PLoS Neglected Tropical Diseases (Oct 2022)

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

  • Ester Cerdeira Sabino,
  • Lucas Augusto Moysés Franco,
  • Gabriela Venturini,
  • Mariliza Velho Rodrigues,
  • Emanuelle Marques,
  • Lea Campos de Oliveira-da Silva,
  • Larissa Natany Almeida Martins,
  • Ariela Mota Ferreira,
  • Paulo Emílio Clementino Almeida,
  • Felipe Dias Da Silva,
  • Sâmara Fernandes Leite,
  • Maria do Carmo Pereira Nunes,
  • Desiree Sant'Ana Haikal,
  • Claudia Di Lorenzo Oliveira,
  • Clareci Silva Cardoso,
  • Jonathan G Seidman,
  • Christine E Seidman,
  • Juan P Casas,
  • Antonio Luiz Pinho Ribeiro,
  • Jose E Krieger,
  • Alexandre C Pereira

DOI
https://doi.org/10.1371/journal.pntd.0010725
Journal volume & issue
Vol. 16, no. 10
p. e0010725

Abstract

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BackgroundChronic 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 findingsWe 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/significanceWe 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.