Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
Unidad de Medicina Tropical y Salud Internacional Hospital Universitari Vall d'Hebron, PROSICS, Barcelona, Spain.
PLoS Negl Trop Dis. 2021 Oct 29;15(10):e0009874. doi: 10.1371/journal.pntd.0009874. eCollection 2021 Oct.
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.
最近的全基因组关联研究（GWAS）确定了染色体 11 上的一个与慢性心脏形式的恰加斯病相关的基因座。在这里，我们旨在通过分析该区域内的单核苷酸多态性（SNP）和 DNA 甲基化（DNAm）水平之间的相关性，来阐明这种遗传关联的潜在功能机制，作为顺式甲基化数量性状基因座（cis-mQTL）。在来自 GWAS 的 37 名慢性恰加斯心肌病患者和 20 名无症状个体的亚集中，共测试了 2611 个 SNP 与 2647 个 DNAm 位点的相关性。我们在 GWAS 主导变异体的每边 1 Mb 处鉴定了 6958 个显著的 cis-mQTL（错误发现率 [FDR] <0.05），其中 6 个可能调节了先前 GWAS 报道的 SAC3D1 基因的表达。此外，慢性恰加斯心肌病患者和无症状个体之间共有 268 个 cis-mQTL 显示出差异甲基化。映射到 POLA2（FDR = 1.04x10-11）、PLAAT3（FDR = 7.22x10-03）和 CCDC88B（FDR = 1.89x10-02）基因体中的 cis-mQTL 最为显著，这些基因在先前的研究中与心血管和血液学特征有关。与 CCDC88B 超甲基化相关的最显著的相互作用之一。该基因参与炎症反应，其甲基化和表达水平在恰加斯心肌病中已有报道。我们的发现支持了先前相关基因组区域的功能相关性，强调了调节新基因的作用，这些基因可能在疾病的慢性心脏形式中发挥作用。
