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

Natalia Anahí Juiz,Alejandro Gabriel Schijman,Elkyn Estupiñán,Silvia Andrea Longhi,Raúl Chadi,Alejandra Garcilazo,Gisela Morales Sanfurgo,Clara Isabel González,Daniel Hernández,Walderez O Dutra

doi:10.1371/journal.pntd.0007033

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.

Highlights

About one third of Trypanosoma cruzi chronically infected people will develop chronic Chagas cardiomyopathy (CCC)
The endemic area covers the north of the country where the conditions, such as high levels of poverty and social exclusion and low population density, mostly rural, favor T. cruzi infection
The pathogenesis of CCC is not completely understood, but it is believed that the human genetic variation may be a determinant factor of disease progression

Summary

Introduction

About one third of Trypanosoma cruzi chronically infected people will develop chronic Chagas cardiomyopathy (CCC). As immune response and chronic inflammation are mechanisms involved in CCC, several studies have been focused on different polymorphisms in chemokines and cytokines genes as genetic markers for susceptibility to develop CCC. They have been carried out in endemic countries such as Peru [7], Mexico [8, 9], Colombia [10,11,12,13,14,15], Brazil [16,17,18,19] and Bolivia [20]. In Argentina, where approximately one million and a half people are infected (4% of the total population), with a prevalence in endemic areas greater than 60% [21], until now only there were association studies for HLA class II DRB1 alleles with CCC [22, 23], but not for those immunological genes mentioned above

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