GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

PLoS Negl Trop Dis. 2021 Oct 29;15(10):e0009874. doi: 10.1371/journal.pntd.0009874. eCollection 2021 Oct.

Abstract

A recent genome-wide association study (GWAS) identified a locus in chromosome 11 associated with the chronic cardiac form of Chagas disease. Here we aimed to elucidate the potential functional mechanism underlying this genetic association by analyzing the correlation among single nucleotide polymorphisms (SNPs) and DNA methylation (DNAm) levels as cis methylation quantitative trait loci (cis-mQTL) within this region. A total of 2,611 SNPs were tested against 2,647 DNAm sites, in a subset of 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals from the GWAS. We identified 6,958 significant cis-mQTLs (False Discovery Rate [FDR]<0.05) at 1 Mb each side of the GWAS leading variant, where six of them potentially modulate the expression of the SAC3D1 gene, the reported gene in the previous GWAS. In addition, a total of 268 cis-mQTLs showed differential methylation between chronic Chagas cardiomyopathy patients and asymptomatic individuals. The most significant cis-mQTLs mapped in the gene bodies of POLA2 (FDR = 1.04x10-11), PLAAT3 (FDR = 7.22x10-03), and CCDC88B (FDR = 1.89x10-02) that have been associated with cardiovascular and hematological traits in previous studies. One of the most relevant interactions correlated with hypermethylation of CCDC88B. This gene is involved in the inflammatory response, and its methylation and expression levels have been previously reported in Chagas cardiomyopathy. Our findings support the functional relevance of the previously associated genomic region, highlighting the regulation of novel genes that could play a role in the chronic cardiac form of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Chagas Cardiomyopathy / genetics*
  • Chagas Cardiomyopathy / metabolism
  • DNA Methylation
  • DNA Polymerase I / genetics
  • DNA Polymerase I / metabolism
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Phospholipases A2, Calcium-Independent / genetics
  • Phospholipases A2, Calcium-Independent / metabolism
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • CCDC88B protein, human
  • Carrier Proteins
  • Repressor Proteins
  • SAC3D1 protein, human
  • Tumor Suppressor Proteins
  • POLA2 protein, human
  • DNA Polymerase I
  • PLAAT3 protein, human
  • Phospholipases A2, Calcium-Independent

Associated data

  • figshare/10.6084/m9.figshare.c.5525706

Grants and funding

This research was supported by grants from Programa Iberoamericano de ciencia y tecnología para el desarrollo (RIMGECH - 217RT0524) to Chagas Genetics CYTED Network. MAH was supported by Ministerio de Ciencia e Innovación-Juan de la Cierva fellowship (IJC2018-035131-I). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.