Association study between CCR2-CCR5 genes polymorphisms and chronic Chagas heart disease in Wichi and in admixed populations from Argentina

Abstract

Several studies have proposed different genetic markers of susceptibility to develop chronic Chagas cardiomyopathy (CCC). Many genes may be involved, each one making a small contribution. For this reason, an appropriate approach for this problematic is to study a large number of single nucleotide polymorphisms (SNPs) in individuals sharing a genetic background. Our aim was to analyze two CCR2 and seven CCR5 SNPs and their association to CCC in Argentina. A case-control study was carried out in 480 T. cruzi seropositive adults from Argentinean Gran Chaco endemic region (Wichi and Creole) and patients from Buenos Aires health centres. They were classified according to the Consensus on Chagas-Mazza Disease as non-demonstrated (non-DC group) or demonstrated (DC group) cardiomyopathy, i.e. asymptomatic or with CCC patients, respectively. Since, after allelic analysis, 2 out of 9 studied SNPs did not fit Hardy–Weinberg equilibrium in the unaffected non-DC group from Wichi patients, we analyzed them as a separate population. Only rs1800024T and rs41469351T in CCR5 gene showed significant differences within non-Wichi population (Creole + patients from Buenos Aires centres), being the former associated to protection, and the latter to risk of CCC. No evidence of association was observed between any of the analyzed CCR2-CCR5 gene polymorphisms and the development of CCC; however, the HHE haplotype was associated with protection in Wichi population. Our findings support the hypothesis that CCR2-CCR5 genes and their haplotypes are associated with CCC; however, depending on the population studied, different associations can be found. Therefore, the evolutionary context, in which the genes or haplotypes are associated with diseases, acquires special relevance.

Narrowing the Relationship between Human CCR5 Gene Polymorphisms and Chagas Disease: Systematic Review and Meta-Analysis

“…Our global analysis of the rs1799988 polymorphism did not find differences between the analyzed groups, but in the analysis of the subgroup of countries formed after Spanish colonization [10,26,28], the codominance model showed an association between the homozygous T/T genotype and the cardiac form of CD, while the recessiveness model associated the same T/T genotype with the cardiac form. Unlike our findings, Nogueira et al [25] identified an increased C/C genotype and C allele in the cardiac group (CCC) compared to the moderate group.…”

“…Machuca and others [28] have already established a relationship between the G allele and some degree of CCC severity, supporting our results. The rs1800024 SNP indicated the T allele as a risk factor for cardiomyopathy in CD, also previously suggested by Juiz and coauthors [26], although different from the results of Machuca et al [28], which related the allele with the severity of the disease.…”

“…The analysis of the generated graphs suggested a correlation between the A allele and the A/A genotype, as well as suggesting a correlation between the G allele and the G/G genotype, while there was a distancing of the A/G genotype from these two groups (Figure 3a). Although the global comparison between cardiac patients vs. asymptomatic patients showed no difference between the groups, when the analysis was limited to patients from countries originating from Spanish colonization, [9,10,[26][27][28], n = 1404, CardCP = 716/ UndCP = 688), in the recessiveness model (G/G vs. G/A + A/A), the G/G genotype was associated with the risk of developing the cardiac form (p = 0.04, OR = 1.38, 95% CI (1.02-1.85), I 2 = 53%, fixed model), as shown in Figure 2c. Other statistical associations were not found.…”

T-Cell Subpopulations Exhibit Distinct Recruitment Potential, Immunoregulatory Profile and Functional Characteristics in Chagas versus Idiopathic Dilated Cardiomyopathies

“…The upregulation of CCR5 in CD8 + T-cells from T. cruziinfected mice has been associated with tissue damage (81,82). Genetic variants of CCR5 have been associated with human Chagas disease (83), and high CCR5 expression by leukocytes has also been associated with severe CCC (27,84). The analysis of CCR5 expression frequency showed a high frequency of CD4 + , CD8 + and TCRgamma-delta+ DN T-cells expressing this molecule in CCC compared to IDC.…”

Genetic Basis of Myocarditis: Myth or Reality?

“…Genetic susceptibility to the development of CCC is a matter of ongoing investigation of immunity genes to identify possible individual and population-based predisposition. Table 4.3 [83][84][85][86][87][88][89][90][91] lists the genes and related variants investigated to date in CD. Although some association studies tested positive, no genetic test is currently performed in the diagnostic work-up of CD.…”