20 years chasing the genetic roots of asthma

Esteban G. Burchard, MD, MPH, started studying the genetics of lung disease as a medical student in 1990. However, his “aha!” moment came in 1997, when he was investigating the genetic determinants of differences in asthma severity between black and white patients at Harvard’s Brigham and Women’s Hospital (BWH) in Boston. A young African-American teenager collapsed from an asthma attack and died, clutching his asthma inhaler, just outside one of the nation’s best children’s hospitals.

It drove home a point for Burchard that physicians and scientists know all too well: Some minority groups make up an alarming share of the country’s 24 million asthma cases, and they account for a disproportionate number of deaths from asthma, too.

Unraveling exactly why, Burchard believed, would improve our understanding of how the disease works—and could lead to the next generation of life-saving asthma treatments. Burchard, who arrived at UCSF in 1998, marks the 20th year of his asthma project in May. His lab, which he named the UCSF Asthma Collaboratory, has brought together researchers across the world, published hundreds of papers, and delved deep into the genetic basis of asthma and of drug response in the disease.

A geographic hunch

The genetic heritability of asthma is well documented but complicated. There is no single asthma gene present in every case. Even though it has long been apparent that some ethnic groups have a higher incidence of asthma, other risk factors—such as exposure to air pollution, tobacco smoke, socioeconomic adversity, and racial discrimination—are also part of predicting the disease. To make progress on the root causes, researchers need to be able to separate the environmental and social exposures from the genetic determinants.

Burchard, a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine, got a lead into the genetic portion of the mystery at a pulmonary conference in 1998. He found himself looking at a Centers for Disease Control (CDC) generated geographic map of asthma prevalence and mortality among U.S. Hispanics/Latinos. Those Hispanics/Latinos living in the Northeast had a higher asthma prevalence and mortality than those living anywhere else in the country.

Burchard was trained in medicine and translational genetics, and one of his projects as a medical resident at Harvard’s BWH was helping to identify a genetic variant that was related to asthma severity. People all possess the same genes—about 20,000 of them—but every gene comes in a handful of “flavors,” or alleles, that vary between individuals and racial/ethnic groups. In the Harvard discovery, researchers found a genetic variant that was associated with asthma severity. This allele shows up 40% more often in African-Americans than in whites.

Something clicked. Burchard, himself Hispanic/Latino, had lived on both coasts, and he knew that Puerto Ricans settled more in the Northeast than the rest of the country. Given what he already knew about an asthma severity gene variant common to African-Americans, he had a hunch about what was going on.

Puerto Ricans have a unique history and a unique gene pool. Puerto Rico was one of the first landing places for Christopher Columbus, and an early site for the mixing of European and indigenous lineages. With slavery, African genes also came to the island. Burchard suspected that African ancestry was at play in Puerto Ricans’ susceptibility to asthma.

Behind the hunch was an even bigger idea, that the CDC’s categorization of “Hispanic” was far too broad to be helpful for studies of asthma among Hispanics/Latinos. In contrast to Puerto Ricans, it’s been found that Mexicans—who are also considered Hispanic—have the lowest asthma prevalence and mortality of any population. Indeed, soon after Burchard began this work, the CDC moved to more specific designations of Hispanic/Latino ethnic groups.

While at BWH, Burchard and his mentors proposed the Genetics of Asthma in Latino Americans (GALA) study. A mere month after getting a grant from the National Heart, Lung, and Blood Institute (NHLBI), a part of the National Institutes of Health (NIH), Burchard took the project with him to UCSF. “I had wonderful mentorship at Harvard, but I’m also a San Francisco native,” Burchard said. “UCSF is a place that has outstanding clinical training and research, and I was fortunate again to find great mentors here.”

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Members of Burchard's research lab, the UCSF Asthma Collaboratory, on the steps of Genentech Hall on the Mission Bay campus.

The trouble with albuterol

Inhalers loaded with the drug albuterol are the first line of defense for most patients having an asthma attack. For most people, the drug (also known as salbutamol and Ventolin), opens tightened airways and gets asthma sufferers breathing normally again. Unfortunately, the first-line drug doesn’t always work.

This is a serious problem, but it is also a clue.

In 2003, one of the first results of the GALA study demonstrated that a patient’s ethnicity was the biggest predictor of albuterol’s effectiveness in treating their asthma. In 2007, additional studies showed that 67% of Puerto Rican children with asthma, and 47% of African-American children with asthma, like the young man who died outside the Harvard hospital, don’t respond to the drug. In other words, the most common drug for asthma doesn’t work equally well for the populations with the worst asthma morbidity and mortality.

Marquitta White, PhD, and Angel Mak, PhD, had just joined Burchard’s lab in 2016 when the NHLBI sponsored Burchard to perform a whole-genome sequencing (WGS) pharmacogenetic study of the albuterol drug response in minority children with asthma. WGS involves mapping all 3 billion of the DNA pairs that make up a person’s genetic code. It’s a process that only recently became cost-effective for large studies.

The first of its kind, the study would compare the genetics of children with asthma who had the best drug response to albuterol to those with the worst drug response, hoping to identify pharmacogenetics factors that might determine how a patient responds to the drug. Figuring out what specific genes are at play when the lungs do or don’t respond to a puff on an inhaler can get us closer to understanding the underlying causes of the disease, and closer to finding better drugs.

On a whiteboard in their lab, researchers White and Mak scrawled “SAVE TILL PUBLISHED” over an outline of their ambitious project. Later, they would add “Ceremoniously erase when published!” On March 6, 2018, their research was published in the American Journal of Respiratory and Critical Care Medicine, the world’s leading pulmonology journal. Walter Eckalbar, PhD, and Zachary Szpiech, PhD, also of UCSF, were among the co-authors on the study.

Burchard Lab

Angel Mak, PhD (left), and Marquitta White, PhD, saved their original project outline on a whiteboard until the research was published.

White says that Burchard’s collaborations were key in finding the right participants for the study, which compared the genes of 1,500 children with Puerto Rican, African, and Mexican backgrounds who responded either very well or very poorly to albuterol.

“Burchard has really great collaborators who keep really good records of their patients,” White said. Those files include patient DNA as well data about “what patients eat, and even details about socioeconomic factors, too.”

The treasure trove of clinical, social, environmental, and biologic data helped the team isolate some of the variations of the albuterol response within in a gene called NFKB1. The gene is closely associated with lung immune system response, and it’s possible that it also interacts with a neighboring gene that helps protect the airways and lungs from inflammation.

“NFKB1 is associated with low drug response and also tracks with African ancestry,” Burchard said. “This might explain the 2003 study (showing an ethnic basis to albuterol response), but it also might explain why Puerto Rican and African American children have higher death rates from asthma.”

According to Mak, the UCSF Asthma Collaboratory’s director of genetic research, the study is just the beginning. A next step would be a look at the genomes of even more Puerto Rican, African American, and Mexican asthma patients to find more genes at play, while exploring social and environmental factors, such as smoking and air pollution, that are associated with asthma, she said. “People from Puerto Rican ancestry have the highest rates of asthma, no matter where they live,” White added.

The result, eventually, will be basic science insights that jump to patient care. “We are a translational science laboratory—the idea is that everything we do will eventually go to the clinic (to treat patients),” White said.

The next breakthrough

After 20 years of research, the UCSF Asthma Collaboratory is just starting to answer the deeper questions about the health disparities of asthma. The albuterol studies explain some of the disease, but the potential for large genetic studies is still mostly untapped.

“We’ve identified about 10 genes in play for asthma,” Burchard said; but so far, his team has only been able to study one gene in depth.

One near-term step is genetic screening to help identify which of the current asthma drugs are best for individual patients. The albuterol studies could help create a simple test, similar to what is available for patients being prescribed Plavix, a blood thinner that doesn’t work for an allele common in Asians and Pacific Islanders.

Burchard’s ultimate goal is to improve health and to save the lives of asthma patients. “I think there is a drug at the end of this,” he said.