Why some people do not respond as well as others to statin therapy

A newly discovered genetic variation, in combination with a second variation, reduces the ability of statin drugs to lower "bad" LDL cholesterol, researchers report at the American Heart Association's Scientific Sessions 2005.

The new variation was found in a gene critical to the synthesis of cholesterol. The combination of the two variations occurred in nine African Americans (3 percent) and one Caucasian (0.2 percent) participating in the study.

"We need to understand more clearly the basis for the wide range of responses to statins, both in the lowering of cholesterol and in outcomes, such as heart attacks and strokes," said Ronald M. Krauss, M.D., lead author of the study and director of atherosclerosis research at Children's Hospital Oakland Research Institute in Oakland, Calif.

"This study is one piece of the overall equation that we and others are trying to fill in to understand why some people do not respond as well as others to statin therapy," he said.

The new finding -- somewhat akin to fitting together the first pieces of a 1,000-part jigsaw puzzle -- has no immediate implications for treating patients, researchers said.

Many clinical studies have demonstrated that statin drugs effectively lower cholesterol and reduce death from cardiovascular disease. Evidence also indicates that genetic inheritance influences the drugs' effectiveness.

"We compared African Americans and Caucasians because they have very different genetic histories," Krauss said. "We were interested in knowing if there were any differences in response to the drugs between the two groups because there is very little information in the scientific literature to answer the question."

Genes commonly have several slightly different forms. These variations result from single nucleotide polymorphisms (SNPs). A SNP is a place where one of the four building blocks of genes has been substituted for another. Typically, however, two or more SNPs are inherited together. Such a combination is called a haplotype.

For their study, Krauss and his colleagues enrolled 296 African Americans and 573 Caucasians at the University of California, San Francisco and the University of California, Los Angeles.

"They were largely representative of the people who are candidates for statin treatment in clinical practice," Krauss said. Participants took one 40-milligram tablet of the drug simvastatin each evening for six weeks.

The researchers identified nine haplotypes in the gene that carries the code for HMGCoA reductase (HMGCR), an enzyme that statin drugs target to reduce the production of cholesterol. The nine included the newly discovered haplotype, designated Hap 2, consisting of 12 SNPs. It also included a previously identified haplotype associated with statin response that consists of two SNPs and is known as Hap 7.