RESUMEN
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.
Asunto(s)
Cardiomiopatía Chagásica/genética , Adulto , Anciano , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Cardiomiopatía Chagásica/metabolismo , Metilación de ADN , ADN Polimerasa I/genética , ADN Polimerasa I/metabolismo , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Fosfolipasas A2 Calcio-Independiente/genética , Fosfolipasas A2 Calcio-Independiente/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The aim of the present study was to analyze IL6 rs1800795 genetic variant in the susceptibility to Trypanosoma cruzi infection and in the development of chronic Chagas cardiomyopathy (CCC), in five independent Latin American cohorts. A total of 3,087 individuals from Latin American countries (Argentina, Bolivia, Peru, and two cohorts from Colombia) were studied. In all cohorts, patients were classified as seropositive for T. cruzi antigens (n= 1,963) and seronegative (n= 1,124). Based on clinical evaluation, the seropositive patients, were classified as CCC (n= 900) and asymptomatic (n= 1,063). No statistically significant differences in the frequency of IL6 rs1800795 between seropositive and seronegative, or between CCC and asymptomatic patients, were found. Furthermore, after the meta-analysis no statistically significant differences were observed. Our results do not support a contribution of IL6 rs1800795 genetic variant in the susceptibility to the infection and the development of chronic Chagas cardiomyopathy in the studied populations.