Abstract
BackgroundGenetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.MethodsWe characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.ResultsWe identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.ConclusionsOur findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.
Highlights
Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases
Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, membrane bound O-acyltransferase domain containing 7 (MBOAT7), LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci
Study descriptions Our primary analyses involved a subset of participants from the Pakistan Risk of Myocardial Infarction Study (PROMIS), a case-control study of first-ever acute myocardial infarction (MI) in nine urban centres in Pakistan consisting of approximately 16,700 cases and 18,600 controls
Summary
Lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. Mass spectrometry-based lipidomics, which aims to capture information on the full complement of lipid metabolites in a given biological sample [1], holds the potential to identify novel insights leading to lipid regulation and dyslipidaemia, potentially providing new mechanisms that link lipid perturbances with cardiometabolic disorders. With increasing rates of cardiometabolic diseases in low- and middleincome countries, there is a need for well-powered studies to understand the mechanisms that lead to such disorders in these settings. This need is especially acute for genetic studies where the overrepresentation of individuals of European ancestry amongst genotyped cohorts has led to ancestral bias in effect size estimates at both the genotype and polygenic score levels [2]. We quantified 340 lipid metabolites in 5662 individuals from Pakistan, from which we identified 253 genotype– lipid associations (lipid quantitative trait loci, or lipid QTLs [3, 4]) at 24 independent loci, providing new insights into lipid metabolism and its impact on cardiovascular and metabolic diseases
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