Gene variation may be why some don't respond to cholesterol-lowering drugs

A variation in the way the body processes a single protein may explain why some people don't respond well to drugs that lower "bad" cholesterol, according to a report in Circulation: Journal of the American Heart Association.

The gene variation, called alternative splicing, explained 9 percent of the drugs' decreased power to reduce low-density lipoprotein (LDL) in study participants compared to people with the standard processing pathway.

The study is the first to show that a change in a biological process contributes substantially to the effectiveness of cholesterol-lowering drugs known as statins.

"Nine percent is a large number," said Ronald Krauss, M.D., senior author of the study and director of atherosclerosis research at the Children's Hospital Oakland Research Institute in California. "When we look at individual variations in genes affecting cholesterol metabolism, we can usually explain only a few percent of the variability in statin response."

The discovery could lead to improved cholesterol treatment and new therapy for other chronic ailments.

"The implications could go well beyond the efficacy of statins by helping us to understand the differences among individuals in how cholesterol is metabolized," Krauss said.

Simvastatin is one of several statin drugs that can effectively reduce the risk of heart attacks in people with high cholesterol. They work by blocking a key enzyme required for the production of cholesterol called HMGCR. However, all people don't have the same response to statins.

Krauss and his team sought a genetic explanation for this variability. They analyzed differences in how the gene responsible for producing HMGCR was processed — or spliced — among more than 900 participants enrolled in the Cholesterol and Pharmacogenetics (CAP) Study. During splicing, some portions of the gene's first product, mRNA, are removed and others are combined. The enzyme that is produced from the normally spliced HMGCR mRNA plays an early and critical role in the body's production of cholesterol, and its activity can be strongly inhibited by statins. The alternatively spliced form, on the other hand, is more resistant to statin inhibition of cholesterol production.

Researchers found that the "alternative splicing" also accounted for 15 percent of the reduced response of apolipoprotein B — a constituent of LDL — to simvastatin and 6 percent of the lower triglyceride response to the drug.

Combining factors already known to affect statin response — age, race and smoking— with alternative splicing explains 24 percent of the variation in LDL response, 29 percent for apoB and 8 percent for triglycerides, Krauss said. Despite this variability, statins are generally highly effective for prevention and treatment of heart disease, and there is not yet sufficient evidence for using genetic testing in evaluating the degree of benefit that individuals might be expected to achieve from statin treatment.

Marisa Wong Medina, Ph.D., co-author of the study, measured the two forms of spliced mRNA in cell lines grown from lymphocytes in people in a simvastatin clinical trial. The greater the proportion of alternatively spliced copies, the lower the clinical response to the drug.

Deciphering alternative slicing promises other benefits, including a deeper understanding of cholesterol metabolism.

"We know that the pathway leading to cholesterol has many side branches, some of which are involved in inflammation," Krauss said. "Statin treatment is thought to be effective in reducing heart disease risk by blocking production of molecules in the cholesterol synthesis pathway that can lead to both cholesterol buildup and inflammatory reactions in blood vessels."

Understanding the genetic regulation of these effects, and the role of alternative splicing of HMGCR and perhaps other genes in the cholesterol pathway, could lead to the development of new drugs for reducing heart disease risk, researchers said

Source: American Heart Association

Related stories:

Blood pressure response to daily stress provides clues for better hypertension treatment
How the body regulates blood pressure in response to daily stress is the focus of a study geared toward helping people whose pressure is out of control.
Could arthritis wonder drugs provide clues for all disease?
Drugs that have helped treat millions of rheumatoid arthritis sufferers may hold the key to many more medical conditions, including atherosclerosis – a leading cause of heart disease – says the researcher who jointly invented and developed them.
Combining medical knowledge to save lives
European researchers hope to gain more insight into cardiovascular disease by combining clinical, laboratory and metabolic records with genomic data.
Cardiovascular disease (CVD) is the biggest killer among chronic diseases, claiming 17 million lives globally every year. Yet doctors can only attribute 50% of cardiovascular diseases to known risk factors.
Study in Circulation provides detail on how low blood flow promotes vascular disease
Better understanding of signaling pathway to lead to new therapies
Researchers have found the first direct proof that a key protein drives the clogging of arteries in two ways, and that lowering levels of it opens them up, according to study results published in the June edition of the journal Circulation. The work establishes cyclophilin A as an exciting target in the design of drugs against atherosclerosis, the number one cause of heart attacks and strokes, which occur when vessels become completely blocked. While the study was in mice, higher levels of the study protein have also been found in the blood of human patients with diseased blood vessels.
Unexpected finding of molecule's dual role in mice may open new avenue to cholesterol reduction
Researchers have discovered an unknown regulator of fat and cholesterol production in the liver of mice, a significant finding that could lead to new therapies for lowering unhealthy blood levels of cholesterol and fats.
Study in 7,000 men and women ties obesity, inflammatory proteins to heart failure risk
Heart specialists at Johns Hopkins and elsewhere report what is believed to be the first wide-scale evidence linking severe overweight to prolonged inflammation of heart tissue and the subsequent damage leading to failure of the body’s blood-pumping organ.
New potential drug target for the treatment of atherosclerosis
A nuclear receptor protein, known for controlling the ability of cells to burn fat, also exerts powerful anti-inflammatory effects in arteries, suppressing atherosclerosis in mice prone to developing the harmful plaques, according to new research by scientists at the Salk Institute for Biological Studies and the Harvard School of Public Health.
Many stroke, heart attack patients may not benefit from aspirin
Up to 20 percent of patients taking aspirin to lower the risk of suffering a second cerebrovascular event do not have an antiplatelet response from aspirin, the effect thought to produce the protective effect, researchers at the University at Buffalo have shown.

News discussion:

Medicine & Health news