Home Economics American Trypanosomiasis Chagas Disease, Second Edition: One Hundred Years of Research
Genetic associations from candidate gene studies to date
Recent reviews of human genetic susceptibility to CD and CCC have catalogued reported associations, in some cases listing associated alleles and significance
levels.18-21 Since it is early in the investigation of susceptibility to CD, few firm conclusions can be drawn, and because of some of the issues outlined above, this chapter merely attempts to summarize available publications.
The tables list studies to date. They may include studies with elements of replication, where results are not repeated, or studies with patient cohorts in common, but reporting some additional information.22,23 Phenotypes listed include “seronega- tives,” where seronegatives are usually presumed to be exposed but not to have had CD, and may also include untested “healthy controls” who would be presumed to be seronegative but from an endemic area, hence exposed. “Asymptomatics” are seropositive and assumed to have had acute infection, and include those categorized as indeterminate. The numbers listed for each of the phenotypes shows the size of the studies and also provides an indication of the questions addressed by the authors, e.g., susceptibility to infection and CD per se through comparison of aysmptomatics with seronegatives, or susceptibility to forms of chronic disease through comparison of these with asymptomatics. It is notable that the most commonly studied chronic form is CCC.
Although more recent investigations often use larger sample sizes, many studies are relatively small and low powered, particularly for considering multiallelic systems or uninformative markers. Associations, whether listed in the tables or described in the text, are as reported by the authors, irrespective of the analytical and statistical methodology employed. The following summaries indicate that investigators have made a good start in the field of human genetic susceptibility to CD.
There are a number of studies where HLA class I and class II genotyping has been carried out, in several countries, some with ethnically mixed populations, as summarized in Table 27.1. Because of the high diversity in this region of the genome, the majority of recent studies have genotyped using sequence specific oligonucleotide probes (SSO). Problems of sampling and genotyping have led to some minor inconsistencies in the literature, even in serial publications from the same country.23 Both susceptibility to CD per se, by comparison of genotypic distributions in seronega- tives versus asymptomatic individuals, and susceptibility to severe disease, by comparison of genotypic distributions in asymptomatics versus those with manifestations of chronic disease, have been tested. Due to the presence of LD between potentially “causative” loci, examination of haplotypes is useful, but has only been employed in a handful of studies (Tables 27.1 and 27.2).29,48 Some have approximated haplotypic analyses, e.g., a very early study by Llop et al. found HLA- B49 conferred protection against CCC in the presence of HLA-Cw3.26 Similarly, the later study of the class II region by Colorado et al. considered combinations of alleles.35 Detailed analyses are sometimes precluded by small sample sizes, and hampered by lack of adequately matched controls.32
Table 27.1 The major histocompatibilty complex class I, class II, and related loci
Table 27.1 (Continued)
Table 27.2 The major histocompatibilty complex continued class III
The less polymorphic HLA-G, MICA, and MICB have also been studied,24’28’29 as have the Killer cell Immunoglobulin-like Receptor (KIR) loci on chromosome 19, together with the genes coding for their HLA ligands on chromosome 6.27 A Spanish study examined HLA associations with cutaneous reactions to benznida- zole, used to treat CD.1,11,37
Although there is no consistent pattern of associations for either class I or class II loci, it seems likely that further investigations will prove useful. Of course bona fide associations with the MHC would carry clear biological implications, e.g., suggest the importance of a key pathogenic epitope triggering autoimmunity, restricted by a single HLA specificity.
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