Review ArticleDiscovery and Validation of New Molecular Targets in Treating Dyslipidemia: The Role of Human Genetics
Section snippets
Will Targeting New Lipid Loci Reduce Cardiovascular Risk? The Role of Mendelian Randomization
Addressing the question of whether a human genetic variant is associated with CHD can be brought into the high-throughput “-omics” era with the use of a genetic epidemiology tool known as Mendelian randomization (Smith et al. 2008). This process, referred to as a randomized trial of nature, capitalizes on the random collection of genetic variants assigned at birth via meiosis and independent chromosomal assortment (Thanassoulis and O'Donnell 2009). Groupings of patients by genotype are thus
Low-Density Lipoprotein Cholesterol
Plasma LDL-C levels are a strong predictor of coronary risk, even in a recent statin trial that achieved a median on-treatment LDL-C of 55 mg/dL (Ridker et al. 2009). Furthermore, the direct role of LDL particles in atherosclerosis has been well characterized—LDL is taken up into the intimal space of the vasculature and is ultimately phagocytosed by macrophages to create lipid-laden foam cells (Ross 1999). Nevertheless, the question has been raised whether all mechanisms that lead to LDL-C
Triglycerides
It is now recognized that plasma TG concentrations are an independent predictor of coronary risk, even after treatment with intensive statin therapy (Sarwar et al., 2007, Miller et al., 2008). Nonfasting measures of TG have been an even stronger predictor of CHD in some studies, potentially indicative of increased atherogenic remnant lipoproteins (Nordestgaard et al. 2007). Hypertriglyceridemia frequently reflects the accumulation of chylomicrons, very-low-density lipoprotein (VLDL), and
High-Density Lipoprotein Cholesterol
An inverse relationship between HDL-C levels and risk of CHD is among the most robust in modern epidemiology. An increment of even 1 mg/dL in HDL-C has been associated with a 3% to 4% reduction in mortality from cardiovascular disease (Gordon 1989). High-density lipoprotein is thought to have a wide range of antiatherogenic properties, including the promotion of reverse cholesterol transport and counteracting proinflammatory and prothrombotic factors. Several therapies, including nicotinic
Lipoprotein(a)
Lipoprotein(a) concentrations, both highly variable and highly heritable in humans, have been linked with CHD across a wide spectrum of epidemiologic studies (Emerging Risk Factors Collaboration et al. 2009). Lipoprotein(a) is a large, LDL-like particle that contains an apolipoprotein B-100 covalently bound to an apolipoprotein(a) molecule. The size of this apolipoprotein(a) component contains multiple “Kringle-like” domain repeats, the number of which depend on the highly polymorphic LPA gene.
Conclusion
Lipids clearly play a major role in the progression of atherosclerosis and have appropriately received substantial interest from experts in basic science, genetics, and drug development. Recently published and upcoming GWAS results have the potential to serve as a major advance in the field, particularly if the mechanistic basis for gene–lipid associations can be determined. Furthermore, the findings offer the opportunity to rapidly implement the principles of Mendelian randomization to
Acknowledgments
AVK gratefully acknowledges funding from the Howard Hughes Medical Institute.
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