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Study identifies genetic variants linked to changes in lipid levels
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Researchers have identified 157 genetic variants associated with alterations in lipid levels, which could lead to the development of new CV medications and guide future treatment.
A worldwide research team pooled genetic and clinical information from more than 188,000 people. They used genome-wide and custom genotyping arrays to identify new loci and refine known loci that influence blood lipids.
The results increase by more than a third the total number of genetic variants linked to blood lipids, according to a press release.
The list includes 62 new loci, 30 of which include genes not previously known to be associated with lipids. Of the 62, 24 were strongly associated with HDL levels, 15 with LDL levels, eight with triglyceride levels and 15 with total cholesterol levels, Cristen J. Willer, PhD, of the University of Michigan Medical School, and colleagues reported in Nature Genetics.
“Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research,” researchers for the Global Lipids Genetics Consortium wrote.
Specifically, the researchers observed an excess of the 157 genetic variants associated with the following conditions:
- CAD (5.1-fold excess)
- BMI (4.1-fold excess)
- Diastolic BP (3.7-fold excess)
- Waist-to-hip ratio (3.4-fold excess)
- Systolic BP (2.5-fold excess)
- Type 2 diabetes (2.3-fold excess)
- Fasting glucose levels (2.2-fold excess)
“These results give us 62 new clues about lipid biology, and more places to look than we had before,” Willer said in a press release.
In a related study published in Nature Genetics, researchers analyzed the same large dataset and found that triglyceride-rich lipoproteins may have a stronger impact on risk for CAD than previously thought.
The researchers assessed 185 genetic variants mapped for plasma lipids. Effect estimates for LDL were strongly associated with effect estimates for CAD, even after adjustment for effect estimates for HDL and triglycerides separately or together. Similarly, effect estimates for triglycerides were strongly associated with effect estimates for CAD after adjusting for effect estimates for HDL and LDL. By contrast, effect estimates for HDL were not associated with effect estimates for CAD after adjustment for effect estimates for LDL and triglycerides together.
“We have demonstrated that [genetic variants] with the same direction and a similar magnitude of association for both triglycerides and LDL tend to associate with CAD risk; loci that have an exclusive effect on triglycerides are also associated with CAD; and the strength of a [genetic variant’s] effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk, event after accounting for the same [genetic variant’s] effect on LDL and/or HDL levels,” the researchers wrote.
For more information:
Do R. Nature Genetics. 2013;doi:10.1038/ng.2795.
Willer CJ. Nature Genetics. 2013;doi:10.1038/ng.2797.
Disclosure: See the full studies for lists of the researchers’ relevant financial disclosures.
Perspective
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Robert Roberts, MD, FRCPC, MACC, FAHA
The Global Lipids Genetics Consortium confirms 157 genetic risk variants associated with plasma levels of LDL, HDL and triglycerides. The discovery of genetic variants that regulate plasma levels of lipids is very important for several reasons.
First, 80% of cholesterol is synthesized endogenously by the body and thus regulated by the individual’s genes.
Second, discovery of these genes responsible for the production and removal of cholesterol provide new targets for the development of not only new therapies, but therapies specific for the class of lipids and the genes regulating that class. Currently, the only effective drugs are statins, which inhibit the synthesis of cholesterol through targeting HMGCoA reductase, the rate-limiting enzyme. The discovery of polymorphisms in the common gene PCSK9 has already generated a new therapy via PCSK9 antibody inhibition. Phase 1 and 2 trials have been completed showing the therapy is safe and adds further efficacy to the statins; since it increases removal, rather than decreases synthesis, it is complementary to statin therapy. (Stein EA. N Engl J Med. 2012;366:1108-1118.)
Third, discovery of these genes has set the stage to understand the individual variation of plasma LDL, HDL and triglyceride levels, which should provide more effective therapy.
Fourth, discovering these genes provides a new and unique method to assess the effect of the individual lipid class regarding its risk or protection for heart disease. Already, we have some surprising findings that may ultimately transform our thinking regarding the protective effect of HDL and the role of triglycerides in heart disease. It is now possible to assess the effect of lifelong exposure to an increased or decreased level of one of these lipids induced by a polymorphism. We have accepted as an axiom that increased plasma HDL levels protect against CAD and MI. This evidence is largely based on interventions such as statins, niacin, exercise or alcohol that increase HDL; however, they also reduce LDL levels. The study by the Global Lipids Genetics Consortium confirms our previous observation (Teslovich TM. Nature. 2010;466:707-713) showing that an increase solely in plasma HDL levels was not associated with decreased risk for MI. This adds to increasing evidence from other sources that the protective effect of plasma HDL has to be reevaluated.
Lastly, the article by Do et al for the first time assesses the effect of polymorphisms in the genes regulating triglycerides and shows that increased triglycerides has the potential for increased risk for CAD. This relationship had been suspected; however, it has remained controversial for several decades. This finding, if confirmed, will add another variable to the management and prevention of CAD.
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