Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Feb 19;118(4):579-85.
doi: 10.1161/CIRCRESAHA.115.306398.

Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Kiran Musunuru  1 , Sekar Kathiresan  2
Affiliations
Review

Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis

Kiran Musunuru et al. Circ Res. .

Abstract

Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.

Keywords: atherosclerosis; coronary disease; genetics; lipoproteins; triglycerides.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The cumulative effects of genetic variants that raise plasma low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels on the risk of myocardial infarction (MI).
Figure 2
Figure 2
The causal role of the lipoprotein lipase (LPL) pathway on the risk of myocardial infarction (MI). LPL metabolizes triglyceride (TG)-rich lipoproteins in the bloodstream. ANGPTL4, APOC3, and APOA5 all modulate LPL activity. Variants in all of the genes encoding these proteins influence MI risk.
Figure 3
Figure 3
Lipid-associated and non-lipid-associated genes identified in a genome-wide association study (GWAS) on coronary heart disease (CHD).
See this image and copyright information in PMC

References

    1. Lloyd-Jones DM, Nam BH, D’Agostino RB, Sr, Levy D, Murabito JM, Wang TJ, Wilson PW, O’Donnell CJ. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004;291:2204–2211. - PubMed
    1. Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, Wood AM, Lewington S, Sattar N, Packard CJ, Collins R, Thompson SG, Danesh J. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000. - PMC - PubMed
    1. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450–458. - PubMed
    1. Emerging Risk Factors Collaboration. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–423. - PMC - PubMed
    1. Heller DA, de Faire U, Pedersen NL, Dahlén G, McClearn GE. Genetic and environmental influences on serum lipid levels in twins. N Engl J Med. 1993;328:1150–1156. - PubMed

MeSH terms