Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature

Abstract

Background Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected. Methodology/Principal findings We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10−9) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302–5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis. Conclusions/Significance We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted.

Interactions between genetic and lifestyle factors on cardiometabolic disease-related outcomes in Latin American and Caribbean populations: A systematic review

“…Moreover, no studies have examined the impact of rural and urban environments on the genetic predisposition to cardiometabolic diseases, highlighting a gap in knowledge in LACP. The higher number of nutrigenetic studies in Brazil compared to the other countries could be attributed to several factors including existing data on genetic studies (176)(177)(178)(179)(180)(181), GWAS done mainly in Brazil (182)(183)(184), increased awareness on nutrigenetics in Brazil or more research facilities available in Brazil compared to other LACP. Future gene-lifestyle interaction studies will need to replicate primary research of already studied genetic variants to enable comparison, and to explore the interactions between genetic and other lifestyle factors such as those conditioned by socioeconomic factors and the built environment.…”