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Genetic variations reduce the ability of statin to lower LDL cholesterol

Researchers reported at the American Heart Association's Scientific Sessions 2005 that a newly discovered genetic variation, in combination with a second variation, reduces the ability of statin drugs to lower LDL cholesterol.

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, lead author of the study and director of atherosclerosis research at Children's Hospital Oakland Research Institute in Oakland.

" 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.

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 ( Zocor ) 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.

The findings included:

The 35 African Americans who carried Hap 7 had a 34.1 percent reduction in LDL compared to 39.8 percent for noncarriers.
Caucasians with Hap 7 showed no significant difference compared to noncarriers.
The 10 participants who carried both Hap 7 and Hap 2 had a much lower LDL reduction -- 24.5 percent compared to 41.9 percent in the 620 volunteers who carried neither haplotype.
Overall, Caucasians had an average drop in LDL of 42 percent versus 39.2 percent in African Americans, a small but statistically significant difference.

When the team excluded the 10 participants who carried both Hap 7 and 2 from the analysis, they found no significant difference in LDL-lowering between the 111 African Americans and 509 Caucasians who carried neither haplotype. The two groups lowered their LDL by 41 percent and 41.9 percent, respectively.

Krauss cautioned that nothing in the study's findings suggests restricting the use of statins in African Americans or in subgroups carrying Hap 2 and Hap 7.

" By no means would we draw that conclusion," he said. " This is just one gene and two haplotypes, and there are certainly many more genes involved. But an understanding of the basis for these genetic differences in statin response could lead to improved treatments for reducing LDL levels."

Source: American Heart Association, 2005