A Genome-Wide Association Study Identifies Novel Susceptibility loci in Chronic Chagas Cardiomyopathy

Abstract

Background: Chagas disease is an infectious disease caused by the parasite Trypanosoma cruzi and is endemic from Latin American countries. The goal of our study was to identify novel genetic loci associated with chronic Chagas cardiomyopathy development in Chagas disease patients from different Latin American populations.

Methods: We performed a cross-sectional, nested case-control study including 3 sample collections from Colombia, Argentina, and Bolivia. Samples were genotyped to conduct a genome-wide association study (GWAS). These results were meta-analyzed with summary statistic data from Brazil, gathering a total of 3413 Chagas disease patients. To identify the functional impact of the associated variant and its proxies, we performed an in silico analysis of this region.

Results: The meta-analysis revealed a novel genome-wide statistically significant association with chronic Chagas cardiomyopathy development in rs2458298 (OR = 0.90, 95%CI = 0.87-0.94, P-value = 3.27 × 10-08), nearby the SAC3D1 gene. In addition, further in silico analyses displayed functional relationships between the associated variant and the SNX15, BAFT2, and FERMT3 genes, related to cardiovascular traits.

Conclusions: Our findings support the role of the host genetic factors in the susceptibility to the development of the chronic cardiac form of this neglected disease.

Keywords: Trypanosoma cruzi; Chagas disease; GWAS; Latin American; cardiomyopathy; genetic association; meta-analysis.

Figure 1.

Manhattan plot of the association test in chronic Chagas cardiomyopathy meta-analysis results. Y and X axes refer the –log₁₀ transformed P-values and positions in chromosomes, respectively. The red horizontal line refers the genome-wide association threshold, stablished at P < 5 × 10^-08, and the blue line refers the suggestive threshold (P < 1 × 10^-06).

Figure 2.

Regional association plot for the genome-wide significant signal. The –log₁₀ transformed P-values of associated variants are plotted by position. The genomic position indicated correspond the top variant associated in this region. The rest of the variants are colored in function of their degree of linkage disequilibrium (LD) with the associated signal. LD is based on pairwise r2 values from the American population from the 1000 Genomes Project. The blue line corresponds to the estimated recombination rates. Nearby genes to the associated and suggestive signals are shown in the bottom of the plot.