College of American Pathologists
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  Is there a place for race in medicine?





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July 2006
Feature Story

Karen Titus

Anyone who stays reasonably caffeinated will find it easy to keep up with the latest news about genetics and race. Merely turning the pages of a newspaper or skimming Web headlines in recent weeks would have told readers of the deadly racial gap in swimming, a gap once thought to have a biological basis; the backlash against a researcher’s work looking at genetic changes and their link to brain size and intelligence; and a racial component to basal-like breast tumors. Readers with a little more time, and perhaps a little more coffee, might have stumbled across a syndicated advice columnist trying to reassure “Penny in California,” who was puzzled by the results of a DNA test—was she still white, even though the test told her she was six percent sub-Saharan African?

Troy Duster, PhD, has seen the stories. He’s read the studies. And he’s not happy with the way these discussions are heading.

Dr. Duster, a professor of sociology at New York University and the University of California, Berkeley, has written widely on race and genetics, a subject that vacillates wildly between being high-minded to touchy to downright taboo. Speaking at Northwestern University this spring, Dr. Duster explored how race and genetics are once again converging in medicine.

The view he takes is dim and long. In the early part of the 20th century, he noted, researchers, particularly those in Germany and Finland, spent decades trying to find a link between the ABO blood system, race, and ethnicity. By mid-century, he says, a general consensus emerged among biologists, physiologists, and anatomists that race had little bearing on their respective fields. “They concluded—after a long period of time, by the way—that race wasn’t very useful.”

The language of commonality grew stronger in later decades, reaching a veritable roar in the era of the Human Genome Project. “The mantra you heard over and over again was, It wouldn’t matter whose genome you sequenced—an aboriginal, a Hutu, a Laplander, a Swede, a Norwegian, an Italian”—because 99.9 percent of human DNA overlaps, Dr. Duster says.

That point was driven home at a June 2000 White House press conference, when Bill Clinton, Tony Blair, and Drs. Francis Collins and Craig Venter announced the first draft of the human genome sequence.

The six-year bridge spanning then and now seems remarkably wide, even naive, in part because when Clinton and Blair spoke of the challenges and dangers of a future partnership between their countries, they meant scientific investigation, nothing more. Genetic information, it was hoped, would transform medicine, and not be used to deny individuals privacy, insurance, or jobs.

On that day, race seemed to be waltzing away from genetics. Prime minister Blair spoke of the human race, a label Dr. Collins, director of the National Human Genome Research Institute, repeated: “I’m happy that today, the only race we are talking about is the human race.” Dr. Venter, then president and chief scientific officer of Celera Genomics, explained that the genome of five individuals—self-identified as Hispanic, Asian, Caucasian, or African American—had been sequenced. This sampling was done out of respect for diversity, he said, “and to help illustrate that the concept of race has no genetic or scientific basis.” Furthermore, he noted, in the five genomes, it was impossible to elucidate ethnicity. “Society and medicine treat us all as members of populations, where as individuals we are all unique, and population statistics do not apply.”

Six years later, much has changed. Race is taking yet another spin through the genetics discourse; it reappears with unsettling regularity, like Christopher Walken in the movies. “There’s been an extraordinary resurgence of the use of race in clinical medicine and molecular biology, pharmacogenomics and pharmacotoxicology, and forensics,” says Dr. Duster.

In untangling the story, he tugs at the thread of semantics that runs through the science. The first 10 years of the Human Genome Project were about sameness, says Dr. Duster, in part because the technology available for analyzing the genome was relatively limited and kept the focus on the overlapping portions of DNA. With the development of supercomputers, the genome’s 3 million SNPs came into closer view—and with it, the ability to focus on differences. “The language at first was ‘individual differences,’” Dr. Duster says, though it was quickly matched by another line of thinking emphasizing group differences. A seminal publication on pharmacogenetics appeared in Science in 1999 (Evans WE, Relling MV. 286:487–491) and called for race to be considered in studies looking at specific genotypes or phenotypes that might be associated with disease risk or drug toxicity.

“What happened to individuals?” Dr. Duster asks. This groupthink, so to speak, continued with an article in the Annual Review of Pharmacology and Toxicology, on the molecular basis of ethnic differences in drug response (Xie H-G, et al. 2001;41:815– 850). The question is simple: Can understanding the molecular foundation of ethnic differences help explain individual responses to drug therapy?

While the question focuses on ethnicity, the answer invariably means race, says Dr. Duster. “Asians require far less warfarin than whites. That’s race. I can understand why you might say Albanians in the United States are an ethnic group, but whites aren’t an ethnic category by any means. Neither is Asian. You might say the Japanese in Hawaii are an ethnic group, but Asians aren’t an ethnic group.”

That distinction between race and ethnicity appears not to matter much, at least not to the pharmaceutical industry. Last June the first “racial” drug won FDA approval: BiDil, a drug for the treatment of heart failure in black patients. Iressa now appears to be following as an “Asian” cancer drug. “It’s about marketing, not about bringing drugs to the right people,” Dr. Duster says, noting that BiDil was not tested in other racial groups during the approval process, making it hard to know whether it truly is more effective in one group than another.

Dr. Duster contends the “right people” will never be found by using race as a guideline. While prostate cancer in the United States occurs in blacks at twice the rate of whites, he says, “It’s a huge mistake to go directly into the genes” and look for racial-based differences. “Because if you move cross-culturally, you’ll see that the rate of prostate cancer among blacks in the Caribbean and in Brazil is different.” Ditto for hypertension—the disease rate in blacks is highly variable depending on geography. And it’s higher in whites—at least those in Poland, Finland, and Russia—than in U.S. blacks.

Tay-Sachs disease, likewise, is common among Ashkenazi Jews, but not among Sephardic Jews. “It’s not a Jewish disease.” Nor can sickle cell disease be regarded as a “black” illness. It’s prevalent among blacks who migrated to the United States via the Middle Passage, but not among blacks of East African descent. “It’s not racial. In other words, any disease you want to tell me about, I’ll tell you there are allelic frequency variations, and it has to do with regions,” Dr. Duster says. “Hemochromatosis—Swedes have a higher rate of it than Italians. But both are, by our classification system, white.

“You can’t use race. You make a huge mistake.”

Ethnicity and race are a convenient shorthand, but it’s hard to say for what, exactly. Skin color? Culture? Religion? Geography? Ancestry? Language? In this wobbly lexicon, the two words slip easily past each other in the scientific literature as well as popular discourse, to the point where both terms are rendered nearly meaningless.

Bringing genetics to bear on the matter isn’t clearing up anything.

Mark Shriver, PhD, is an associate professor of anthropology at Penn State University, though he’s probably more widely known for his partnership with DNAPrint Genomics, which offers a DNA test to identify genetic ancestry.

The company has garnered plenty of press in recent years, with its testing used to identify perpetrators in long-dormant criminal cases as well as to trace genetic ancestry. Those who tuned into the PBS special “African American Lives” early this year could have seen Dr. Shriver’s company inform a host of prominent citizens of their ancestry. (Oprah Winfrey, as it turns out, is not a Zulu warrior, despite her hopeful claims.) Likewise, any number of ordinary folks are partaking in what some call recreational genomics, thanks to ancestral testing provided by DNAPrint Genomics and similar companies. For many, the answers are surprising.

Dr. Shriver’s ancestry may take the cake in that regard. In a six-year period, he went from being 28 percent African to 11 percent African.

The reason for that “change” is simple, but the implications are huge. The way researchers look for race-based differences is a failure of simple logic, according to Dr. Duster; for that matter, he says, the entire premise of mixing race and genetics is deeply flawed.

The starting point is not: another seminal report in Science, this one published in 2002 (Rosenberg NA, et al. 298:2381–2385), which has subsequently been the basis for many applications in epidemiology. In their study of the genetic structure of human populations, the researchers used genotypes at 377 autosomal microsatellite loci, looking at 1,056 individuals from 52 populations. As an accompanying article further explains King M-C, Motulsky AG Science. 2002;298:2345–2349), the populations were defined by geography, language, and culture.

The two papers make it quite clear that most alleles are widespread and that region-specific alleles are rare, with a median relative frequency of one percent. When genetic variation occurs, it is usually between individuals within the same group; differences between groups are not the norm. Genetic differences, the authors note, are more a matter of gradations in allele frequencies. In other words, differences cannot be classified as distinctive “diagnostic” genotypes. While different populations may experience differences in disease frequency or treatment outcome, genetics may not be the culprit. An individual’s alleles might reveal ancestral migration patterns, but disease could be another matter completely.

This rather strict view starts to break down, says Dr. Duster, with another well-known paper (Jorgenson E, et al. Am J Hum Genet. 2005;76:276–290). While the Rosenberg study looked at a large number of groups—52—this one slims things down considerably, to four racial/ethnic groups: whites, African Americans, Mexican Americans, and East Asians.

The results of this study of ethnicity and human genetic linkage maps “challenged the widely held belief that race is only a social construct,” says Dr. Duster, quoting a Stanford University press release.

Of course it did. The Jorgenson paper didn’t start with the DNA, he says, but rather started with the phenotype. After they looked for differences among these groups, they asserted the differences were reflective of each group.

Restricting the search to four groups skews the findings even more, Dr. Duster says. A study that looks at a large number of groups, as the Rosenberg study did, is, naturally, going to sketch a universe that is populated by a wide variety of human beings. A study that looks at four groups, on the other hand, will reinforce the idea that there are indeed four distinct racial groups. “So, what does being 100 percent white mean?” asked Dr. Duster. In this model, an analysis might find SNP patterns that are more common in a group of white people than in a group of black or Asian people. This comparatively higher pattern becomes the de facto “100 percent white,” though it’s hardly 100 percent of anything.

This is the path Dr. Shriver traveled when he became less black—he changed the sampling procedure, Dr. Duster says.

Dr. Duster is the first to laugh at that bizarre shift, but there’s nothing funny about the implications. He has plenty to say about the so-called DNA dragnets being used for criminal screening, as well as a pilot program for New York City police to look at the feasibility of using handheld DNA devices at routine traffic stops, collecting and analyzing samples in the hopes of making match with the CODIS database.

More than anything, though, he seems bothered by the re-emergence of DNA and race because it’s dumb science, and even dumber medicine.

Defining race is nearly impossible, which makes it tricky for anyone who wants to study its impact. BiDil is approved for people who say they were black— “self-identified” is the common term. So how do they decide? Is it based on appearance? Family history and lore? Belief? You don’t have to look far before you bump into someone like Barack Obama, the U.S. senator—or the changing ancestry of Dr. Shriver—and suddenly the question doesn’t seem quite so silly. A recent JAMA study looked at race and breast cancer subtypes (Carey LA, et al. 2006;295:2492–2502), in which race was determined by self-identification and subjects were categorized as either African American or non-African American—which is almost meaningless from a scientific standpoint, says Dr. Duster, given that genetically speaking, humans are multiracial.

Nor is there any clear evidence that genetic ancestral maps reveal anything more than likely migration patterns. Is there a sound basis for using them for medical investigations? Dr. Duster says no; many researchers, however, appear to be tilting in the opposite direction.

Dr. Duster speaks of all this as a dangerous road. Perhaps a better metaphor is a perilous intersection, where sociology and science, race and ethnicity, geography and genetics all seem bent on colliding once again.

Karen Titus is CAP TODAY contributing editor and co-managing editor.