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.
Highlights
Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi that affects ~7 million people around the world and is endemic in Latin America
Genome-wide association studies (GWAS) have provided extensive information regarding the genetic component of complex traits, including parasitic diseases such as Chagas disease
A total of 2,611 single-nucleotide polymorphisms (SNPs) were tested against 2,647 DNA methylation (DNAm) sites in 37 chronic Chagas cardiomyopathy patients and 20 asymptomatic individuals after passing their corresponding quality control (QC) criteria
Summary
Chagas disease is a parasitic infection caused by the protozoan Trypanosoma cruzi that affects ~7 million people around the world and is endemic in Latin America (https://www.who.int/ health-topics/chagas-disease#tab=tab_1). 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]. 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]. The DNA methylation (DNAm) of a particular locus might be driving this modulation through methylation quantitative trait loci (mQTLs), which are correlations among single-nucleotide polymorphisms (SNPs) and DNAm levels in the context of a specific trait [8]
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