The identification of genes and regulatory elements underlying the associations discovered by GWAS is essential to understanding the aetiology of complex traits (including diseases). Here, we demonstrate an analytical paradigm of prioritizing genes and regulatory elements at GWAS loci for follow-up functional studies. We perform an integrative analysis that uses summary-level SNP data from multi-omics studies to detect DNA methylation (DNAm) sites associated with gene expression and phenotype through shared genetic effects (i.e., pleiotropy). We identify pleiotropic associations between 7858 DNAm sites and 2733 genes. These DNAm sites are enriched in enhancers and promoters, and >40% of them are mapped to distal genes. Further pleiotropic association analyses, which link both the methylome and transcriptome to 12 complex traits, identify 149 DNAm sites and 66 genes, indicating a plausible mechanism whereby the effect of a genetic variant on phenotype is mediated by genetic regulation of transcription through DNAm.

Integrative analysis of omics summary data reveals putative mechanisms underlying complex traits.

Foam cell formation and further accumulation in the subendothelial space of the vascular wall is a hallmark of atherosclerotic lesions. Targeting foam cell formation in the atherosclerotic lesions can be a promising approach to treat and prevent atherosclerosis. The formation of foam cells is determined by the balanced effects of three major interrelated biologic processes, including lipid uptake, cholesterol esterification, and cholesterol efflux. Natural products are a promising source for new lead structures. Multiple natural products and pharmaceutical agents can inhibit foam cell formation and thus exhibit antiatherosclerotic capacity by suppressing lipid uptake, cholesterol esterification, and/or promoting cholesterol ester hydrolysis and cholesterol efflux. This review summarizes recent findings on these three biologic processes and natural products with demonstrated potential to target such processes. Discussed also are potential future directions for studying the mechanisms of foam cell formation and the development of foam cell-targeted therapeutic strategies.

https://pharmrev.aspetjournals.org/content/pharmrev/71/4/596.full.pdf

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products.

Lysosomal acid lipase (LAL), encoded by the lipase A ( LIPA) gene, hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The essential role of LAL in lipid metabolism has been confirmed in mice and human with LAL deficiency. In humans, loss-of-function mutations of LIPA cause rare lysosomal disorders, Wolman disease and cholesteryl ester storage disease, in which LAL enzyme-replacement therapy has shown significant benefits in a phase 3 clinical trial. Recent studies have revealed the regulatory role of lipolytic products of lysosomal lipid hydrolysis in catabolic, anabolic, and signaling pathways. In vivo studies in mice with knockout of Lipa highlight the systemic impact of Lipa deficiency on metabolic homeostasis and immune cell function. Genome-wide association studies and functional genomic studies have identified LIPA as a risk locus for coronary heart disease, but the causal variants and mechanisms remain to be determined. Future studies will continue to focus on the role of LAL in the crosstalk between lipid metabolism and cellular function in health and diseases including coronary heart disease.

Lysosomal Acid Lipase in Lipid Metabolism and Beyond.

Rationale: Macrophages face a substantial amount of cholesterol following the ingestion of apoptotic cells and the lysosomal acid lipase (LIPA) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment.
 Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response due to impaired generation of 25-OHC and 27-OHC. Reduced synthesis of 25-OHC after LIPA inhibition contributed to defective mitochondria associated membrane (MAM) leading to mitochondrial oxidative stress-induced NLRP3 inflammasome activation and caspase 1-dependent Rac1 degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.

Lysosomal Cholesterol Hydrolysis Couples Efferocytosis to Anti-Inflammatory Oxysterol Production.

Purpose of reviewLysosomal acid lipase (LAL), encoded by the LIPA gene, is an essential lysosomal enzyme that hydrolyzes cholesteryl ester and triglyceride delivered to the lysosome. This review highlights the novel pathophysiological role of LAL, the functional genomic discoveries of LIPA as a risk

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Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies.

Objective—Genome-wide association studies have linked variants at chromosome 10q23 with increased coronary artery disease risk. The disease-associated variants fall in LIPA, which encodes lysosomal...

Jasbir S. Moore

Papers

Coronary Artery Disease-Associated LIPA Coding Variant rs1051338 Reduces Lysosomal Acid Lipase Levels and Activity in Lysosomes.