Native America's Alleles

Arizona's Pima Indians have the world's highest rate of diabetes, and the rest of the world is catching up fast. Can geneticists figure out why?

By Jeff Wheelwright|Sunday, May 01, 2005
RELATED TAGS: DIABETES, GENES & HEALTH
gene-opener
gene-opener

Mary Thomas, lieutenant governor of the Gila River Indian Community in southern Arizona, developed type 2 diabetes when she was a teenager. Diabetes is so prevalent among Pima Indians that they are the best source of data about the disease.

Robert Silvers

Pecos Road runs due west along the southern boundary of Phoenix. On the city side of the road, new subdivisions of retirement homes are pushing up their tile roofs like mushrooms that sprout with no rain. On the other side of the road lies the flat scrub of the Gila River Indian Community, some 600 square miles, most of it empty. The reservation shimmers out of the reach of the builders like a desert mirage.

This land was no good to anyone in 1859, when it was allocated to the Pima Indians. Today it has 13,000 Native American residents, living in squat cinder-block houses in scattered, dusty hamlets; three casinos that have boosted the tribal income to $100 million annually from $4 million; irrigated cotton, alfalfa, and citrus, for Pimas were always farmers; and a hospital and two kidney-dialysis clinics, with another medical clinic in the planning stage. Kidney failure is a deadly complication of diabetes, and Pimas, so far as scientists can tell, have the world’s highest rate of type 2 diabetes. The Pimas have grown to hate this superlative perhaps more than the disease itself.

Mary Thomas, the 60-year-old ex-governor of the tribe and presently its lieutenant governor, drove me around the community. A few miles south of Pecos Road, we came to the St. Johns Mission, a quiet, whitewashed church. There was once a Catholic boarding school for Indian children on the grounds. Thomas said that when she was 17 and in school here, she went for an eye test and was told she had diabetes.

“So you have type 1 diabetes?” I asked. In type 1 diabetes, the pancreas stops making insulin, the hormone that facilitates absorption of glucose from the blood into cells. Without sufficient insulin, glucose levels in the blood skyrocket, damaging organs, vessels, and nerves. Children with type 1 disease require insulin therapy for the rest of their lives.

“No,” Thomas said flatly. “I have type 2.” Forty years ago it was almost unheard of for teenagers to have this version of diabetes, in which high blood sugar occurs even when the person makes insulin. Doctors described that rather unusual condition as “mild” diabetes or “mature onset” diabetes. Today it is called type 2, or non-insulin-dependent, diabetes.

None of these terms do justice to today’s epidemic. In all population groups in America but especially among minorities, type 2 diabetes is spreading like a Sun Belt suburb. Unfortunately, Native Americans are ahead of the curve as the average age of diagnosis declines and the crippling consequences multiply. Roughly half of adult Pimas have diabetes, and other tribes are gaining on that rate.

Worldwide the disease is accelerating too. Health officials here and abroad expect up to half a billion cases by midcentury. Westernized diets and lifestyles are blamed—the fare paid by poor people for their fast passage to the modern world. So although the Pimas’ problem is small in the total number of cases, the impact on their community is huge.

Mary Thomas considers herself fortunate. Her health is not good, but by injecting insulin twice a day and taking a handful of oral medications, she has avoided the worst complications of diabetes: kidney disease, heart attack, stroke, blindness, and chronic infections that lead to foot amputation. Her mother, who was also a diabetic, died at age 68 of heart disease. “My diabetes is OK,” Thomas said, “but I can’t seem to get my weight off.” She carries 245 pounds on a big frame.

Because Indians’ risk of type 2 diabetes is at least twofold higher than  it is for white Americans, and yet their lives are not so radically different, researchers think there must be a genetic element at work. But why indigenous Americans? Is diabetes a racial hallmark?

Race is a blind alley, geneticists believe. “No genetic markers are unique to this race,” said Leslie Baier, who studies the Pimas’ DNA for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). She means that no unique genetic variants, or alleles, have been found in Native American groups. Still, the demands of surviving in a difficult environment may have influenced their genes, making Indians innately susceptible to diabetes.

gene-zunisign
gene-zunisign

The type 2 diabetes epidemic is not limited to the Pima of Arizona. The disease is also rampant at the Zuni Pueblo, about 30 miles south of Gallup, New Mexico.

Joe Schmelzer
The first and most famous articulation of the genetic theory of diabetes was by University of Michigan geneticist James V. Neel. In 1962, before the scope of the Pima health crisis was discovered, Neel published a paper titled “Diabetes Mellitus: A ‘Thrifty’ Genotype Rendered Detrimental by ‘Progress’?” Calling diabetes an “enigma,” Neel wondered why it should be so common and heritable when it was so destructive. (His essay merged the juvenile “early onset” type with the “late onset” type.) Perhaps the individuals who had acquired the so-called thrifty gene were “exceptionally efficient in the intake and/or utilization of food,” Neel wrote. “It must be remembered that during the first 99 percent or more of man’s life on Earth, while he existed as a hunter-gatherer, it was often feast or famine. Periods of gorging alternated with periods of greatly reduced food intake.” In short, a gene variant that may have been helpful in times of hunger would be harmful in times of unrelenting plenty.

Neel and those pondering diabetes after him came to realize that the thrifty gene or genes, if they existed, were not the critical part of the story. Type 1 disease is now thought to be an autoimmune condition in which inheritance plays a fairly minor role. As for type 2, “it is a complex disorder with strong environmental and genetic components,” said Robert Williams, an anthropological geneticist at Arizona State University. The catchall term “environment” stands for diet, lifestyle, and any other ingredient of health over which a person has at least some nominal control. The Indians’ diabetes epidemic, everyone agrees, was triggered by an unfavorable change in environment since the mid-20th century, that is, Neel’s “progress.”

Thomas well understands what took place. “Historically for the Pima, our DNA was steady all over the country,” she said. “Our diet was lean. We ate fish and game, beans and quail. Then, with the white man, a new diet came. They offered it to the Indians, and the Indians kind of became addicted to it. There was an onslaught of salts and sweets. And our DNA was forced to change.” Then she corrected herself, saying the DNA didn’t change—it couldn’t have, for genes evolve slowly within large populations, at the pace of millennia. She was referring rather to the physical transformation of people, an environmental effect that can happen rapidly. “You see a change in people. We’re evolving. People are getting taller, fatter. It’s not just the Pima,” she concluded, “but Americans.”

Scientists at the NIDDK laboratory in Phoenix have been studying type 2 diabetes on the reservation since the time when Mary Thomas was given a diagnosis. A whole floor of the Indian Health Service hospital in Phoenix is dedicated to Pima research subjects. Many studies have been prospective: The researchers took Pima volunteers who had “insulin resistance” or “impaired glucose tolerance,” the two precursors of diabetes, and monitored them as they developed the full-blown disease. A young Pima was most susceptible if both parents had contracted diabetes before age 45, less vulnerable if only one parent was diabetic, and least likely to become sick if both parents were healthy. The family studies of the Pima were the first in the world to demonstrate that type 2 diabetes was heritable. It was possible that habits fostering diabetes were being passed along too. In the last decade the work has moved from the physiology and pedigrees of diabetes into molecular biology. Although many valuable facts have been learned, including the discovery of a helpful class of drugs, no breakthroughs have been made, clinical or genetic, that might stop the disease.


About the series
This is the last of three articles exploring the relationship between race, genes, and medicine in three far-flung populations. Although race is a socially powerful concept, most geneticists think it has no foundation in biology. Modern DNA studies show that the world’s population is too homogeneous to divide into races.

But while dismantling the barriers of race, scientists have uncovered patterns of genetic mutation and adaptation in human populations. As archaic bands of Homo sapiens left Africa and spread over the world’s continents, their DNA evolved. Geography has left faint marks on everyone’s DNA. Although the differences are small, they show up in the diseases that different groups get and how these groups respond to drugs.

To measure these differences is not to resurrect race by another name but to emphasize the role of history in shaping medical legacies. Researchers seeking genetic explanations for health have to explore the events written in the record of DNA. In the first article about African Americans, geneticist Georgia Dunston points out that Africa contains the richest DNA diversity because it is the site of humanity’s oldest genes. Africans and their recent descendants in America may harbor clues to fighting diseases that other populations don’t possess.

The second and third articles follow gene hunters into more isolated and homogeneous gatherings of people—the Finns at the top of the European continent and the Native Americans in Arizona and New Mexico.

In the future, doctors will examine the genetic portraits of individuals, not populations. The path to understanding how individuals fit into genetically similar populations would run straighter if not for the old stigmas of race. Two of the three groups in Discover’s series, being minorities, are wary of genetic studies that may stereotype them further. In the past, science was not an innocent bystander when people were separated into races.

genes-ladies
genes-ladies
Three generations of a Zuni family are participants in a diet and exercise program designed to fight diabetes. From left: Dora Weeka, Eloise Westika, and Carvella Weeka.
Joe Schmelzer

“The realization came upon us that we were getting worse,” Thomas said, “and they were publishing studies and pamphlets. We said, ‘Hey, where’s the benefit?’ We have been used as a natural laboratory. They want to keep us under the microscope for as long as possible.”

Thomas’s tone was mild and weary. Even when she said, “They’re not really wanting us to get well, I think,” she didn’t show her feelings. When I asked if she was fatalistic about diabetes, she said no. We sat silently in the car near the church. The mission school she attended was torn down, and the one-story building that replaced it is the Gila River Diabetes Education and Resource Center, where people can learn about staying healthy. The new medical clinic is going to be built next door, paid for by slot machines, another bitter fruit of the community’s progress.

Across the Indian Country of the West the collective feelings about genetic research are not hard to discern. The Navajo—at almost 300,000, the largest tribal population—have ruled out all participation in genetic studies. The Northern Plains tribes, which are mainly Sioux, have devised stiff protections and protocols many pages long. Researchers making proposals are required to state how the Indians could be harmed by the DNA findings as well as helped.

Last year the tiny Havasupai tribe of northern Arizona filed a $50 million lawsuit against Arizona State University and its scientists over a long-term project that looked for genes contributing to diabetes. The Indians claim that their consent was abused, their blood samples were mishandled, and that sacred information was written up without their approval. Almost as an aside, the lawsuit points out that no diabetes genes were revealed. The researchers have denied the legal charges.

The climate isn’t totally hostile. The Salt River Pima-Maricopa Indian Community, on the eastern edge of Phoenix, is talking with a company called Translational Genomics about possible research into the tribe’s ills. At the Zuni Pueblo reservation in western New Mexico, where I was headed after Gila River, the tribal council has cautiously opened the door to medical geneticists. And a long-running National Institutes of Health study called Strong Heart, which explores cardiovascular disease in Native Americans, has added a genetic component, so far without controversy.

Jacob Moore, an Indian who manages legislative affairs for the Salt River tribe, gave me a blunt explanation for the wariness: “Tribes in general have been taken advantage of for so long that there’s distrust. The attitude is, ‘The mainstream society has taken everything else. Once they have our genetic code, there isn’t anything left they can take from us.’ ”

By genetic code Moore did not mean the DNA that all people share. He was referring to a core identity that is, though he didn’t say so, both cultural and biological. On both fronts Indians are being threatened by assimilation. While maintaining their tribal affiliations, most Native Americans do not live on reservations. They intermarry with other ethnic groups; already their DNA shows substantial European American heritage. This exchange between population groups can be tracked through distinctive sets of genetic markers that provide clues to a person’s ancestry.

These markers are alleles that have accumulated in different proportions among the world’s populations. The markers usually aren’t genes; often they are meaningless sections of a DNA sequence that lie interspersed between genes and are inherited just as genes are. And a single marker doesn’t carry much information about ancestry; only a combination of markers does. Let’s say your lab is handed an anonymous blood sample for DNA analysis. Testing for a single marker doesn’t tell you much about the person’s background, because that one allele, whatever form it takes in the person, probably occurs in every band of people on Earth. But a select panel of markers, each chosen for its frequency in one population and its infrequency in another, can be used to make a reliable prediction about the ancestry of the person. You may have to test 100 markers or even 500—and the cost will be extravagant—but it can be done. (This is not the same as constructing a DNA match, as in a paternity suit or a criminal investigation, where just a handful of markers is needed.)

The bottom line: All human beings inherit the same set of genes, but the various chemical spellings of our genes bear some relation to the geographic origins of our forebears. So when geneticists dispute the biological notion of “race,” with its false implication that certain genes pertain to certain races, they also recognize that DNA analysis can shed light on ancestry.

Not surprisingly, a scientist who studies markers for clues to ancestral origin is not a welcome figure in Indian Country. The tests might call into question who is an Indian—a question with psychological pitfalls and also financial consequences for one claiming benefits, say, from the tribe’s investments. Robert Williams, the anthropological geneticist at Arizona State University, collided with the question in a study for the Strong Heart cardiovascular project. His analysis of 12 tribal groups was abruptly halted after he found that the amount of European heritage varied widely among the groups.

Studies of the Indians’ origins are another sore point. The peopling of the Americas—how Indians came here and when—has been the subject of countless Ph.D. theses and scientific articles. The thrust of the genetic and archaeological evidence is that the ancestors of Native Americans walked or paddled from Siberia between 13,000 and 17,000 years ago, at the height of the last ice age. But any Native American of a traditional bent already knows where he or she came from. Unless the knowledge has been lost, each tribe has a story of its creation. The Havasupai, for instance, believe their ancestors emerged from beneath the earth of the Grand Canyon.

“Some people have an insecurity because their beliefs are being threatened,” said Francine Romero, an Indian health researcher who specializes in population genetics. “The fear is that the research is going to cast doubt not only on who they are but also on their relationship to their environment. But I still rely on my traditional beliefs. The two are complementary for me. One hundred years from now, what we know about science will have changed too.”

The present scientific understanding is that the starting point of all human beings is in East Africa. Our genes originated and evolved there, and more variants emerged as we dispersed. Native Americans, therefore, are the youngest people in the world, having been the last to break off from the migratory pathway of humanity. But where on the pathway do the Indians’ diseases arise?

One line of argument holds that a condition like type 2 diabetes, because it occurs in populations everywhere, was a latent passenger on the journey from Africa. The diabetes-susceptible genotypes, according to this theory, are old. Another argument is that the Darwinian pressure upon the Asians who struggled through the ice to the New World was so extreme that most didn’t survive. Group DNA was forced into a genetic bottleneck, which stripped the old baggage away. What emerged on the far side was a rare suite of genetic variants that have since expanded in Native Americans. Accordingly, the Indians’ brand of diabetes is theirs alone. It may be different from the condition in Europe or in Africa, though the environmental triggers are the same.

A study by Williams has thrown a beam of light on the ancient liabilities. After typing the markers for ancestry in several thousand Pimas, Williams put the results in order, ranging from full-heritage Indians to the highly admixed. Then he turned to the medical records. Pimas who had the most gene variants from European American sources were least likely to have diabetes. Conversely, the full-heritage Pimas, the most “Indian” in biological terms, were most at risk. European blood for some reason was modestly protective.


AFRICAN AMERICANS FINNS NATIVE AMERICANS
Hallmark trait (also pertains to other groups) Sickle-cell anemia Lactose intolerance Type 2 diabetes (genes unknown)
Aboriginal population Africa Africa Africa
Historical migration to the Americas Finland the Americas
Genetic variation within group High Low Low
Single-gene disorders wtih increased frequency Sickle-cell anemia, thalessemia, and a related blood disorder Northern epilepsy and nearly 40 others Cystic fibrosis, albinism, and a few others
Common diseases with increased prevalence Type 2 diabetes, heart disease, obesity, and prostate cancer Type 2 diabetes, heart disease in East Finland Kidney disease, heart disease, and highest rate of type 2 diabetes
Attitude toward disease genes Fearful of stigma Part of national heritage Suspicious of researchers
Gene-testing experience Apprehension due to testing in 1970s for sickle-cell trait Screening and counseling available Fear of exploitation; lawsuit regarding genetic studies filed
Group’s own health focus: genes versus environment Environment Both Environment

What to expect in the future:
Elimination of all ethnic and racial categories in favor of individual genotyping for disease risk.

genes-end
genes-end

Zuni Indians work out in a class that is part of the Healthy Lifestyles campaign to combat obesity and diabetes. Up to 40 percent of the adult participants are diabetic. The program attracts participants because it is based in the community, not in the hospital.

Joe Schmelzer

It was a strong sign of a genetic effect, without revealing the active genes themselves, a much harder question. Molecular investigations of diabetes genes have bogged down not only at NIDDK but also at laboratories around the world. As Finnish geneticist Leena Peltonen wrote in a recent review, “The enthusiasm regarding the use of population isolates for the identification of predisposing genes for common, polygenic diseases has turned to a silent drudgery.” Translation: Isolated, inbred groups like the Finns, the Amish, and the Pimas were a happy hunting ground for medical geneticists a decade ago, thanks to successes in probing such groups for rare disease genes. But type 2 diabetes, Parkinson’s, heart disease, Alzheimer’s—the common maladies of mankind—give up their genes reluctantly. The gene variants involved must be numerous, cryptic, and weak.

If the diabetes genes can’t be found, can’t they at least be stopped?

The Zuni Pueblo—“pueblo” refers to the contiguous adobe houses the Indians used to build—lies on the high desert of New Mexico, just over the Arizona line. Unlike Gila River, the Zuni reservation has neither mountain ranges nor cities around it. Its landmark is a startling red mesa jutting straight up from the plain. It is called Dowa Yallane. The Zuni hid on Dowa Yallane for a time in the late 1600s, after revolting against the Spaniards and killing a missionary priest.

Like other tribes, the Zuni were decimated by epidemics and warfare brought to them by European Americans. The natives passed through a second population bottleneck, losing 90 percent of their numbers, then rebounded during the 20th century. The fragmentation of the Indian nations, followed by intermarrying and population expansion, was not the best means of maintaining genetic health. The Zuni, a community of 10,000, have the highest measured rate of cystic fibrosis in the world, as well as the highest rate of end-stage kidney disease. Two sharply different sorts of disease genes are at work. The gene variant for cystic fibrosis was introduced by a Spanish or Italian “founder” many generations ago, according to the marker analysis. The gene took off within the pueblo, and one in 13 residents carry it today, but the disease doesn’t strike unless two copies are passed to a child from two parental carriers.

Cystic fibrosis needs no environmental trigger. The kidney disease that afflicts Zuni, however, is related to lifestyle because type 2 diabetes is the cause of the majority of the cases. About one-third of Zuni adults over 40 have diabetes. People also suffer from a nondiabetic form of kidney disease. Some even exhibit both types at once. It is disturbing to enter the tribe’s newly renovated dialysis clinic, which treats three shifts of patients each day, and see the young bodies as well as the elderly hooked up to the machines and their pale, drawn faces while their blood is cleansed.

Last fall a team of researchers from the University of New Mexico, having tracked kidney disease on the reservation for several years, persuaded the tribal council to approve a DNA analysis. The scan of affected families may identify relevant genetic susceptibilities, but the geneticist for the project cautioned the council that the results will be slow to come. When I met with the Zuni leaders afterward, they told me they were not holding their breath.

“We asked them, ‘You’ve already taken blood. Now what?’ ” recalled Carmelita Sanchez, the lieutenant governor.

“What’s the intervention at the time the research is going on?” Carleton Albert, a councilman, said.

“Interim solutions, that’s what we’re asking for,” said another councilman,  Edward Wemytewa. “Add a human dimension to the science. When you do your survey of people, do a lecture on behavior modification at the same time. Maybe a talk about the value of our traditional foods.”

“We need to have regular updates, and we need to be informed when you make a presentation,” Albert said.

The project leader, Philip Zager, a kidney specialist at the University of New Mexico, assured me that the genetics phase of the Zuni Kidney Project was going to be “community based.” Albert’s retort to that was, “They say they want to listen, but I’m not sure they do.” 

Diabetes and kidney disease are so severe that the Zuni could not spurn the genetic approach. The hopes of most members of the council were pinned elsewhere, however. In the late 1990s medical researchers at NIDDK and in Finland conducted trials combining exercise, diet, and drug therapy as a way to head off diabetes in overweight people with high blood sugar. The American study, called the Diabetes Prevention Program, included Zuni and Pima volunteers among its 3,200 participants. In both trials the aggressive interventions did not prevent diabetes in everyone who was followed, but the onset of the disease was slowed overall.

Between 1991 and 2000 the number of adults with type 2 diabetes in the United States increased by 49 percent. Diabetes prevalence rates among adults: 50 percent of Pimas, 11 percent of African Americans, 8 percent of Hispanics, and 8 percent of Caucasians.

How exercise helps is murky, but increased activity seems to stimulate a gene called GLUT4. The gene’s protein aids insulin in transporting glucose into muscle cells. Meanwhile, losing weight cuts back the hormonal activity of fat cells, which in turn reduces a person’s resistance to insulin. When the results of the trials were published three years ago, Indian Health Service doctors and tribal health officials got the message: Environment was the way to go.

Ruby Wolf is the unofficial wellness czar of the Zuni. Thanks to federal grants, Wolf’s Healthy Lifestyles campaign is an inescapable fixture of the community. T-shirts and posters proclaiming the slogan are ubiquitous. Once a month the Healthy Lifestyles staff holds a rally, race, or some other event to promote weight loss, better nutrition, and fitness. “We know what works,” said Wolf, “but it’s got to be fun and educational.” A new swimming pool, spinning (stationary bicycle) classes, school lectures, public weigh-ins, softball tournaments —I couldn’t write down fast enough all the things she had planned for the Zuni.

“We don’t have a minute to lose,” she said, adding that her parents died of diabetes. “That’s where our ambition and drive come from. I want nonstop stimulus and nonstop intervention.

“People say about diabetes, ‘Well, I guess it’s my destiny.’ No. I went to our spiritual leaders and asked them about our prayer that says, ‘From this day forward the road and path are what we choose.’ And they said, ‘Yes, that is a powerful prayer.’ I took it for the sweatshirt we’re giving away this Saturday. If you run, if you’re 4 years old or 89, you get one.”

Wolf showed me the handsome hooded sweatshirt, with its circular emblem on the back and the words “Zuni Healthy Lifestyles, Your Life’s Direction.” “If we’re going to prevent diabetes, we’ve got to build on the 25 percent of the community that comes to our events,” she said.

She has even hired an epidemiologist to gather health data on the participants because doubters demanded scientific evidence of the gains. The epidemiologist, Chetna Mehrotra, is an Indian, but an Asian Indian; she was as enthusiastic about conquering diabetes as Wolf. I couldn’t resist pointing out the closeness in DNA between the two women. The incidence of type 2 diabetes, for that matter, is increasing faster in Asia than anywhere outside the Native American communities. But Wolf and Mehrotra were not interested in genes.

Piñon smoke and red dust hung in the wintry air of Zuni Pueblo. Responding to the health campaign, the community store has put a salad bar next to the hamburger grill and soda cooler, and I saw people using it. Leaving town at dusk, I drove onto a dirt road toward the snow-patched flanks of the sacred mesa, Dowa Yallane. At a bend in the road, I saw a lone warrior in black, jogging.

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