Mechanisms of genetically-based resistance to malaria.

Atopic diseases, including asthma, allergic rhinitis, and atopic dermatitis, are caused by environmental factors in genetically predisposed individuals. Although the prevalence of these diseases has risen dramatically over the past two decades, it has been difficult to identify the underlying causes of these diseases due to the complex interplay between the genetic and environmental factors involved. Using a congenic mouse model of asthma, we simplified this complex trait and identified the novel T cell immunoglobulin domain, mucin-like domain (TIM) gene family, that encodes transmembrane proteins expressed by CD4 T cells. Recent studies demonstrate that the TIM family, particularly TIM-1, plays a critical role in immune responses that regulate the development of atopic diseases. In humans, certain polymorphic variants of TIM-1 are strongly associated with protection against atopy, and this association occurs only in individuals who have had past infection with hepatitis A virus (HAV). Since TIM-1 functions as the cellular receptor for HAV, activation of T cells through TIM-1 by HAV or by its natural ligand may affect T cell differentiation and the development of Th2-driven allergic inflammatory responses. Epidemiologically, HAV infection is associated with a reduced risk of developing atopy, and because the incidence of HAV infection has been significantly reduced in industrialized countries over the past 30 years, the discovery of a genetic interaction between HAV and TIM-1 provides the first molecular genetic evidence for the hygiene hypothesis.

TIM-1, a novel allergy and asthma susceptibility gene.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.

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Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics

Genetic predisposition to malaria has been shown by epidemiological, case–control and linkage studies. In particular, case–control studies have recently shown association between hemoglobin C and resistance to severe malaria in Mali and to clinical malaria in Burkina Faso. In a longitudinal study of families living in an endemic area, we investigated whether hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. We surveyed 256 individuals (71 parents and 185 sibs) from 53 families during 2 years. Hemoglobin C carriers had less frequent malaria attacks than AA individuals within the same age group (P ¼ 0.01). Since age correlated with malaria attack and parasitemia (P < 0.0001), we took age into account in association analyses. We performed combined linkage and association analyses, which avoid biases due to population structure. Using multi-allelic tests, we evidenced association between hemoglobin genotype and phenotypes related to malarial infection and disease (P < 0.001). We further analyzed individual hemoglobin alleles and detected negative association between hemoglobin C and malaria attack (P ¼ 0.00013). Analyses that took into account confounding factors confirmed the negative association of hemoglobin C with malaria attack (P ¼ 0.0074) and evidenced a negative correlation between hemoglobin C and parasitemia (P ¼ 0.0009). These associations indicate that hemoglobin C reduces parasitemia and confers protection against mild malaria attack.

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Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack

Plasmodium falciparum represents one of the strongest selective forces on the human genome. This stable and perennial pressure has contributed to the progressive accumulation in the exposed populations of genetic adaptations to malaria. Descriptive genetic epidemiology provides the initial step of a logical procedure of consequential phases spanning from the identification of genes involved in the resistance/susceptibility to diseases, to the determination of the underlying mechanisms and finally to the possible translation of the acquired knowledge in new control tools. In malaria, the rational development of this strategy is traditionally based on complementary interactions of heterogeneous disciplines going from epidemiology to vaccinology passing through genetics, pathogenesis and immunology. New tools including expression profile analysis and genome-wide association studies are recently available to explore the complex interactions of host-parasite co-evolution. Particularly, the combination of genome-wide association studies with large multi-centre initiatives can overcome the limits of previous results due to local population dynamics. Thus, we anticipate substantial advances in the interpretation and validation of the effects of genetic variation on malaria susceptibility, and thereby on molecular mechanisms of protective immune responses and pathogenesis.

Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies.

Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31–q33

A genome-wide scan was conducted for the levels of total immunoglobulin G (IgG) and IgG subclasses directed against Plasmodium falciparum antigens in an urban population living in Burkina Faso. Non-parametric multipoint linkage analysis provided three chromosomal regions with genome-wide significant evidence (logarithm of the odds (LOD) score >3.6), and five chromosomal regions with genome-wide suggestive evidence (LOD score >2.2). IgG3 levels were significantly linked to chromosomes 8p22-p21 and 20q13, whereas IgG4 levels were significantly linked to chromosome 9q34. In addition, we detected suggestive linkage of IgG1 levels to chromosomes 18p11-q12 and 18q12-q21, IgG4 levels to chromosomes 1p31 and 12q24 and IgG levels to chromosome 6p24-p21. Moreover, we genotyped genetic markers located within the regions of interest in a rural population living in Burkina Faso. We detected genome-wide significant and suggestive linkage results when combining the two study populations for chromosomes 1p31, 6p24-p21, 8p22-p21, 9q34, 12q24 and 20q13. Because high anti-parasite IgG3 and low anti-parasite IgG4 levels were associated with malaria resistance, the chromosomal regions linked to IgG3 and IgG4 levels are of special interest. Although the results should be confirmed in an independent population, they may provide new insights in understanding both the genetic control of IgG production and malaria resistance.

Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

There is accumulating evidence of host genetic control in malaria infection and, in humans, some genes have been associated with severe malaria. Nevertheless, other important genes controlling blood infection levels, malarial disease and immune responses are likely to be identified. In this paper, we focus on segregation and linkage analyses of blood infection levels in an urban population living in Burkina Faso. We found evidence of a complex genetic control and a linkage to chromosome 5q31-q33. The identification of genes controlling complex traits related to malaria infection should be helpful in understanding protective mechanisms and the relationship between infection, malaria attacks and severe malaria.

B Kumulungui

Papers

Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31–q33

Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13

Genetic dissection of plasmodium falciparum blood infection levels and other complex traits related to human malaria infection