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Genetics and race: Researchers explore why rates of diseases vary from one population to another

Tuesday, May 07, 2002

By Byron Spice, Science Editor, Post-Gazette

Tobago is a small part of a tiny nation, a tropical Caribbean isle with an area of just 116 square miles located northeast of its larger partner, Trinidad.

Robert Ferrell, professor of human genetics at the University of Pittsburgh Graduate School of Public Health, examines a test tube holding blood from a man from Tobago. Researchers hope to unravel why men of African descent on the tiny Caribbean isle have a much higher incidence of prostate cancer than white Americans or African Americans. (John Beale, Post-Gazette)

But when it comes to prostate cancer, Tobago looms big.

Men of African descent on Tobago have a rate of prostate cancer that, as best as can be estimated, is three or four times higher than that of white Americans and maybe twice as high as African Americans.

The government of Trinidad and Tobago is looking for some answers and so is Clareann Bunker, an epidemiologist at the University of Pittsburgh Graduate School of Public Health. For the past five years, Bunker and her colleagues have tried to screen all 5,000 Tobagoan men between the ages of 40 and 79 for prostate cancer.

With about 63 percent of the men screened to date, Bunker doesn't yet have a complete answer, but she thinks she knows part of the reason: genetics.

Compared to Caucasian males, men of African descent are more likely to carry a genetic mutation that helps them efficiently process the male hormone testosterone, Bunker said. That results in the growth of strong bones but, in combination with a virus called human herpesvirus 8, also seems to heighten the men's risk of prostate cancer.

That's not to say that the men's diet and lifestyle don't contribute to their high prostate cancer rates, said Robert Ferrell, a Pitt professor of human genetics. "But so far," he added, "we haven't been able to identify any obvious environmental explanation." East Indians, the other major population group on Tobago, don't share the same high risk of prostate cancer.

Clickhere to readPart I.

It's too soon to say whether the findings from Tobago will provide any insight for African-American men, who die of prostate cancer at twice the rate of their white counterparts. But as more attention is paid to this and other disparities in health between black and white Americans, it seems only natural to wonder how much might be attributed to underlying genetic differences.

It's a line of inquiry that is fraught with danger of misinterpretation. And despite the fact that genes can have powerful effects on the health of individuals, "genetics does not account for disparity in health care," Ferrell said.

A social construct

The problem is, what constitutes a race might seem obvious to most people, but race doesn't mean much from a biological standpoint.

Genetically speaking, nothing differentiates one race from another. All humans share the same set of genes. There is no African gene, no Caucasian gene, no Asian gene.

Certainly, genetic differences exist and even small differences can have big effects; consider that animals as different as chimpanzees and humans share 99 percent of their genetic code.

And even among humans, genetic variations obviously exist between individuals. Some genes are expressed, or "turned on," in some people and not in others. Some genes tend to develop mutations, which may alter body functioning or physical appearance, and these mutations get passed on to offspring.

But these variations don't occur neatly along racial lines. Scientists calculate that there is an average genetic variation of 5 percent between racial groups. But that leaves a whopping 95 percent of variation that occurs within racial groups.

Even the most obvious distinguishing factor -- skin color -- can vary enormously within a race, said Joseph L. Graves Jr., an evolutionary biologist at Arizona State University West in Phoenix. And the dark skin of a sub-Saharan African is not unlike the dark skin of a Caucasoid in India, added Graves, author of a 2001 book, "The Emperor's New Clothes: Biological Theories of Race at the Millenium."

That's why most scientists say race is a social construct, not a biological one. In other words, social rules determine what races are and what they mean.

For instance, someone is commonly considered "black" if he has one black parent and one white parent, or even if he just has one black grandparent. From a biological standpoint, however, there is no logic for such labelling.

If race has a bearing on health, it may simply be as a marker for the geographic origins of certain populations. In the Eastern Hemisphere, where humans have lived for at least 2 million years, differences that developed in skin color were closely correlated with latitude and, thus, exposure to sunlight. (The same pattern is not apparent in the Western Hemisphere, where humans migrated only about 35,000 years ago).

Sickle cell anemia, most closely identified in the United States with black Americans, is often found in African and Mediterranean peoples, Ferrell noted, apparently because that genetic mutation offered an advantage in battling the malaria endemic to those areas. Sickle cell anemia is rarely seen in descendants of people from northern Europe, where malaria is absent.

Conversely, cystic fibrosis is a common genetic disorder in people of northern European descent, but far less so in Africans.

In this case, no one is sure why, Ferrell said, but presumably some environmental factor that favored people with the cystic fibrosis mutation existed in northern Europe thousands of years ago and was not also present in Africa.

Those are both diseases that are caused by a single mutation, so the genetic link is clear-cut. But for the major diseases that cause or contribute to most deaths and disabilities, the genetic contribution is harder to pinpoint.

For these diseases, such as heart disease, high blood pressure and cancer, multiple genetic mutations are thought to increase the susceptibility of some individuals, but environmental factors, such as diet and lifestyle, also play an essential role in development of these diseases.

So it's much harder to make the case that high blood pressure is a bigger burden on blacks because of their genetic makeup, even though it plagues a third of all African Americans, compared to a quarter of European Americans. Black Americans are 80 percent more likely to die of stroke than whites.

Some have speculated that African slaves who were better able to retain salt were more likely to have survived the deprivations of the Middle Passage on their way to America and that the same genetic makeup, passed on by the survivors, has put later generations of black Americans at risk for developing high blood pressure.

But there are also a number of societal and cultural factors -- the stress of living in a prejudiced society, lack of access to health care, poor diet -- that also might predispose African-Americans to hypertension.

Complicating matters is that no one really knows which combination of genes is responsible for susceptibility to hypertension.

It's likely that a large number of mutated genes may contribute to high blood pressure, but that not all patients may have all those mutations.

"I don't think there's such a thing as black hypertension, Hispanic hypertension and white hypertension," said Ferrell, whose lab does the genetic analysis for a large, four-city study of high blood pressure that is comparing black, white and Hispanic populations. "It's too complicated. It can't be that simple."


What researchers are looking for in such studies are certain genes that tend to mutate more than others. Some of these so-called polymorphisms -- such as the one related to prostate cancer risk in Tobagoan men -- arguably have an effect on health and how people respond to medications.

But Graves said biomedical researchers need to take greater care in analyzing this data. In his book, he questions whether the prostate cancer polymorphism is truly the indicator that some researchers have suggested. That particular polymorphism can vary in length -- men with long versions are thought to be at increased risk for the cancer. The definition of long and short is arbitrary. Depending on what cutoff is used, he said, the frequency of the long form isn't necessarily much greater in black Americans than it is in whites.

On the other hand, Graves is persuaded that differences in the frequency of another mutation -- the CCR5 gene -- might help explain why there are more people of European as compared to African descent who are resistant to the AIDS virus.

The CCR5 mutation increases the resistance to infection by the human immunodeficiency virus and is much more common in people of European descent.

At the same time, non-genetic factors -- principally the lack of male circumcision and an associated greater prevalence of chanchroid sores -- play important roles in the spread of HIV in sub-Saharan Africa, he added.

Differences in the frequencies of certain polymorphisms also can affect how people respond to medications, said Dr. Bruce Pollock, chief of geriatrics and neuropsychiatry in the Pitt psychiatry department.

For instance, African Americans seem to have a higher frequency of one mutation that reduces the liver's ability to break down certain tricyclic antidepressant drugs, so they are more likely than their white counterparts to suffer side effects. Blacks also have a higher frequency of a mutation that increases the speed at which a newer class of antidepressants, such as Prozac, take effect.

But none of these mutations are specific to one race and it is only their frequency that varies, Pollock emphasized.

"Nobody would make clinical decisions based on a racial profile," he said. "Race is a very crude predictor of any sort of differential response to medication."

About 8 percent of whites carry a mutation that would cause trouble with warfarin, a blood-thinning drug, compared to 2 or 3 percent of blacks. It's a difference that might be noticeable across populations, but isn't of much use in treating an individual. "I don't think you'd be less vigilant [for side effects] in this case," he added.

Last year, the New England Journal of Medicine published a study showing that African Americans with heart failure were less likely than whites to benefit from a type of drug known as an ACE inhibitor.

And a Massachusetts company has developed a drug called BiDil -- actually a combination of existing medications -- which it says is designed specifically for black heart patients.

But Dr. Alastair J.J. Wood, a pharmacologist at Vanderbilt University, said the variation between members of a race makes it impossible to use race as the basis for tailoring drug therapies.

"If Chinese people were, on average, smaller than Caucasians, that doesn't help you in selecting a shirt size for a Chinese man," he observed.

Tailoring therapies

One of the ultimate dreams of geneticists and pharmacologists is to someday tailor drug therapies to each patient, an idea called pharmacogenomics. In so doing, each person would receive the drug that is most effective for him and causes the fewest side effects.

Racial groupings would be meaningless, because the tailoring would be based on genetic analysis of each individual, not on groups.

The prospect of widespread genetic screenings necessary for pharmacogenomics has raised fears that it might lead to widespread genetic discrimination, particularly as some individuals are identified as at risk for a lethal disease. In that regard, they say, genetic discrimination would be like racial discrimination.

That analogy doesn't fly with Graves, a member of Howard University's human genome advisory group.

"The fact that we're making pills that work for only one group -- now that's genetic discrimination," he said. Individualizing care by using genetic information is one way of reversing that discrimination.

Coming in June: Is money the real driver in health disparities?

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