The global market for statins has reached heart-stopping proportions, registering at almost $20 billion in 2012. In the US, one out of every four adults over the age of 45 is on statins, making these medications one of the leading types prescribed. The drugs work by lowering the liver’s production of low-density lipoproteins, also known as ‘bad’ cholesterol, which form the artery-clogging plaques that can lead to heart attack. But statins can cause significant side effects, ranging from sleeplessness to an increased risk of type 2 diabetes and potential liver damage.
One of the most common side effects is muscle pain and injury, which afflicts up to 38% of people taking statins. Now, researchers have hit upon a new gene variation that could explain why some individuals are less prone to this type of adverse reaction to such drugs.
The scientists themselves sound surprised at the discovery. “We weren’t focused on finding the cause of the muscle damage,” says Ronald Krauss, director of atherosclerosis research at Children’s Hospital Oakland Research Institute in California and lead author of the new study, which appears online today in Nature. “We were looking at cell lines from patients on statins to discover new gene variants and we found one that affects how the drug works.”
It’s not the first effort to look at statin side effect risks though the lens of genetics. Five years ago, researchers found that individuals on high doses of simvastatin—a statin marketed as Zocor by New Jersey-based Merck—who also carried a specific variant in the SLCO1B1 gene were fifteen times more likely to have muscle pain and injury, also known as myopathy. Based on these findings, which also correlated with markedly higher blood levels of a muscle damage biomarker, the US Food and Drug Administration set new guidelines recommending alternative medications for patients who need more than 40 milligram a day of simvastatin to lower their cholesterol.
In the new study, Krauss and his colleagues screened cultures of white blood cells, taken from 480 different patients on simvastatin. The researchers examined more than 10,000 genes, and narrowed their focus on four genes that specifically showed the most robust changes in activity when the cells were exposed to simvastatin. Of that quartet of genes, they selected the glycine amidinotransferase (GATM) gene for further study because it codes for an enzyme that makes creatine, a molecule that helps muscle cells store energy.
To test whether or not GATM was associated with muscle damage, the scientists compared cells from 72 people taking statins who reported myopathy against cells taken from 220 people on statins who didn’t have muscle damage. They discovered that only 40% of people on statin prescriptions who had muscle problems carried the protective variant called rs9806699. By comparison, 49% of the people on statins who didn’t report any muscle ailment had at least one copy of the GATM variant. Researchers found similar results when they looked for that same variant in cells from a further 100 participants who reported myopathy as a side effect in a different statin study of more than 12,000 people. Overall, about 25-30% of the subjects included in these studies had at least one copy of the GATM variant. However, these investigations only included participants of European descent; researchers remain unsure of how frequently this gene is found in the general population.
“More work needs to be done,” notes Lara Mangravite, first author on the paper and a biologist at Sage Bionetworks in Seattle. “We see that GATM has a role in muscle biology, but we need to know how it changes the cholesterol production in the liver, which then affects the wellbeing of the muscle.”
Krauss speculates the GATM variant may be protecting people by suppressing the statin-induced ramp-up of creatine production, thereby lowering the concentration of this energy-producing molecule and perhaps reducing muscle cells’ risk of being over-stressed.
Even though the effect of the GATM variant probably isn’t big enough to be thinking about a clinical test for the gene before prescribing statins, it’s still an important study, according to Alan Shuldiner, director of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine in Baltimore. “We’re seeing that more drug–gene effects have multiple genes involved and now we have two genes on the map for statins,” he says.
But, ultimately, a person’s genetic predisposition to muscle problems from statins might not influence whether they receive such drugs. “This is an impressive finding from a research perspective, but what next? Clinically there’s still no substitute for statins,” says pharmacogenetics researcher Julie Johnson, dean of the University of Florida College of Pharmacy in Gainesville.
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