BioWorld International Correspondent

LONDON - Genes play a strong part in determining blood levels of proteins that influence a person's risk of coronary heart disease, a study of twins has suggested. The researchers who carried out the study say their findings emphasize the importance of research into the genes that regulate the blood's ability to clot, for example.

The finding paves the way for studies aimed at identifying the genes responsible, with a view to eventually being able to screen populations to pinpoint individuals at high risk of having myocardial infarctions or strokes, who could be offered preventive treatment. Such genes also would provide targets to aid the development of drugs to reduce the risk of such events.

Investigators based at the Twin Research and Genetic Epidemiology Unit at St. Thomas's Hospital in London, and at the Academic Unit of Molecular Vascular Medicine at the University of Leeds, UK, involved more than 500 female Caucasian twin pairs in their study which examined levels of blood proteins involved in hemostasis. Their results are reported in a paper in the Jan. 13, 2000, issue of the The Lancet titled, "The genetics of haemostasis: a twin study."

Marlies de Lange, a Ph.D. student at St Thomas' Hospital who is first author of the paper, told BioWorld International, "We looked at factors in the blood which determine the ability of clots both to form and to be dissolved, and which are known to be associated with the risk of cardiovascular disease. We showed that there is a strong genetic basis for these factors."

The team, led by Peter Grant from the Leeds Unit, measured the concentrations of fibrinogen, factor VII and VIII, von Willebrand factor, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator, and factor XIII in monozygotic twins and dizygotic twins. These proteins have all either been associated with risk of coronary heart disease, or polymorphisms in the genes encoding them have been shown to influence protein levels and an individual's risk of cardiovascular disease.

Grant and his colleagues then used mathematical modeling to assess "heritability," the extent to which the degree of variation in levels of these proteins could be attributed to genetic factors. De Lange explained that the team compared the resemblance in protein levels in monozygotic twins, whose DNA is 100 percent the same, with that in dizygotic twins, whose DNA is normally about 50 percent similar, about the same as that for nontwin siblings.

"If identical twins resemble each other more than nonidentical twins, this must be due to genes," she said. "If identical twins are always exactly the same, whereas nonidentical twins show differences, then the variation is determined solely by their genetic makeup. If monozygotic and dizygotic twins resemble each other to the same degree, then the variation is due solely to environmental factors."

The results showed that the pairs of monozygotic twins did resemble each other more than the pairs of dizygotic twins, allowing the researchers to conclude that genetic factors were responsible for the levels of the blood factors under study.

"We then used model fitting techniques to find out the extent to which the genes were important in determining the levels," said de Lange. The team concluded that genetic factors accounted for between 41 percent and 75 percent of the variation in concentrations of fibrinogen, factor VII, factor VIII, PAI-1, tissue plasminogen activator, factor XIII A-subunit and B-subunit, and von Willebrand factor. For factor XIII activity, the figure was 82 percent and 38 percent for factor XIIa.

In the case of factor XIII activity, de Lange said, the study showed that the effect of genetic factors was "huge." She said, "This means that there is less influence from the environment causing variation in levels of factor XIII activity. Factor XIII plays a big role in stabilizing a clot that has formed, and high levels of this factor are associated with risk of development of coronary heart disease. If we could find the gene or genes which regulate the activity of factor XIII, then it would be possible to screen for people who are prone to develop coronary heart disease, as well as develop more effective drugs, which would target the proteins encoded by these genes."