NEW YORK (GenomeWeb News) – New research has identified genetic polymorphisms that are associated with muscle-related side effects in individuals taking high doses of a cholesterol-lowering statin.
In a paper appearing in today’s issue of the New England Journal of Medicine, a team of researchers from the UK used large genome-wide association studies of individuals taking Merck’s statin Zocor (simvastatin) to uncover genetic variants that are linked to the risk of the statin-induced muscle disease myopathy. Their findings suggest that this painful — and potentially lethal — side effect appears to be intimately linked to variants in a gene called SLCO1B1, which influences statin transport into liver cells.
“[T]he genotyping of SLCO1B1 polymorphisms may be useful in the future for tailoring both the statin dose and safety monitoring … in order to obtain the benefits of statin therapy more safely and effectively,” the authors wrote.
Statins, a class of drugs that lower low density lipoprotein cholesterol, are frequently prescribed in an effort to decrease the risk of heart attack and stroke. But in a small subset of individuals the drugs can cause myopathy, particularly at high doses or when taken in conjunction with other compounds.
In extreme cases, this muscle pain or weakness can lead to muscle breakdown, kidney failure, and death. Bayer yanked its statin Baycol (cerivastatin) off the market in August 2001, citing concerns over myopathy-related side effects and deaths. The drug was eventually linked to dozens of deaths around the world.
Overall though, the risk of statin-related myopathy is thought to be very low — about one in 10,000 at the normal dose. It is primarily a concern for those taking elevated statin doses, author Jane Armitage, a clinical epidemiologist at the University of Oxford’s Clinical Trial Service Unit, told GenomeWeb Daily News. “Statins are a very safe group of drugs, particularly when used at the standard doses,” she said.
Even so, identifying genetic factors that contribute to this risk could be crucial, especially since there is still a debate over the potential benefits of higher statin doses, which some suggest could produce more dramatic decreases in cholesterol and better protection against heart disease and stroke.
For the latest paper, the researchers took advantage of two statin trials — the Merck-funded Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and the Heart Protection Study, which was funded by Merck, Roche Vitamins, the Medical Research Council, and the British Heart Foundation.
For the first part of the work, the researchers selected a subset of individuals from the more than 12,000 who were participating in the SEARCH trial. That randomized trial included individuals who had already had a myocardial infarction and was designed to determine whether they benefited from taking 80 milligrams — rather than 20 or 40 milligrams — of simvastatin daily.
Using Illumina’s Sentrix HumanHap300-Duo BeadChip microarrays, the researchers genotyped 85 individuals who had been diagnosed with reversible, definite, or incipient myopathy at more than 300,000 SNPs and compared them with 90 individuals who did not have the side effect.
The team also genotyped thousands of individuals involved in the Heart Protection Study, a trial that took place in the UK from 1994 to 1997. In that trial, 20,536 individuals with diabetes or vascular disease were assigned to groups receiving either 40 milligrams of simvastatin daily or placebo.
Based on these studies, the researchers pinpointed two SLCO1B1 SNPs — rs4149056 and rs2306283 — that influenced statin-related myopathy risk. Their results suggest that as much as 60 percent of the myopathy associated with simvastatin treatment is due to variation in the SLCO1B1 gene.
Because SLCO1B1 codes for OATP1B1, a polypeptide believed to function in the uptake of drugs by the liver, the researchers speculated that gene variants may alter the way statins are used by the body. When this gene variant is present, the drug is not transported as efficiently into the liver cells where it can act. Instead, the concentration of the drug in the blood remains high.
The findings are especially relevant for those taking high doses of statins. For these individuals, the authors concluded, carrying one of the SLCO1B1 polymorphisms identified in the study “may produce particularly high risks of myopathy.” Armitage noted that the genetic variants may also be very relevant for those who are susceptible to myopathy in general, such as the elderly or those with impaired kidney function.
In an accompanying editorial in the same issue of NEJM, Yusuke Nakamura, a researcher at the University of Tokyo’s Human Genome Center, noted that the SEARCH group’s genome-wide approach illustrates the potential value and power of large association studies, demonstrating an “unequivocal association” between statin-induced myopathy and SLCO1B1 polymorphisms.
“Among many potential causes of adverse drug reactions, genetic variants that cause susceptibility to a drug reaction loom large,” Nakamura wrote. “The identification of such variants is expected to improve the management of patient care by determining which patients should avoid a specific drug and which patients should take a modified dose of the drug.”
In the future, he added, more large association studies could potentially improve patient care, curb healthcare costs, and make new drug development more efficient. “Indeed,” Nakamura wrote, “a global mechanism for collecting data on patients with severe adverse reactions would benefit the field of pharmacogenomics enormously and encourage the development of new technologies.”