Parasitic diseases have exerted major selective pressures on human populations. However, these are common multifactorial diseases in which susceptibility determined by human genetic variation is only part of a much more complex scenario involving multiple environmental factors as well as genetic diversity in the parasite and vector. It is remarkable that inherited factors have been defined at all, given the inherent difficulties of interrogating the genetic basis of common multifactorial disease. Yet the magnitude of effects observed for several genetic variants is substantial with selective advantage driving allele frequencies to high levels, in some populations to fixation as seen for the Duffy antigen receptor in West Africa. The malaria hypothesis advocated by Haldane in which selective advantage of heterozygotes has driven alleles to high frequency despite deleterious effects of the variant allele in the homozygous state has been reviewed for thal-assaemia and Hb S. Hb C, found predominantly in central West Africa, appears to be rising in allele frequency with unidirectional positive selection and no apparent deleterious phenotype in the homozygous form.

The evidence to support a role for genetic variation in determining malaria susceptibility have been highlighted here by the striking examples of particular ethnic groups showing increased resistance to malaria such as the Tharu of Nepal or Fulani of West Africa. The correlation by latitude and altitude of a+ thalassaemia and malaria endemicity, as well as geographic variation observed for allele frequencies of Hb S, G6PD, Duffy blood group antigen, and other variants is a remarkable testament to the power of selection exerted by malaria. Equally remarkable is the elegance of some of the underlying molecular mechanisms by which functional variants exert their effects which in some instances have been elucidated, notably for the promoter SNP regulating expression of the Duffy blood group antigen which controls entry to red blood cells of the P. vivax parasite. We have seen how the parasite is not an idle bystander in this process, varying the surface antigen PfEMPI to avoid immune detection and producing G6PD, which may be significant given the role of inherited G6PD deficiency in protection from severe malaria. Diversity in the human receptors for the PfEMPI ligand such as ICAM1 are important determinants of susceptibility, as is diversity in other immune genes such as HLA-B53 encoding MHC class I molecules.

The range of genes involved in malaria susceptibility, and geographic variation in sites where specific genetic variants are thought to have arisen, or be significant, again reinforces the ongoing selective pressure exerted by this infectious disease. For other parasitic diseases genetic variation has also been shown to be highly significant, as illustrated here for leishmaniasis and helminth i nfections. Again these are striking examples, in leishmaniasis highlighting the role mouse studies can play in defining susceptibility and resistance genes while in Ascaris infections the remarkable power of pedigree analysis for the Jirel population in Nepal was shown. It is notable how linkage analyses in leishmaniasis and helminth infections, including ascariasis and schisto-somiasis, have proved powerful approaches despite the inherent difficulties of applying this approach to complex traits (Section 2.3.5). The application of genome-wide association studies to malaria and other parasitic diseases is awaited with interest.

The elucidation of the role of human genetic variation in susceptibility to infectious disease should continue to provide new insights into disease pathogenesis, ranging from the process of red cell invasion and parasite multiplication, to immune recognition and sequestration. New opportunities for intervention, in terms of vaccine and drug development, are provided by such studies while targeting of specific treatments to individual patients is a further longer term objective. The multifaceted interaction between man and parasites continues. Future study of our variable genomes should continue to increase our understanding of susceptibility to parasitic disease, hopefully leading to better treatments for millions of the world's poorest people still plagued by such diseases.

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