). Increased frequency of malaria attacks in subjects co-infected by intestinal worms and Plasmodium falciparum malaria.
    47. (2008). Inhibition of histamine-mediated signaling confers signifi cant protection against severe malaria in mouse models of disease.
    48. (2007). Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.
    49. (2004). Interleukin-1 gene cluster polymorphisms and susceptibility to clinical malaria in a Gambian case-control study.
    50. (1935). L’immunite ´, la pre ´munition et la re ´sistance inne ´e. Arch Inst Pasteur Alge ´rie XIII:
    51. (1998). Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31-q33 chromosome region.
    52. (2003). Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31-q33.
    53. (1998). Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33.
    54. (1995). Malaria: toxins, cytokines and disease.
    55. (2004). Mapping of a new quantitative trait locus for resistance to malaria in mice by a comparative mapping approach with human Chromosome 5q31-q33.
    56. (2002). Merlin–rapid analysis of dense genetic maps using sparse gene flow trees.
    57. (1990). Multipoint analysis of human quantitative genetic variation.
    58. (1998). Multipoint quantitative-trait linkage analysis in general pedigrees.
    59. (1995). Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria.
    60. (1993). Neutralizing monoclonal antibodies to glycosylphosphatidylinositol, the dominant TNF-alpha-inducing toxin of Plasmodium falciparum: prospects for the immunotherapy of severe malaria.
    61. (2001). Nitric oxide synthase 2(Lambarene) (G-954C), increased nitric oxide production, and protection against malaria.
    62. (1998). PedCheck: a program for identification of genotype incompatibilities in linkage analysis.
    63. (1999). Plasmodium falciparum clinical malaria: lessons from longitudinal studies in Senegal.
    64. (2005). Polymorphisms within the PHF11 gene at chromosome 13q14 are associated with childhood atopic dermatitis.
    65. (2003). Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma.
    66. (2002). Powerful regression-based quantitative-trait linkage analysis of general pedigrees.
    67. (2001). Prenatal risk factors of wheezing at the age of four years in Tanzania.
    68. (2006). Protective CD8+ T cells induced by malaria sporozoites do not undergo modulation of interleukin-7 receptor expression.
    69. (2007). Rapid Dissemination of Plasmodium falciparum Drug Resistance Despite Strictly Controlled Antimalarial Use.
    70. (1985). Rapid evaluation of malaria parasite density and standardization of thick smear examination for epidemiological investigations.
    71. (1996). Reducing the oral quininequinidine-cinchonin (Quinimax) treatment of uncomplicated malaria to three days does not increase the recurrence of attacks among children living in a highly endemic area of Senegal. Trans R Soc Trop Med Hyg 90:
    72. (2000). Robust LOD scores for variance component-based linkage analysis.
    73. (1994). Robust variance-components approach for assessing genetic linkage in pedigrees.
    74. (2000). Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster.
    75. (2005). Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases.
    76. (1949). The association of characters as a result of inbreeding and linkage.
    77. (1994). The Dielmo project: a longitudinal study of natural malaria infection and the mechanisms of protective immunity in a community living in a holoendemic area of Senegal.
    78. (1996). The future of genetic studies of complex human diseases.
    79. (2004). The IL12B gene is associated with asthma.
    80. (1993). The relative efficiency and power of smallpedigree studies of the heritability of a quantitative trait.
    81. (2005). Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis.
    82. (2005). Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families.
    83. (2004). Undernutrition as an underlying cause of malaria morbidity and mortality in children less than five years old.
    84. (2001). Variance component methods for detecting complex trait loci.
    85. (2007). Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.
    86. (1992). Whole genome amplification from a single cell: implications for genetic analysis.
    87. (2007). XLinked G6PD Deficiency Protects Hemizygous Males but Not Heterozygous Females against Severe Malaria.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.