January 1, 2006 (Vol. 26, No. 1)

Researchers Strive to Quantify Racial Role in Disease Risk & Treatment

Results from the Human Genome Project and the cataloging of human genetic variation are spurring discussions that may turn modern concepts of race on their ears.

The latest word is that, “among modern humans, there’s no such thing as race,” according to Joseph L. Graves, Jr., Ph.D., dean of university studies and professor of biological sciences, North Carolina Agricultural & Technical State University (www.ncat.edu). And, he adds, there never was.

Dr. Graves, an evolutionary biologist, and other geneticists, say there is no genetic basis for the variations we typically ascribe to “race.” Specifically, there are no genetic variations that are found in every member of one race but not in others. The biological descriptors often associated with race, including risk factors for certain diseases, can be found in many populations.

As Michael Liebman, Ph.D., executive director, Windber Research Institute (www.wriwindber.org) adds, “The idea of race persists in cultures, but it’s not a genetic definition and it gets confused with cultural relationships.”

Our concept of race is merely a social constructa socio-demographic group defined by geography and culture with no genetic basis.

That, however, doesn’t mean that concepts of race or ethnicity are meaningless in terms of understanding biology, improving medical care, or reducing health disparities. There are, however, genetic variations that tend to fall along the lines of what we call “race.”

Geographic Ancestry

Such “genetic variation can be used to make a reasonably accurate prediction of the geographic origins of an individual’s ancestors,” observes Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute (www.genome.gov).

The correlation between ancestral origins and self-identified race and ethnicity is often imprecise, he continues, “because of other non-genetic connotations of race, the lack of defined boundaries between populations, and the fact that many people have ancestors from multiple regions of the world.”

For example, Dr. Graves explains, the sub-Saharan population has more genetic variation than other groups because they stayed in one geographic location. “All others are subsets of that group, with mutations unique to their regions.”

Mutations are rare, however, and occur at a rate of one in one hundred thousand to one in one million. Most of those occur in the portion of the 85% of an individual’s DNA that is neutral, or non-coding, Dr. Graves says. That 85% signals geographic origins and “tells you where you’ve been.”

“The remaining 15 percent is under the influence of natural selection and, therefore, has less variation,” says Dr. Graves. Of that 15%, 10% accounts for variations between geographically distinct groups and the remaining 5% accounts for variations between groups from different continents. Despite such variations, any two unrelated people are 99.9% identical.

“Of that 0.1 percent of differences, most fall in parts of the genome that can tolerate variation without any consequences,” Dr. Collins says. “A small number of those variants, however, can play a key role in predisposition to illness, longevity, and other factors affecting health status.

“There’s a strong argument that discovering those specific disease-associated genetic variations would allow us to identify disease risks and be able to do something about it,” Dr. Collins explains.

“Most of the common variations will likely be found anywhere in the world but, potentially, in different frequencies,” Dr. Collins says.

Impact on Health

There are genetic variations that influence health, but that’s different from talking about racially based diseases, points out Dr. Graves.

For example, some people discuss Crohn’s disease as an example of an “ethnically based disease.” Inflammatory bowel disease, of which Crohn’s diseases constitutes approximately 50% of cases, affects American Jews of European descent four to five times more frequently than other populations.

Crohn’s disease itself affects American Jews of Central European descent two to three times more frequently than other populations. Largely overlooked is the fact that it is being diagnosed among Hispanics and African-Americans with increasing frequency.

In fact, Dr. Collins says, the associations often made between race and disease only occasionally have anything to do with DNA. Most diseases are not single-locus genetic diseases and often are quite complex, involving many genetic loci as well as environmental factors.

Take the case of hypertension, a leading cause of heart disease. “In the U.S., the African-American population (which is descended mainly from western and central Africans) is prone to hypertension. But, their western African ancestors weren’t,” according to Dr. Graves, though they share many genetic variants in common. “If African-Americans are predisposed to hypertension, it’s because of environmental effects.”

The prevalence for biological-based conditions is 2.5 times higher among African-Americans than among those with European ancestry and is based upon the relative harshness of the environment.

In this case, environmental factors like healthcare access, education, social status, and stress, rather than genetics, become the disease triggers.


Recent findings emphasize that a haplotype (HapK) confers a modest risk of myocardial infarction in European-Americans, but confers a three-fold larger risk in African-Americans, according to multi-center research from deCODE Genetics (www.decode.gom), Emory University, the National Cancer Institute, the Icelandic Heart Association, and others.

The HapK variation is found in 27% of the Icelandic population, only 6% of African-Americans, and is very rare in Africans. If genetics was the primary risk factor for myocardial infarctions, the risk for African-Americans would be significantly lower, Dr. Graves asserts.

Dr. Collins, however, says “that conclusion cannot be supported by existing scientific evidence. More than one genetic variation likely contributes to the risk of myocardial infarction and many of those genetic variations have yet to be discovered.”

“The popular media represented that finding as a race-based factor for heart attack,” Dr. Graves says, although the study’s investigators explained clearly that the increased risk could be either genetic or environmental. The gene associated with HapK causes inflammation in arteries, which, in turn, is influenced by one’s disease state, emotional state, and other factors.

The acknowledged poorer outcomes among African-Americans with heart failure were behind last June’s FDA approval of BiDil for the treatment of heart failure in African-American patients.

As Manuel Worcel, M.D., CMO, NitroMed (www.nitromed.com), elaborates, studies showed “a stronger efficacy in African-Americans than in Caucasians, but it is not only effective in African-Americans.”

The African-American Heart Failure Trial found that BiDil decreased the risk of mortality by 43% in African-Americans. Broader studies are being planned to identify why BiDil, administered with such background therapies as ACE inhibitors or beta blockers, is effective in this population and to determine whether it is also effective in other populations.

Experts have hypothesized that its effectiveness in an African-American population is based on its effectiveness against hypertension, the form of heart disease most common among African-Americans. Dr. Worcel says its success is based upon the fact that BiDil is a vasodilator with nitric oxide-enhancing properties. “Where genomics can play a role, I don’t know.

“Be very careful in saying that genes determine things,” Dr. Worcel cautions. “Humans have a way of getting around what our genes say.” In heart disease, he suspects patients’ environments play a pivotal role.

Not Ruling Genomics Out

NitroMed isn’t ruling out the role of genomics, however. The Genomic Risk Assessment for Heart Failure is underway now, conducted by the University of Pittsburgh and the Heart Failure Society of America. “We want to examine the transcription of genes and signals, looking at DNA, mRNA, and proteomic variations,” says Dr. Worcel.

NitroMed used a population as a surrogate for a genetic profile in developing BiDil while it’s searching for the genetic basis to its effectiveness.

“Using race is a blunt instrument for identifying those who respond to the drug, but it’s the best tool we have right now,” notes Mario Ehlers, M.D., Ph.D., CMO, Pacific Biometrics (www.pacbio.com).

Therefore, “It’s appropriate that BiDil is targeted at a particular population group. Further research will likely identify the basis for the effectiveness observed in African-Americans.”

“It’s important that pharmaceutical companies are looking at diverse groups of the population,” Dr. Collins says, “but it’s a double-edged sword. Some will interpret this as indicating that African-Americans and Caucasians are biologically different.”

The cancer treatment IRESSA from AstraZeneca (www.astrazeneca.com), Dr. Collins says, “may represent a better example of a drug that takes into consideration genetic variation.”

Results of clinical trials of IRESSA in patients with non-small-cell-lung cancer were disappointing initially, but a detailed analysis showed 15% of patients taking it saw a dramatic response. When researchers looked closer, they realized that the best responses occurred among patients of Japanese ancestry.

Further investigation traced the sources of the response to a mutation in the EGFR gene that occurred more frequently in Japanese patients with lung cancer. That realization helped shift marketing from race toward a more specific and accurate test.

“The most common misperceptions,” when discussing race, Dr. Graves says, “involve social and biological conceptions of race, which not enough scientists understand.” Yet, from a drug development perspective (not to mention a social perspective) such an understanding is crucial.

As Dr. Ehlers says, “If we go to the next level of drug development, we will have to understand the diversity of people.”

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