Project description
Genetics help to advance knowledge of coronary artery disease
Scientists perform genome-wide association studies (GWAS) to identify which genes are involved in human disease and to predict the presence of disease. Over the past few years, GWAS have discovered hundreds of single nucleotide polymorphisms (SNPs) – the most common type of genetic variation amongst people – that are closely linked to coronary artery disease (CAD). However, these SNPs normally describe only a few heritable traits. To better understand disease mechanisms, the EU-funded EnDeCAD project will explore the role of each CAD locus at the molecular level. The knowledge gained should improve risk prediction, biomarker identification and treatment selection in delivering healthcare.
Objective
In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.
Fields of science
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
70211 KUOPIO
Finland