Research Shows Why Statins Don't Work for Everyone

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By Ed Edelson
HealthDay Reporter
Monday, June 16, 2008; 12:00 AM

MONDAY, June 16 (HealthDay News) -- A genetic quirk in the production of one protein helps explain why some people don't get the full cholesterol-lowering benefit of statin drugs, researchers report.

Statins include blockbuster medications such as Crestor, Lipitor, Pravachol and Zocor.

The protein, abbreviated as HMGCR, plays a critical role in production of LDL cholesterol, the "bad" kind that clogs arteries, explained lead researcher Dr. Ronald Krauss, director of atherosclerosis research at the Children's Hospital Oakland Research Center in Oakland, Calif.

Some people use the HMGCR enzyme to produce LDL in an alternative way, however, and this difference is "strongly related to the LDL-lowering effect of statins," Krauss said.

At the heart of the process are protein fragments called exons that are spliced together to produce an active protein, he explained. Statins block LDL cholesterol production by binding to a particular exon when the protein is assembled. But depending on how this HMGCR splicing occurs, a statin drug has a better or worse chance of working as it should to lower cholesterol.

Krauss' team reported its findings in the June 17 issue ofCirculation.

Krauss and his colleagues studied the genetic activity of HMGCR production in laboratory cell lines obtained from about 200 participants in a cholesterol study.

They found the alternatively spliced and less active version of the HMGCR protein in many of the cell lines. "Everyone has it to a greater or lesser degree," Krauss said. The incidence of the alternatively spliced protein was the same in whites and blacks, he said.

There have been previous reports of genetic variations in the protein, one of them from the group led by Krauss. Those involved point mutations, in which a specific unit of the protein chain was abnormal, he said. This is the first report of an alternatively spliced version.

"Statins are used by millions of people, so anything that affects the response to them is important," noted Dr. Michael Y. Tsai, director of the Lipid and Cardiovascular Risk Assessment Laboratory at the University of Minnesota.

"But this only accounts for 6 to 15 percent of the variation in response, so it is not enough to be clinically useful," Tsai added.

Nevertheless, he said, "this is making progress in the right direction."

Krauss agreed that there's more to the statin response than HMGCR. So, testing patients for the alternative splicing version of the protein before writing a statin prescription probably isn't in the cards for the near future, he said.

"This identifies a piece of the puzzle," Krauss noted. "There is considerable variation among individuals in how they respond to statins. If we can put all the pieces of the puzzle together, that would have clinical value. This is a big piece but not enough for clinical application."

More information

To learn about statins and who should be taking them, consult the American Heart Association.

SOURCES: Ronald Krauss, M.D., director, atherosclerosis research, Children's Hospital & Research Center, Oakland, Calif; Michael Y. Tsai, M.D., Ph.D., director, Lipid and Cardiovascular Risk Assessment Laboratory, University of Minnesota, Minneapolis; June 17, 2008,Circulation



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