Genetic Find Fuels Debate over Race-Based Medicine

November 17, 2005

Icelandic company DeCode Genetics claims to have discovered a gene variant that raises heart attack risk in African Americans by over 250%, adding fuel to the ongoing controversy about race-based medicine.

The report, by Dr Anna Helgadottir and colleagues from DeCode, was published online by Nature Genetics and reported in the New York Times online on 11 November 2005.

DeCode initially identified the gene variant among Icelanders, then looked for it among three American populations: in Philadelphia, Cleveland and Atlanta.

Although the gene is present among various ethnic groups, its effects seems to vary. Among Americans of European descent, the variant is common but is associated with only a small increase in risk (about 16%). In contrast, in African-Americans - only 6% of whom carry the variant - carrying the variant gene increases the risk of heart attack 3.5-fold, compared with African Americans who carry the normal variant of the gene.

Dr Kari Stefansson, DeCode's chief executive told the New York Times he would "consult with the Association of Black Cardiologists and others as to whether to test a new heart attack drug specifically in a population of African-Americans."

The drug in question - now known as DG031- inhibits a different but closely related gene. Moreover, it is about to move into Phase 3 clinical trials, which marks the last stage before a drug manufacturer seeks approval from the US Food and Drug Administration (US) to market the drug.

Race-Based Medicine Controversy

Last year, heart drug BiDil (a combination of hydralazine and isosorbide dinitrate) became a topic of controversy when it was shown to sharply reduce the incidence of heart attack among African-Americans- first in a study of the general population, in which it was not effective, then in a targeted study of African Americans.

BiDil, invented by Dr Jay N Cohn, a cardiologist at the University of Minnesota, prompted objections to what was perceived as "race-based medicine".

The issues of genetics and race are closely intertwined in medicine. While geneticists agree that genes are the medically significant factors that predispose a person to disease, it may be useful for physicians to take race into account, as the genes that predispose a person to a variety of diseases follow racial patterns.

The gene variant discovered by DeCode Genetics is called leukotriene A4 hydrolase (LA4H) and is involved synthesizing leukotrienes (agents that maintain inflammation). The newly discovered variant is a more active version of a gene that helps to regulate the body's inflammatory response to infection.

Dr Stefansson said he believed that the more active variant might have become more widespread among Europeans and Asians because it gave extra protection against infectious disease. However, along with the extra protection, a higher risk of heart attack may have come because arterial plaques could become inflamed and rupture.

He further hypothesizes that, because the more active gene variant came into favor long ago, Europeans and Asians have had time to make genetic adaptations to offset the heightened heart attack risk.

The more active gene variant would have passed from Europeans into African Americans only in the past few generations, which is too short a time for African Americans to develop genes that protect against heart attack.

Testing the New Drug

DeCode Genetics is in the process of testing DG031, a drug that affects another gene also involved in controlling leukotrienes. They hypothesize that, because DG031 reduces leukotriene levels and inflammation, it may also help African-Americans who have the gene variant.

However, as with the BiDil trial, opinions vary as to whether is useful.

"It would make scientific, economic and particularly political sense to have a significant part of the clinical trials done in an African-American population," Dr Stefansson said, according to the New York Times.

A spokeswoman for the black cardiologists' group that supported the BiDil trial, reportedly stated that the group's officials were not prepared to discuss the topic.

Dr Troy Duster, of New York University, an adviser to the federal Human Genome Project and a past president of the American Sociological Association, reportedly saw no reason to object to the proposed drug trial. However, he noted that the trial should focus on African-Americans who have the risk-associated gene-variant, and also that it should take into account that people with ancestry from different African regions might have variations in risk.

In contrast, Dr Charles Rotimi, a genetic epidemiologist at Howard University, reportedly believes that a separate study of African Americans would be undesirable, saying that the variant gene's relative over-activity may be caused by greater exposure to deleterious environmental factors.

Dr Cohn, who invented BiDil, said it was "always best to study a drug in a highly responsive group," rather than testing a drug in larger populations where possible benefits to subgroups could be entirely missed.

Source:
Genetic Find Stirs Debate on Race-Based Medicine, New York Times, 11 November 2005.

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