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Gene links to heart health
By Roberta Friedman

It's a typical question asked in any medical history taking: "anyone in your family have high blood pressure, die of a heart attack?" Doctors know that the risks for cardiovascular disease are partly determined in the genes. And a few genes for severe forms of inherited risk, a familial form of high cholesterol for example, have been pinpointed.

"There are genotypes being produced as we speak," says Hilary Coon, a geneticist and statistician at the University of Utah in Salt Lake City. Coon and colleagues reported recently in the Annals of Human Genetics that evidence points to a single gene accounting for modestly raised levels of the LDL-C form of cholesterol in some people. And it is not one of the genes already associated with cholesterol.

LDL inheritance is not cut and dried, Coon says. "We don't expect simple Mendelian inheritance. Most of the successful gene hunting has been for the very rare, very high levels of cholesterol." The project is not looking in "those people, who are way off the map" for LDL, Coon says. Rather, the researchers are hunting for genes that control more subtle changes that nevertheless may be linked to cardiovascular disease. Even "mild elevation (in LDL) is a risk factor" for cardiovascular disease.

Coon and colleagues found evidence for a common gene accounting for mild elevations in LDL-C in a segregation analysis of the records of 3,227 people surveyed in the Family Heart Study, conducted by the National Heart, Lung, and Blood Institute. The researchers inferred the existence of the gene using a statistical analysis of the LDL levels collected in the survey. The gene appears to account for 24 percent of the variation in levels of LDL-C. The best fitting model is for a relatively common recessive gene that in combination with other genes, exerts a minor effect. Geneticists call this pattern polygenic control over a trait. But alternative genetic explanations are not ruled out by this evidence, Coon says.

None of the known genes related to cholesterol explain mild elevations in LDL levels, according to Coon. "There's something else than the genes that appear in the literature. There's something else we should look for." Previously identified genes include one that codes for the LDL receptor, the gene for apolipoprotein E, and the gene coding for the enzyme cholesterol 7alpha-hydroxylase, suspected of playing a role in cholesterol levels in the blood.

According to Aldons Lusis, a geneticist in the department of medicine at the University of California, Los Angeles, statistical models can tell you about the existence of a gene, but that is not the same as actually finding the gene. Still, Lusis says, "Segregation analysis gives a model that fits best with the concept that there are novel genes" determining levels of LDL. Discovery of these genes could lead to new ways to diagnose people at risk. "Athero-sclerosis is a disease that develops over a lifetime," Lusis says. Because more than half of all deaths in the United States are related to heart disease, knowing who carries a cholesterol-elevating gene could prove important. Such knowledge could allow physicians to recommend precautions, such as special diets or cholesterol-lowering drugs. Researchers could also use new genetic information to find targets for the development of new drugs better suited to mildly elevated cholesterol levels.

The development of the family of drugs called statins grew in large part from our understanding of the genetics of rare cases of extremely high cholesterol, Lusis says. "We already have statins," he adds, "But they don't eliminate heart disease and they have side effects." Understanding the genetics of mild elevations of LDL might lead to a family of drugs that would address problems in a much wider group of people.

Once Coon and colleagues determined statistically that a gene must exist, they turned to looking at DNA to find the gene itself. The Family Heart Study data, clinical data from 583 random-sample families and 649 coronary-prone families, includes carefully banked DNA. "We have DNA on a subset of those families used for the segregation analysis," Coon says. "We have 100 families genotyped with almost a complete genome scan, and expect another 100 fairly soon."

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Coon, H., Leppert M.F., Kronenberg, F., Province, M.A., et al. Evidence for a major gene accounting for mild elevation in LDL cholesterol: The NHLBI Family Heart Study. Ann Hum Genet 63, 401-412 (September 1999).

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