Genomics of lipid metabolism: Identifying novel causal pathways and new therapeutic targets for reducing risk of coronary heart disease


Coronary heart disease (CHD) is one of the leading causes of death worldwide; mortality rates are expected to continue to rise over the coming decades. Circulating lipids have been shown to be strongly and linearly associated with risk of CHD; however, despite considerable efforts to demonstrate causality, available evidence is conflicting and insufficient. Study of the underlying metabolic pathways implicated in the association between lipids and CHD would help to disentangle and elucidate these complex relationships. Direct infusion high-resolution mass spectrometry was performed on 5,551 participants from the Pakistan Risk of Myocardial Infarction Study; raw data were then processed, cleaned, and normalized to extract signals corresponding to 444 known lipid metabolites. Cross-correlations of lipid metabolites and their correlations with circulating lipids were examined, and the association of principal components of lipid metabolites with CHD risk factors was assessed. Genome-wide analyses were conducted to analyze the association of each lipid metabolite with 7.2 million genotyped and imputed single nucleotide polymorphisms (SNPs). Following conditional analyses on the lead SNP within each loci, we identified genome-wide significant associations at 148 independent metabolic loci and 54 novel loci. We then used functional annotation to link the variants associated with each metabolite to the most probable causal genes, and two-sample Mendelian randomization to examine the causal effect of lipid metabolites on risk of CHD. Analyses of circulating lipid metabolites in large epidemiological studies could lead to enhanced understanding of mechanisms for CHD development and identification of novel causal pathways and new therapeutic targets.