Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics

The recent FDA approval of monoclonal antibodies targeting PCSK9, a therapeutic target in the regulation of LDL cholesterol, underscores the capability of unbiased human genetic studies to identify tractable drug targets to treat dyslipidemia and CAD. Unbiased human GWAS have identified >150 loci linked to plasma lipid traits, many of which were not previously known to be associated to lipid metabolism. Of these loci, 28 have a primary association with circulating plasma TGs, an independent risk factor for CAD. Top GWAS loci for TG highlight two specific TG metabolic pathways: the well-studied LPL-pathway of peripheral TG lipolysis and clearance, and the hepatic pathway of de novo synthesis of fatty acids and TG (lipogenesis). The latter group includes novel genes with as yet poorly understood roles in lipid metabolism. Large-scale whole-genome and -exome sequencing have identified rare variants in LPL-pathway genes, solidifying a causal role for both genes and TGs in CAD progression. These analyses have also identified genetic variants with the potential for future structure/function studies and targeted drug discovery. Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. the main protein constituent and integral component of TG-rich lipoproteins such as VLDL, chylomicrons, and LDL particles. ApoB expressed in hepatocytes is co-translationally lipidated to generate VLDL. ApoB is crucial for the hepatic uptake and clearance of remnant particles from the circulation by multiple receptors. Heritable mutations in APOB, the gene encoding ApoB, underlie multiple Mendelian disorders of lipid metabolism, including familial hypercholesterolemia. extremely large TG-rich lipoprotein particles (200–500 nm in diameter) produced in small intestinal enterocytes and secreted into the lymph. Chylomicrons are assembled from a truncated form of ApoB and diet-derived TGs. They traffic TGs to the heart, skeletal muscle, adipose, and other tissues for nutrition and storage. Chylomicron remnants have more recently been appreciated as independent mediators of cardiovascular risk because of their ability to promote atherogenesis in a manner similar to LDL. the standardized mean difference between two groups for a given metric. For example, for a given risk SNP, the effect size is the mean plasma [TG] in individuals with the SNP minus the mean plasma [TG] in individuals that lack it (controls), divided by the standard deviation of the measurement in the latter group. a statistical method to test the over-representation of a given SNP in a given patient cohort, compared to a cohort of healthy controls. Because human populations have different underlying SNP frequencies, ethnic matching of the case and control cohorts is important to eliminate false-positive GWAS hits. accumulation of fat (TG in the form of cytoplasmic lipid droplets) in hepatocytes. Transient hepatic steatosis is not inherently pathogenic and can occur in otherwise healthy individuals without consequences (e.g., in response to a large meal). Chronic steatosis is considered the first step in the non-alcoholic fatty liver disease (NAFLD) spectrum, and is a risk factor for progression to non-alcoholic steatohepatitis (NASH). often analogized to randomized drug trials, Mendelian randomization is a statistical comparison method to ascertain how a genetic variant that robustly affects an intermediate trait contributes to a secondary trait such as disease risk. For example, variants in a gene that only contribute to TG levels but do not affect LDL-C may be useful to test the causal impact of altered TG on cardiovascular disease independently of LDL. Individuals are 'randomized' at birth by their genotype for the particular variant that alters TG levels in a genotype-dependent manner. The nature of these studies helps to avoid traditional limitations in assessing the direct contribution of intermediate traits to multifactorial diseases, such as confounding effects from environmental and behavioral factors. common, naturally-occurring single-base variations in the genome, and the largest source of genetic variation in humans. While common and often nondeleterious, particular SNPs may contribute to variation in a myriad traits or disease risks in the population. Common SNPs of small effects may also underlie genomic regions of importance for such traits.