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Liliana Macri is planning a trip to Italy this fall. She is looking forward to seeing her extended family, with whom she shares far more than traditions, mannerisms and physical features. The 23- year-old has beta thalassemia, a blood disorder that afflicts two of her cousins and countless others of Mediterranean descent all over the world.
Macri's disease is directly linked to her heritage. As ethnic groups enter the United States, physicians learn about a growing group of diseases that affect specific populations, ranging from hemoglobin disorders to cystic fibrosis and diabetes to Tay-Sachs. The more science uncovers about human genetics, the more apparent it is that patients' ethnic origins can provide valuable insights and clues in the diagnosis and treatment of such diseases. "Many disorders we see every day are ones that we only used to read about in textbooks," says Dr. Bertil Glader, a pediatric hematologist at Packard Children's Hospital.
As scientists and clinicians assume responsibility for caring for an increasingly diverse population, genetic and ethnic connections to disease may become clearer. And according to Dr. Ernle Young, who co-directs the Stanford Center for Biomedical Ethics, understanding and valuing cultural diversity is critical to ensure the best possible care. "I don't think many white, mainstream health care organizations are sufficiently aware of or sensitive to the cultures and values of patients from different ethnic groups," he says. "We need to develop an appreciation and respect for cultures that differ from our own."
Often the differences go beyond disease. Among some ethnic groups, organ transplantation success rates seem to differ as well, and physicians finally are beginning to understand some of the reasons why.
At a recent symposium sponsored by the biomedical ethics center, experts looked at the transplantation issue in depth. One reason for varying success rates, they agreed, is that immunogenetic differences among ethnic groups have a direct impact on the rates of rejection in organs and tissues that have been transplanted. Said Dr. Clive Callendar, who directs the Transplant Center at Howard University Hospital, "These differences perhaps explain why survival rates among blacks who undergo kidney transplants, for example, are lower than all other ethnic groups. We have fewer black organ and tissue donors, and we are relatively ignorant of the immunogenetic make-up of blacks compared to our knowledge of the immunogenetic make-up of whites."
An understanding of one facet of the genetic make-up of Native Americans has helped members of this ethnic group understand why diabetes is such a common ailment among them. In a study published in the journal Diabetes, researchers found that the disease affects more than 50 percent of Arizona's Pima Indians over the age of 35. The study suggests that this extremely high rate may be a result of the inability of the Indians' bodies to break down all the sugars they consume. The researchers also suggest that because food sources were erratic for the ancestors of the Pima, their metabolisms developed an ability to keep blood sugar levels elevated after eating in preparation for subsequent periods of famine. The bodies of Pima Indians today may not produce enough insulin, which breaks down sugars so that the body can use the energy. Today's steady supply of food and a sedentary lifestyle appear to be incompatible with the metabolism that evolved as a selective advantage by the Pima's ancestors.
Even certain hemoglobin disorders may have had some use to the ancestors of those who are affected by the diseases today. "G6PD deficiency, sickle hemoglobin, and thalassemias comprise a group of diseases that tend to occur in what is called the malarial belt of the world," Glader points out. "Some people think that the genes for these diseases must somehow be protective against malaria. Otherwise, what would be the selective advantage that has persisted through the centuries?"
Each of these diseases raises questions about how and why certain diseases occur frequently within an ethnic population. Stanford geneticist Dr. Uta Francke points to Finland as an example of a country in which certain diseases, such as congenital nephrosis, are prevalent. "Finland was settled by relatively few original families, and there is likely to be a founder effect. When you have a large population in geographic isolation that may have common ancestors with rare recessive disease genes, there is a higher incidence of certain disorders."
Some diseases affect natives of specific countries, other diseases branch out to entire regions. Italians like Macri aren't the only Mediterranean descendants affected by blood disorders such as beta thalassemia. People of Greek, North African, Sephardic Jewish, and Arab descent have a higher incidence as well. The disease causes severe anemia and appears in infants in their first four to six months of life. Some of the younger patients are now being treated with bone marrow transplants. The vast majority need transfusions of red blood cells to survive. Macri, for example, has undergone blood transfusions at Stanford every month for the last 13 years.
G6PD deficiency is yet another blood disorder that occurs among essentially the same group of people. According to Glader, G6PD deficiency can result in the rapid destruction of blood cells in the presence of infection or certain drugs. In Mediterranean countries, even exposure to the fava bean or its pollen can cause G6PD deficiency.
Many natives of Southeast Asia, on the other hand, suffer from a different set of hemoglobin disorders. "With the massive migration of Southeast Asians into the United States, many of whom come to California, we now see a fair amount of these hemoglobin disorders here at Stanford," Glader says. "Eighty percent of the affected individuals are either children or adults of childbearing age who stand to pass on the disorders."
Equipped with genetic charts translated into Vietnamese, Lao and Khmer, Glader explains the characteristics of hemoglobin E syndromes to the families of young Asian American patients. Unlike other ethnic groups in this country, many Americans of Southeast Asian descent carry the genes for hemoglobin E -- a variant hemoglobin that results in a spectrum of diseases from mild anemia to more severe blood disorders. Hemoglobin E disorders are protein abnormalities that result from specific genetic mutations that, according to Glader, vary from country to country in Southeast Asia and affect as much as 25 percent of the region's populace.
Hemoglobin disorders are among the clearest examples of ways that members of one ethnic group carry different genes that express certain diseases. "Mutations do occur in all populations," Francke says, "it's just that some mutations are present in some populations with higher frequency."
The most well-known hemoglobin disorder is sickle-cell disease, which affects 1 in 400 African Americans. But blacks are not the only ethnic group affected by the disease. About 20 percent of Shiite Moslems in Saudi Arabia and Kuwait also have the sickle cell trait, and it is not unknown among other groups.
"Genes are very mobile," Glader explains. "What you see reflects history: the Romans travelled." The sickle gene arrived in Mediterranean countries from central West Africa through the trade routes across the Sahara. This may account for the occasional case of sickle cell disease among European Americans who trace their ancestry to southern Italy, Sicily, Turkey or Cyprus. Not all disease genes are identical by descent. The same mutation can occur more than once in the same or different populations.
A common method of treating sickle cell patients is through blood transfusions, which often results in numerous complications. A recent study published in the New England Journal of Medicine revealed that one-third of sickle cell patients who receive transfusions develop antibodies against different foreign proteins, making it difficult to find compatible blood for subsequent transfusions.
Researchers found that 82 percent of the antibodies produced by sickle cell patients were commonly found in the blood of white donors. Moreover, the researchers suggested that the complications were partly a result of immunogenetic differences common among different racial groups. To combat this, blood banks, including Stanford's, match blood by factors. Like organ donation networks, blood banks are trying to increase the amount of blood donated by black and Hispanic donors to satisfy the needs of patients.
Not all cases of sickle cell disease are the same in this country, and it appears that there are geographic differences as well. "In Saudi Arabia and Jamaica, it tends to be a milder phenomenon," Glader notes. "We don't know how much of it is genetic and how much of it is environmental."
Many children born in California are screened to see if they have inherited the sickle cell trait from their parents. "For many years we've screened for certain disorders, such as hypothyroidism or phenylketonuria, and now we screen for sickle cell as well," Glader says. "One of the problems with screening for that disease is determining who to screen. It's not always clear what a baby's background is.
"Ethnic background is an essential part of a patient's medical history," he continues. "It's one of the key areas to look for clues. A physician should consider ethnic background very heavily. If I know that a patient is of northern European extraction, I think along certain lines, like blood cell membrane defects or spherocytosis. If a patient's ancestors are from the Mediterranean, I think of thalassemias or G6PD deficiency. If someone is black, I think of sickle cell anemia and, if someone is of Southeast Asian descent, I think of hemoglobin E syndromes. But, at all times, I realize that any of these disorders can affect any group."
One of the most common genetic diseases that affects European Americans is cystic fibrosis (CF). Unlike many other ethnically linked diseases, cystic fibrosis is not always caused by the same mutation in the CF gene, although one mutation accounts for approximately 70 percent of CF gene mutation. Because the other 30 percent is caused by a wide variety of genetic mutations, not all of which have been identified at a genetic level, a screening test may not be completely informative. "One in 20 Caucasian people are carriers," Francke says. "They may never know unless they marry another carrier and have a child who has the disease." Carrier testing is available, however, for relatives of affected children. The overall incidence of the disease is similar to the rate that sickle cell disease affects African Americans or that Tay-Sachs disease, a progressive neurological dysfunction that appears in children, occurs among Ashkenazi Jews.
Tay-Sachs disease is one of the few ethnically linked diseases that is being avoided effectively. Because they know that they are in an at-risk group, many American Jews of Eastern European descent organized voluntary screening when it became possible to distinguish carriers of the gene that causes the disease. If both members of a couple are carriers, they may decide not to marry or not to have children because of the one-in-four chance that their children would have the disease. Alternatively, they can have prenatal testing and choose to abort an affected fetus.
"If you screen everybody in the population," Francke notes, "you could theoretically prevent the birth of any more affected children. You don't wipe out the mutant gene, but you identify the carriers. The Tay-Sachs screening program has nearly eliminated the disease in this country because people became aware that they were carriers."
As scientists continue to identify genes that lead to disease, they may discover even more linkages between ethnicity and various diseases. "As we learn more about the relative frequencies of different inherited disorders," Francke says, "I'm sure that ethnicity will become an increasingly important factor in diagnosis. Each population has its own things to worry about, no racial or ethnic group has been spared. On balance, we all carry our burden of recessive disorders."
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