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Analysis Reveals Cholesterol-related Locus Linked to Statin Side Effect

NEW YORK (GenomeWeb News) – Researchers from Seattle's Sage Bionetworks, the University of Chicago, the Children's Hospital Oakland Research Institute, and elsewhere reported today that they have detected a new cholesterol-related locus with apparent ties to the risk of muscle-related side effects in those taking statin drugs.

As they reported online today in Nature, the researchers compared array-based gene expression patterns in cells from almost 500 individuals involved in a trial of simvastatin, a statin that's marketed as Zocor by Merck and sold generically under several different names. From there, they went on to track down a statin-related expression quantitative trait locus, or eQTL, on chromosome 15 that affects the expression of an enzyme-coding gene called GATM.

Dialed down expression of that gene, in turn, leads to a dip in levels of certain cholesterol components, the group found through its subsequent mouse and cell line experiments. And data from other statin trials indicated that the GATM-linked eQTL had ties to a statin side effect, too, namely a form of muscle weakness called myopathy that occurs in some people taking the drugs.

"[T]his study has provided evidence that functionally significant genetic effects can be discovered using a novel cell-based screen for gene-by-treatment effects on transcriptional expression," the University of Chicago's Matthew Stephens and Children's Hospital Oakland researcher Ronald Krauss, the study's co-senior authors, and their colleagues wrote.

"This approach has led to the identification of GATM as a genetic locus associated with statin-induced myopathy," they noted, "and as a potential link between cellular cholesterol homeostasis and energy metabolism."

In their attempt to tease apart genetic variants with ties to statin response and risk, the researchers focused on transcriptional profiles in cell lines generated from individuals of European-American ancestry who were or were not exposed to the drug.

Since statins exert control over low-density lipoprotein, or LDL, levels in the blood by acting on a transcriptional network controlled by the sterol-response element binding protein, they reasoned that such an expression-based analysis might be apt to uncover genetic factors contributing to the drug's effects.

Using Illumina's Human-Ref8v3 beadarray, they assessed gene expression patterns in 480 lymphoblastoid cell lines, representing individuals who'd been given activated simvastatin or a control buffer for at least a day as part of the Cholesterol and Pharmacogenetics, or CAP, clinical trial.

More than half of the genes typically transcribed in lymphoblastoid cell lines showed significant shifts in expression after statin treatment, the team found. But just 21 of those genes had expression changes amounting to 50 percent or more.

When they considered genotype information for the trial participants, meanwhile, the investigators came up with a long list of apparent eQTLs in the lymphoblastoid cells, including half a dozen simvastatin-related cis-eQTLs.

One of these caught the team's attention in particular: a chromosome 15 site containing the rs9806699 SNP and dozens of other variants in linkage disequilibrium with it.

That eQTL apparently influences the expression of GATM, the researchers noted, which codes for a glycine aminotransferase enzyme that is involved in a critical creatine production step. GATM is believed to participate in both lipid metabolism and myopathy-related processes, prompting a series of follow-up studies to assess its potential role in statin-related myopathy.

Through an analysis of data for 72 statin takers who experienced myopathy and 220 unaffected, matched controls, for instance, the study's authors found that individuals carrying the less common version of the GATM eQTL variants were less prone to statin-related myopathy.

A similar association turned up when the group considered data for another 100 individuals with statin-induced myopathy who'd been enrolled in the Study of Additional Reductions in Cholesterol and Homocysteine, or SEARCH, study.

When researchers knocked down GATM expression in cells line derived from liver cells, they found a subsequent dip in the cells' secretion of an apolipoprotein B protein ingredient of LDL cholesterol. Mice that were missing the GATM gene had lower-than-usual cholesterol levels, too, supporting the gene's general role in cholesterol-related processes.