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Heritability

How important is genetics for infectious disease susceptibility? Prior to spending time and resources in the search for genes contributing to susceptibility, it is

advisable to have an idea of the heritability of relevant phenotypes. Heritability is the proportion of the phenotypic variance due to genetic factors. For infectious diseases it is likely that host genetic diversity will be a major player for some disease outcomes, whereas pathogen or vector diversity will be of paramount importance for others. In general, heritability of susceptibility to infectious disease is not high and findings might be confounded by the difficulties of sorting genetic from shared household effects. Although there are uninfected individuals in areas with a high prevalence of CD, this is not necessarily genetic resistance and household and environmental risk factors need to be understood. Importantly, measures of heritability are time-, place-, and population-dependent. Some of the more robust estimates of heritability in the literature for infectious diseases, other than CD, do not concern genetic control of infection per se, but rather severity or particular manifestations of disease, sometimes many years after the original infection.

For CD, although there are indications of genetic involvement from mouse models, evidence from human studies has been limited. There are a number of indications that may point to a genetic component to any disease, and a number of ways of measuring heritability. Historically, racial differences in susceptibility might have suggested genetic involvement, as is the case for cutaneous leishmaniasis. CD is often prevalent in populations that are racially mixed, but this does not necessarily give clarity and no comments on racial differences in susceptibility appear in the literature. The first measures of heritability for many diseases came from the use of twin studies, where twins are either concordant or discordant for disease. There are few references with any mention of twins in the CD literature. These refer to disease progression in individual twin pairs rather than assessing cohorts of twins.5 The infrequency of “family studies” in the CD literature is particularly relevant here. There were early estimates of a heritable component to immunoglobulin levels in a CD-infected Brazilian population6 and an effect of sibling history on Chagas-associated cardiopathy.7 The involvement in the early 1980s of one of the world’s most eminent human geneticists, Newton Morton, is notable.6 Subsequent substantial work that was carried out in this area for CD is by Williams-Blangero et al.4,8 In a study of seropositivity for T. cruzi in 716 Brazilian adults, 525 of whom were assigned to 146 pedigrees, an estimate of the heritability of infection of 56% was obtained, with a further 23% of the variation due to shared environment/ common household.8 A more recent study by Silva-Grecco et al., also in Brazil, looked at 41 families with 526 individuals and found evidence of familial clustering of seropositivity to T. cruzi, with 15 families showing seropositivity in >50% of individuals.9 A sporadic model of seropositivity was clearly rejected, although the causes of familial aggregation could not be established. They also considered cardiomyopathy in a subset of families, with 6 families showing cardiomyopathy in > 50% of individuals.

Whilst most work has focused on qualitative traits, Williams-Blangero et al. have analyzed quantitative traits to determine heritabilities for seropositivity and traits obtained from ECGs, in an ongoing longitudinal study of >1300 individuals.4 The heritability for seropositivity to T. cruzi rose from 56%, obtained using a dichotomous trait, to 64%. ECG-related traits were also highly heritable, though

surprisingly less heritable than seropositivity. A subsequent question concerns whether putative genes control more than one of the traits. There was no good evidence that genes controlling seropositivity also controlled cardiovascular traits.4

In the context of heritability of susceptibility to infectious disease per se, an estimate of 56% is very high. However such high heritabilities have been calculated sometimes for immunoglobulin/antibody levels. Nevertheless this high estimate gives some cause for optimism that a hunt for genes might be worthwhile.

 
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