Genetic 'bar codes' predict effect of statins

April 24, 2002

HONOLULU, April 24 - Searching for patterns of genetic variation, rather than a single variation, may be a more promising approach to predicting a person's response to cholesterol-lowering therapy, according to research presented today at the American Heart Association's Asia Pacific Scientific Forum.

In recent years, researchers have studied genes to determine their effect on the risk of heart disease, as well as how they influence treatments for heart disease such as cholesterol-lowering drugs.

Researchers from Ruprecht Karls University and Albert Ludwigs University in Germany, and from Genaissance Pharmaceuticals in the United States studied the cholesteryl ester transfer protein (CETP) gene that is involved in keeping the balance between the good and bad types of cholesterol. They suspected that variations in this gene could affect a person's response to cholesterol-lowering drugs.

"Not all people have the same response to treatment and we think this could be linked to genetics," says study author Gualberto Ruaño, M.D., Ph.D., chief executive officer of Genaissance Pharmaceuticals, Inc., in New Haven, Conn.

When they analyzed participants' CETP genes, researchers were looking for genetic markers for heart disease. However, they found that individual gene variations called single nucleotide polymorphisms (SNPs) - small alterations in genes - were not associated with the person's cholesterol levels after drug treatment. But, when they looked at a pattern of gene variations called a haplotype, they did find an association.

"A haplotype is a combination of variations in a gene. Variability is measured at two levels: the individual level that SNPs and the haplotype level. Think about the SNP as a single band in a bar code, and the haplotype as the bar code that has all of those organized," explains Ruano.

This research was part of an ongoing longitudinal study spearheaded in Germany. Out of 3,000 individuals in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) - all had high levels of CVD - researchers chose 98 people who were prescribed statins, a class of cholesterol-lowering drugs, and documented their treatment. The participants were followed about five weeks, which is considered sufficient time for statins to have an effect, says Ruano.

They measured low-density lipoprotein cholesterol (LDL-C, "bad" cholesterol), high-density lipoprotein cholesterol (HDL-C, "good" cholesterol), triglycerides and blood levels of CETP before and after treatment with statin drugs. They then compared activity levels of CETP with changes in LDL-C, HDL-C and triglyceride levels after treatment.

For reference DNA, researchers determined the variations of the CETP gene in a group of Caucasian, African-American, Asian and Hispanic-Latino people.

They examined the relationship of each person's CETP gene SNPs and haplotype to his or her response to statin therapy (as measured by changes in HDL-C, LDL-C and triglyceride levels).

The researchers found that, in general, the individual SNPs had little effect on the amount of protein, the activity of the protein, or the person's response to statin therapy. However, when they looked at haplotypes, individuals had very different responses to statin treatment.

People with two copies of a particular CETP haplotype showed at least three times the increase in HDL-C levels compared to those with one or no copies of this haplotype.

Haplotype analysis may allow for highly individualized treatment of patients with lipid disorders, Ruano says.

Ruano's team has launched a larger study of about 800 patients in the United States to further test the association of certain genetic haplotypes with the efficacy and safety of statin treatment.

"Sometime in the next five years we would expect genetic testing like this to be as common as cholesterol screening, with as little as a 30-minute wait for test results," says Ruano.
Co-authors include Bernhard R. Winkelmann, M.D.; Catharine B. Stack, Ph.D.; Joel C. Stephens, Ph.D.; Michael M. Hoffmann, Ph.D.; Madan Kumar, Ph.D.; Krishnan Nandabalan, Ph.D.; Richard S. Judson, Ph.D.; Alan R. Tall, M.D.; Winfried März, M.D.; and Connie M. Drysdale, Ph.D.

Maggie Francis or Carole Bullock
AHA News Media Relations
Hawaii Convention Center
Honolulu, Hawaii
Ph. 808-792-6515

Abstract 51

American Heart Association

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