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Association study between CCR2-CCR5 genes polymorphisms and chronic Chagas heart disease in Wichi and in admixed
Natalia Anahí Juiz1, Elkyn Estupiñán2, Daniel Hernández3
1INGEBI-CONICET, Buenos Aires, Argentina.
Insights
Genetic variations in CCR5 influence chronic Chagas cardiomyopathy (CCC) risk and protection. Specific single nucleotide polymorphisms (SNPs) and haplotypes show population-dependent associations with CCC development.
Area of Science:
- Genetics
- Immunology
- Infectious Diseases
Background:
- Chronic Chagas cardiomyopathy (CCC) susceptibility is multifactorial, potentially involving numerous genes with small effects.
- Studying single nucleotide polymorphisms (SNPs) in genetically similar populations is a key strategy for identifying disease susceptibility markers.
- The CCR2 and CCR5 genes are implicated in immune responses and may play a role in Chagas disease progression.
Purpose of the Study:
- To investigate the association between specific CCR2 and CCR5 gene single nucleotide polymorphisms (SNPs) and chronic Chagas cardiomyopathy (CCC) in an Argentinean population.
- To analyze the potential role of these genetic markers in differentiating between asymptomatic individuals and those with CCC.
Main Methods:
- A case-control study was conducted with 480 T. cruzi seropositive adults from Argentina, including Wichi, Creole, and Buenos Aires populations.
- Genotyping of nine SNPs within the CCR2 and CCR5 genes was performed.
- Statistical analyses, including Hardy-Weinberg equilibrium and allelic association tests, were applied to assess SNP and haplotype associations with CCC.
Main Results:
- The CCR5 SNPs rs1800024T (protective) and rs41469351T (risk) showed significant associations with CCC in the non-Wichi population (Creole + Buenos Aires).
- No significant association was found between other analyzed CCR2-CCR5 polymorphisms and CCC development.
- The HHE haplotype in the CCR5 gene was associated with protection against CCC specifically in the Wichi population.
Conclusions:
- CCR2-CCR5 genes and their haplotypes are associated with chronic Chagas cardiomyopathy (CCC), but these associations are population-specific.
- The study highlights the importance of considering evolutionary context and population genetics when investigating gene-disease associations.
- Further research is warranted to elucidate the precise mechanisms by which these genetic variations influence CCC pathogenesis.
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.
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