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

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.

Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection.

We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case-control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease (P=0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P. falciparum infection levels.

Host genetics and parasitic infections.

Parasites still impose a high death and disability burden on human populations, and are therefore likely to act as selective factors for genetic adaptations. Genetic epidemiological investigation of parasitic diseases is aimed at disentangling the mechanisms underlying immunity and pathogenesis by looking for associations or linkages between loci and susceptibility phenotypes. Until recently, most studies used a candidate gene approach and were relatively underpowered, with few attempts at replicating findings in different populations. However, in the last 5 years, genome-wide and/or multicentre studies have been conducted for severe malaria, visceral leishmaniasis, and cardiac Chagas disease, providing some novel important insights. Furthermore, studies of helminth infections have repeatedly shown the involvement of common loci in regulating susceptibility to distinct diseases such as schistosomiasis, ascariasis, trichuriasis, and onchocherciasis. As more studies are conducted, evidence is increasing that at least some of the identified susceptibility loci are shared not only among parasitic diseases but also with immunological disorders such as allergy or autoimmune disease, suggesting that parasites may have played a role in driving the evolution of the immune system.