Genetics and Asthma: A Former Harold Amos Scholar Researches the Impact of Ancestry on Disease and Health Disparities

    • August 28, 2013

The problem. To what extent does racial and ethnic background affect a person’s risk of disease and response to drug therapies?

Esteban González Burchard, MD, MPH, a professor at the University of California, San Francisco (UCSF), is leading the nation’s largest gene-environment study of asthma among Hispanic and African American youth to find the answers—answers that could help improve the diagnosis and treatment of racially and ethnically diverse populations worldwide.

“There have been tremendous advances in biomedical research in the last 10 years. There have been tremendous advances from the Human Genome Project. But the majority of these advances are applicable to European populations,” says Burchard, an alumnus of RWJF’s Harold Amos Medical Faculty Development Program. (See Program Results Report for more information.)

“What we’ve created is a bio-repository for minority children that allows us to extend some of the advancements in science to these populations that are understudied—not only underserved, which is the basis of health care disparities, but understudied.”

The start. Burchard’s own background is in a word—his word—complex. He grew up in a Hispanic neighborhood in San Francisco’s Mission District, one of four children in a one-parent family. The one parent was his mother, a public high school teacher of Mexican heritage.

His father was—again, Burchard’s word—Caucasian, a more exact ethnic identity unknown to the son. To add to the complexity, young Esteban was close to—and partially raised by—a Chinese family.

“You should get a beer and pull up a chair,” he replies when asked how he got from there to the joint appointment he holds today in the UCSF schools of medicine and pharmacy. Geographically, it’s not far. His research office on the university’s Mission Bay campus and his clinic at San Francisco General Hospital are in walking distance of his childhood haunts.

But in every other respect it’s been a considerable journey—a journey on which his mother was a powerful propellant. Gloria González Burchard, a Spanish teacher at Mission High, believed in education and did not tread lightly when it came to expectations: Her son would go to college. “There was no alternative,” he says.

There were, however, some bumps on the way. At one point he got kicked out of high school, says Burchard. “My parents were divorced [when I was] at an early age, and I became a troubled youth,” he says. Salvation came on the wrestling mat. A high school coach took the young man under his wing, molding him into a strong competitor with new self-confidence and discipline.

“That just transformed my life,” he says of wrestling, which he continued as an undergraduate at San Francisco State (167-pound weight class). He was a California state finalist and twice awarded NCAA Division II Academic All-American honors. The sport “was tremendously helpful in preparing me to compete, to go to medical school, and to compete in medical school, and even now has helped me to compete.”

Also helpful in those youthful years was an aptitude for science, stimulated in part by an early career—age nine or so—in a wee niche of commercial fishing.

“We didn’t have child care so my mom before work [in the summer months] would drop me off at the water, and I would fish all day,” explains Burchard. “I would catch minnows and sell them to the poachers and buy lunch.” His fishing spot, he adds, was right across the street from what is now his Mission Bay office.

In addition to monetary rewards, the young fisherman came away from that spot with a fascination for sea life—a fascination that led him to choose a marine biology major when he started college. His interest subsequently migrated to cellular and molecular biology, and by graduation he was firmly focused on genetics and a career as physician scientist.

At Stanford University School of Medicine, where he earned his MD in 1995, Burchard worked in a lab researching heart and lung transplant immunology, an experience that increased his understanding of pulmonary medicine as well as genetics.

Turning a corner. After Stanford the next stop was Boston and a Harvard residency program at Brigham and Women’s Hospital. But even as he headed east, Burchard wasn’t certain where his career was going. “I had this interest in health disparities, but then I had this great training in genetics. I couldn’t see how they could blend.”

Burchard explains how he found the answer: Jeffrey M. Drazen, MD, a Harvard professor and specialist in pulmonology (and currently editor-in-chief of the New England Journal of Medicine), asked the newly minted doctor if he would be interested in joining his lab to study the genetics of asthma.

“I said, ‘Jeff, thank you, but I’m not really interested. I don’t see how this could help me with my interest in health disparities and my training in genetics.’ And he told me, ‘Son, you’re making a mistake. Give it a shot.’ So I listened to Jeff and gave it a shot.”

His first project was researching the genetics of asthma severity. “We identified a genetic mutation that was associated with asthma severity, and the frequency of that mutation was almost twice as common in Blacks as in Whites. That was when I fell in love with what I was doing. It was really serendipitous—much like turning the corner and finding the love of your life. ... Here, for the first time in my experience, I saw a biologic basis to help [address] disparities.”

A hypothesis. In common parlance Hispanics or Latinos (Burchard uses both terms) are lumped together as a single ethnic group. But in fact the label encompasses a heterogeneous mix of Native American, European, and African ancestries.

At a meeting of pulmonary physicians, Burchard saw that Hispanics in the Northeast had a higher rate of asthma than Hispanics in the rest of the country.

“I knew, from having lived in Boston, that the majority of Hispanics on the east coast were Puerto Ricans,” he says. “And being Hispanic myself, I knew that Puerto Ricans had a lot of African ancestry.” He also knew that Puerto Ricans suffered from asthma at a significantly higher rate than other Hispanic groups.

In contrast, says Burchard, Hispanics in the West, Midwest and South are primarily Mexican Americans, who have very little African ancestry and relatively low asthma prevalence. “So I coupled that with my findings in Jeff’s lab, and I hypothesized that the differences in asthma rates and asthma mortality among Hispanics were due to genetic differences.”

Exploring that hypothesis has been a key focus of Burchard’s career. Collaborating with other investigators across the United States and beyond, he has led a series of studies to learn how specific genetic factors interact with environmental influences to impact asthma prevalence, severity, and medication responsiveness among racial/ethnic populations.

The research. Burchard’s initial study was titled Genetics of Asthma in Latino Americans (GALA)—a name his mother came up with. “She was a whiz at Scrabble,” he says parenthetically. Burchard—who moved to the University of California, San Francisco in 1998 for specialty training and later joined the faculty—collaborated with institutions in New York, California, Puerto Rico, and Mexico City to recruit Puerto Rican and Mexican children with asthma into the comparison study.

Along with a higher risk of hospitalization and emergency department visits, the Puerto Ricans were on average less responsive to albuterol, a common asthma medication used to increase airflow to the lungs. The findings, the researchers reported in a 2004 journal article, suggest that ethnic-specific genetic factors contribute to differing responses to the drug.

While the sample of 700 families was admittedly small, the results suggest that “there may be subgroups of subjects with asthma that may not respond well to commonly prescribed asthma therapies. If replicated, this finding could have important clinical and public health implications,” the team wrote.

To pursue those implications, Burchard organized a second asthma study, this one with a far larger number of Latino children and also with more attention to the environmental determinants of health, such as air pollution and in utero smoking. Burchard christened the new study GALA II, but—reflecting its broadened focus—the acronym this time stood for Genes-Environments & Admixture in Latino Americans.

Supported by a National Institutes of Health (NIH) grant, GALA II is ongoing with more than 4,300 Latino children recruited from multiple cities. Using the same NIH funding, Burchard also initiated a parallel study in the San Francisco Bay area called Study of African Americans, Asthma, Genes & Environments (SAGE).

Combined, the GALA I, GALA II, and SAGE samples total more than 9,000 children—constituting the largest pediatric gene-environment study of asthma in minority children in the United States, according to Burchard.

For a more detailed description of the research, see Burchard’s UCSF lab website, which lists more than 100 articles and publications by study collaborators and provides links to media interviews with Burchard about the work.

Because of past abuses and fears of future ones, genetics, race, and medicine can be a controversial combination—“a hot-button issue,” Ira Flatow, host of NPR’s Science Friday, said in a broadcast discussion with Burchard and others. (A transcript of the January 15, 2010 program—“Is There a Biological Basis For Race?”—is online.)

Burchard acknowledges the potential for misuse and need for ethical safeguards. But on the NPR program, he likened genetics to nuclear energy: potentially dangerous but also highly beneficial. “We cannot bury our head in the sand for fear of what someone might do,” he said.

The RWJF connection. In 2005 Burchard was awarded a grant by RWJF’s Harold Amos Medical Faculty Development Program and used part of the four-year fellowship (Grant ID # 51892) to earn an MPH at the University of California, Berkeley—an experience that he says significantly increased his appreciation of the social and environmental determinants of health. “The Harold Amos program allowed me time to go back to school and retool. And it allowed me to broaden my thinking beyond just genetics,” he says.

Instead of a traditional master’s thesis, Burchard capped his course work by writing the grant proposal that became GALA II, with its heightened attention to nongenetic factors. “That was a paradigm shift that the Amos faculty development program allowed me to experience.” Without the program, he would not have gotten GALA II and SAGE underway, he says.

In addition to the Berkeley curriculum, the Amos program’s lectures and interactions contributed to the shift, Burchard says.

RWJF perspective. The Harold Amos Medical Faculty Development Program is a four-year postdoctoral fellowship launched by RWJF in 1983. Its purpose is to increase the number of faculty from minority and other historically disadvantaged backgrounds who achieve senior rank in academic medicine and dentistry.

RWJF’s objective is to increase diversification of the medical and dental professions and, as a consequence, improve the health care received by the nation’s underserved populations. A commitment to eliminating health disparities is among the program’s selection criteria.

“Ultimately,” says RWJF senior program officer David M. Krol, MD, MPH, “we would like to see these individuals from disadvantaged backgrounds becoming full professors at prestigious institutions, putting out important, valuable work, looking at a variety of different issues—including how to decrease the disparities between rich and poor, majority and minority—while climbing the academic ladder.”

Esteban Burchard is one of more than 180 Amos program alumni in academic medicine today. His career and research exemplify the academic achievement and professional contributions that the program was designed to stimulate.

“The measure of the success of the program is the success of the individuals” who participate in it, says Krol.