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 three 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 3,413 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=3.27x10 -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.

GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

“…This study was approved by the Ethics Committee from the Vall D'Hebron University Hospital, Barcelona, Spain (PR (AMI) 297/2016). The Ethics Committees for the GWAS data was described elsewhere [4]. Protocols used in the study followed the principles of the Declaration of Helsinki and all individuals included in the study signed written informed consents.…”

“…All donors were recruited by the health care system from the Vall D'Hebron University Hospital, Barcelona, Spain. The study population is composed by a subset of patients from Bolivia from the previous GWAS [4]. A total of 57 seropositive individuals for T. cruzi antigens were classified into chronic Chagas cardiomyopathy patients (cases, n = 37) and asymptomatic (controls, n = 20) according to the presence of cardiac abnormalities.…”

“…Given the existence of differential susceptibility to Chagas disease and in the development of its chronic cardiac form, several genetic studies have been performed in order to elucidate genetic variation associated with disease risk [3]. A recent genome-wide association study (GWAS) carried out in Latin American populations identified a significant association with the chronic cardiac form located at ~6.4Kb downstream of the transcription start site of the SAC3D1 gene, in the region q13.1 of chromosome 11 [4]. Moreover, several other genes within this locus were previously related with cardiovascular traits and were found to have functional relevance in the disease [4].…”

“…A recent genome-wide association study (GWAS) carried out in Latin American populations identified a significant association with the chronic cardiac form located at ~6.4Kb downstream of the transcription start site of the SAC3D1 gene, in the region q13.1 of chromosome 11 [4]. Moreover, several other genes within this locus were previously related with cardiovascular traits and were found to have functional relevance in the disease [4]. As in other complex diseases, the associated and suggestive variants mapped in non-coding regions of the genome [5,6], being these well-known to exert their effect through modulating gene expression [7].…”

Indeterminate form of Chagas disease: historical, conceptual, clinical, and prognostic aspects

“…In line with the latter hypothesis, focal myocarditis lesions in the IF were interpreted as being subject to a self-limited evolutionary cycle, balanced by the onset of some lesions and the discontinuation of others, which would allow a long host survival. In addition, it is postulated that the genetic factors of the patient are related to the diversity in the clinical course of CD 11 . Biomarkers for CHD progression are being studied in the immunological and molecular fields, in which enzymatic, humoral, and immunological interactions may be related to a set of genetic markers (polymorphisms) already existing, when the patient is infected, and these different responses to the parasite may determine disease progression 12 .…”