Oakland, CA - Differences in processing the enzyme that is the direct target of statin inhibition may explain why some people don't respond well to this class of drugs, say US researchers [1]. This finding, thought to be due to "alternative splicing" of the enzyme, is the first to establish a substantial contribution of a biological process to variation in statin efficacy, say Dr Marisa Wong Medina (Children's Hospital Oakland Research Institute, CA) and colleagues in their paper published online June 16, 2008 in Circulation.

Senior author Dr Ronald M Krauss (Children's Hospital Oakland Research Institute) told heartwire that his team found that individuals differed in the degree to which this enzyme was spliced, "and this is probably genetic, although we don't yet fully understand all the reasons." Such differences explained 9% to 10% of the variability in response to statins, which he says "is a large number, because when we have previously looked at variations in genes affecting cholesterol metabolism, we can usually only explain no more than 1% to 2% of the variability in statin response."

However, he is at pains to stress that this new finding, "while a big piece of the puzzle, is still not enough of a predictive value to make this a test we would recommend." And in any case, the test itself is only a research tool that, for various reasons, is unlikely to become clinically available, he notes. "The general area of pharmacogenetics in cardiology is an evolving field that is going to require filling in a lot of blanks, it's not going to be single features that are going to be sufficient." But he does believe the work might help lead to better genetic testing in the future and/or could aid in the development of new drugs.

Wong Medina et al analyzed differences in how the gene responsible for producing 3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR, was spliced, using lymphocyte cell lines extracted from 170 of the more than 900 participants enrolled in the Cholesterol and Pharmacogenetics (CAP) study, who were treated with simvastatin 40 mg/day for six weeks. The enzyme that is produced from the normally spliced HMGCR messenger RNA plays an early and critical role in the body's production of cholesterol, and its activity can be strongly inhibited by statins, they explain.  

They identified an alternatively spliced transcript of HMGCR that lacks exon 13, HMGCRv_1, and measured its expression in the 170 cell lines. They found that greater upregulation of HMGCRv_1 in vitro was significantly correlated (p<0.0001) with smaller in vivo reductions of plasma total and low-density-lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B and explained 6% to 15% of the variation in statin response of these measurements.

"Our findings point to a major role of HMGCR alternative splicing in influencing cholesterol response to statin treatment and exemplify how alternative splicing can act as a modifier of drug response," they note.

"This is just a part of the overall picture," Krauss stressed, "but it's a big piece of it. In the past we've had no more than 1% to 2% of the variability in response to statins explained by any given gene."

In addition, there have been reports of specific variants in this gene related to the level of blood cholesterol itself, says Krauss, "and we have reasonable evidence that this is also related to the splicing phenomenon. This is something that could help us understand one of the mechanisms by which genes affect blood cholesterol levels in the population."

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, he says. For example, a compound that could modify the splicing process "could wind up increasing the efficacy of statins by 10% to 20% or more," he concluded.