Third of Inherited Cholesterol Disorders Linked to Gene Variations
During a scan of the human DNA, a team of multinational researchers have discovered 95 genetic variants that affect blood cholesterol levels. The findings demonstrate how complex it is to regulate dyslipidemia and may lead to improved treatments to lower cholesterol and prevent heart disease.
Genetics Cause Up to 10 Percent of Early-Onset Coronary Artery Disease
Cholesterol is a blood fat that is essential for many body functions, but when made (or consumed) in excess, can increase the risk of the formation of blood plaques in the arteries, which can lead to heart attack or stroke. Diet and exercise affect cholesterol levels, but genetics plays a big role in whether someone may be predisposed to having abnormal readings.
Dr. Francis Collins, director of the National Institutes of Health, and a team of researchers mapped the DNA of more than 100,000 people to identify the genes that affect the various forms of cholesterol, including HDL, LDL, and triglycerides. Of the 95 found, 59 had not previously been identified.
Harvard Medical School geneticist Dr. Sekar Kathiresan said the team has likely only uncovered a portion of the few hundred total genes that are responsible for the regulation of cholesterol levels. The variations they found account for between a quarter and a third of genetic cholesterol disorders.
Daniel Rader of the University of Pennsylvania and colleagues found one DNA sequence that affects a gene called SORT1. One in five people have a genetic variation that predisposes them to having low levels of LDL and VLDL (very low density lipoproteins). They have a 40 percent lower than average risk of heart attack.
In mice, the researchers validated the findings of three other novel genes, called GALNT2 (which affects HDL), PPP1R3B (associated with HDL, LDL and total cholesterol) and TTC39B (associated with HDL), by showing that changing their expression altered lipid levels.
"These results help refine our course for preventing and treating heart disease, a health problem that affects millions of Americans and many more people worldwide," said Dr. Collins, who will use the evidence to steer the NIH to more quickly translate the findings into the development of drugs and treatments to regulate cholesterol levels.
Statin drugs to control cholesterol, such as Pfizer’s Lipitor and AstraZeneca’s Crestor, are the most prescribed and best-selling drugs globally to lower cholesterol. Stains work by blocking a key enzyme called HMG-CoA reductase thus inhibiting the liver’s ability to produce LDL cholesterol.
Teslovich TM, et al "Biological, clinical and population relevance of 95 loci for blood lipids"Nature 2010; 466: 707-713.
Musunuru K, et al "From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus" Nature 2010; 466: 714-721.
Shuldiner AR, Pollin TI "Variations in blood lipids" Nature 2010; 466: 703-704.