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Human genetic susceptibility to Chagas disease

M.-A. Shaw

University of Leeds, St James's University Hospital, Leeds, United Kingdom

Chapter Outline

Phenotypes for study 629 Heritability 630 Candidate gene studies 632

Genetic associations from candidate gene studies to date 633 HLA 634

Focusing on the MHC class III region 638 Chemokines and their receptors 638 Cytokines and their receptors 639 Other genes 642

Genome-wide association studies 644 The future 645 References 646

Why should we study the genetics of susceptibility to Chagas disease (CD) and associated traits such as cardiomyopathy? At one level, this is to improve our basic knowledge of the biology of disease processes in a range of population groups and settings. In a more practical sense we would hope studies would contribute to development of diagnostic biomarkers and new therapeutics.

Phenotypes for study

There are a number of phenotypes that have been used in genetic studies of CD. Broadly speaking investigations have been focused on two questions: firstly concerning genetic control of infection per se as the phenotype, and secondly on genetic control of chronic disease phenotypes. One advantage of addressing host genetic susceptibility, as opposed to, e.g., immunological questions, is that it is not necessary to enroll cases showing active disease and under treatment as “susceptible.” Nevertheless, for CD, active cases have often been recruited.

With respect to infectious disease, an individual defined as resistant must necessarily have been exposed. Whereas scientists working in highly endemic areas may

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be confident that recruits have been exposed, this cannot be taken as a certainty. Many studies employ anti-Trypanosoma cruzi antibody levels to classify individuals as seropositive or seronegative. Those who are seropositive will have had the acute phase and entered into the chronic phase of disease. Some studies, less satisfactorily, will use “healthy controls” rather than individuals tested as seronegative, although both groups are relying on individuals being exposed.

Of those individuals for whom disease progresses from a quiescent phase and enters into the chronic phase, the most common phenotype studied is that of cardiomyopathy (CCC). Since 20—30% of infected people may develop CCC, the numbers available for study should not be limiting. In a few instances the information from electrocardiograms (ECGs), used to diagnose CCC, is employed directly as pheno- types.1 Other phenotypes used for the chronic forms of disease include digestive forms and mixed cardiomyopathic and digestive forms. Since such conditions develop over many years, control groups should be carefully matched for age and sex.

A phenotype receiving little attention, which we might speculate has a genetic component to susceptibility, is congenital CD. Whereas congenital transmission can occur during acute and chronic stages of infection, the majority of cases occur from chronically infected mothers. The transmission rate has been estimated to be 5%, although rates vary across South American countries, which could be due to a number of variables including population diversity.2,3

Other phenotypes that have occasionally been used in the context of CD progression include survival analysis and responses to drugs, since the main drugs prescribed, nifurtimox and bedznidazole, have associated adverse side effects.1 However, the vast majority of the work on susceptibility to CD and disease progression, and the work reviewed here, have been carried out using qualitative, usually dichotomous, traits, such as seropositivity versus seronegativity, or presence or absence of cardiomyopathy. For the future, it is worth considering that use of quantitative traits may more accurately reflect disease states.4

In the context of CD, family studies are not common. This limits genetic analyses to case control studies. Family studies are useful for establishing the magnitude of the genetic component of disease. Fortunately, traditional linkage-based approaches for identification of regions of the genome controlling disease susceptibility, requiring family details, are no longer commonly employed in studies of multifactorial disorders, i.e., those controlled by multiple genes plus the environment. Similarly, there is a dearth of longitudinal studies. Longitudinal studies would be especially beneficial for studies of phenotypes relating to disease progression. Many of the studies in the literature for other infectious diseases, have focused on severe consequences of infection. Identifying individuals at high risk of severe consequences or chronic disease, such as CCC, ultimately would enable resources to be targeted to this subset of patients.

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