Download Gene a Pain for Statin Users

Gene a Pain for Statin Users
A genetic variant may help explain why some patients experience
muscle discomfort and dysfunction while taking the cholesterol-lowering
medications.
By Kate Yandell | August 28, 2013 Summary from The Scientist
Using a novel approach, researchers have discovered a genetic variant that may
contribute to the muscle pain and weakness experienced by some statin users,
according to a study published in Nature today (August 28). Under statin-treated
conditions, the variant affects expression of the gene for glycine
amidinotransferase (GATM), which controls the synthesis rate of creatine, a
molecule muscles use for energy.
“The authors used a really
unique approach for trying
to understand why some
people might respond
differently [to statins],” said
Deepak Voora, a physicianscientist studying
pharmacogenetics at Duke
University, who was not
involved in the research.
“That approach will have implications for studying other drugs.”
To find relevant genetic variants, the researchers collected lymphoblastoid cells
from patients participating in a trial testing simvastatin, also known as Zocor.
Statins generally act in the liver, but the researchers noted that
lymphoblastoids—immortalized immune cells that are easily generated from
blood samples—were a reasonable proxy for liver cells’ response to statins.
“The notion of using lymphoblastoid cell lines to understand drug effects is very
interesting,” said Dan Roden, a pharmacogeneticist at Vanderbilt University who
was not involved in the study. “It’s a very, very interesting way of finding new
signals.”
The researchers treated the cells with statins and, examining expression
quantitative trait loci (eQTLs), looked not only for genes whose expression the
drug affected, but whose changes in expression suggested variation among all of
the cell lines’ drug responses.
They eventually focused on the gene for GATM, which showed promise because it
encodes an enzyme that limits the rate of creatine synthesis. “Creatine is a
major source of energy for skeletal muscle,” said Voora. “It makes sense that
something that alters the level of creatine within the muscle might predispose
the individual to muscular side effects.”
Indeed, when the researchers analyzed the link between the GATM expressionrelated variant and whether patients in other clinical trials experienced muscle
problems, or statin-induced myopathy, they found the association was
significant.
“We found there is this genotype that both affected GATM expression response
and also affected predisposition to myopathy,” said Lara Mangravite, director of
systems biology at Sage Bionetworks in Seattle and lead author of the study.
Previously, researchers had looked for genetic variants associated with statin
response using traditional genome-wide association studies (GWAS) comparing
single nucleotide polymorphisms (SNPs) between patients with and without
statin-induced muscle problems. The GWAS approach yielded one important set
of variants of the gene SLCO1B1, which helps control the rate of statin uptake in
the liver.
While some patients are now screened for SLCO1B1 variants to help predict their
response to statins, Mangravite does not envision a similar scan for GATM. “I
don’t think this is going to turn into a clinical biomarker test,” she said. “I don’t
think that the effects are of the magnitude that would cause that.” Rather, she
noted, the gene could help scientists elucidate how statins can cause myopathy,
and understand how to create treatments that avoid similar adverse effects.
To further understand the function of GATM, the researchers knocked its
expression down in liver cells, finding that it altered their response to cholesterol
depletion. “There is interplay with cholesterol metabolism and muscle
metabolism,” said Mangravite. “We don’t know what that mechanism is.”
Moreover, Mangravite pointed out that GATM’s effects on myopathy have yet not
been fully explained. Roden called the possibility that GATM variation leads to
myopathy a “very appealing hypothesis that probably needs more work.”
“They used these cell lines and an extensive survey of eQTLs after exposure to
come up with a plausible gene for mediating statin effects,” he said.
“If other people find the same gene, that will be the true test of these findings,”
added Voora.
L.M. Mangravite, “A statin-dependent QTL for GATM expression is
associated with statin-induced myopathy,” Nature,
doi:10.1038/nature12508, 2013.