Geneticist Dr. Esteban Burchard was studying asthma at Brigham and Women’s Hospital in Boston years ago when, he recalled, “a black teenager died of an asthma attack right outside the hospital entrance. Which is ridiculous. There are 20 hospitals in Boston!”
The death reflected a harsh reality in the United States: Asthma hits African-Americans particularly hard, and the health care system often fails them. An estimated 15.3 percent of black children have the disease compared with 7.1 percent of white children, according to the Centers for Disease Control and Prevention. Overall, African-Americans are nearly three times as likely to die from asthma as white people.
Last year, Burchard, now a professor at the University of California, San Francisco, Schools of Pharmacy and Medicine, and a team of more than 50 researchers published a paper with one surprising explanation for those disparities. A set of genetic mutations found mostly in people of African ancestry may make them less likely to respond to albuterol, the most-prescribed asthma drug in the world.
An earlier study Burchard co-authored found that 47 percent of African-American children and 67 percent of Puerto Rican children with moderate-to-severe asthma suffered from a diminished response to the drug.
The new research raises the possibility that a cheap genetic test could one day be developed to help identify patients who are resistant to albuterol and could benefit from alternative treatments.
“With albuterol and asthma, such a test could be really useful and important, because a patient’s risk profile goes up dramatically if we know they are not going to respond to this particular treatment,” said Dr. Valerie Press, an internist and assistant professor at the University of Chicago Medical School who treats asthma patients and conducted studies on the disparities in the disease and their effects on care.
The development of a genetic test for asthma would mark another example of the potential of precision medicine — treatments tailored to patients’ genetic profiles and unique physiological characteristics.
But it won’t be easy. Many factors besides genes and ancestry — including environmental exposures, stress, and social forces such poverty and racism — influence asthma incidence and the effectiveness of treatments.
“Say you have a kid with asthma, and they have to take medications to control it,” said Dr. Juan Celedón, who runs an asthma research lab at the University of Pittsburgh Medical Center Children’s Hospital. “If a child is supposed to be taking one of those controllers daily but he/she is not taking it, one outcome will be reduced response to bronchodilators like albuterol.”
Nevertheless, a genetic screening test could be valuable because albuterol resistance is often overlooked amid other problems.
“When all you see are signs of poor outcomes — such as more visits to the emergency department — it can be very difficult to interpret the reason,” Press said. “You may say, ‘Well, maybe they didn’t have access to primary care, so they didn’t get the prescription. Or maybe they didn’t get the correct instructions.’”
Asthma rates vary widely between different minority groups, some living in similar low-income environments. Overall asthma incidence among Latinos, for example, is 6.6 percent, below the national rate of 8.3 percent, according to the CDC. But among Puerto Ricans, that figure is 14.3 percent, exceeding the rate of 11.6 percent for African-Americans (but is still less than the rate for black children, 15.7 percent). For people of Mexican descent, meanwhile, the rate is only 5.7 percent.
Those differences hint at the role that genetics and ancestry play.
“If I combine Puerto Ricans and Mexicans together, it makes it look like Hispanics have lower rates of asthma than whites,” said Celedón. “It’s only when you separate them that you begin to see these sharp differences. … Among Puerto Ricans, there’s been extensive work already showing that the proportion of African ancestry, and particularly a Hispanic racial admixture, is associated with lower lung function and susceptibility to asthma. Whereas with Native American ancestry, it’s the opposite.”
When Burchard first set out to study the genomics of these differences in the 2000s, he said, he ran into a significant obstacle. Existing genomic databases were — and still are — dominated by DNA samples from people of European ancestry, and to a lesser degree Asian ancestry. This lack of diversity makes it virtually impossible to study the genetics of diseases in minority populations without going out and collecting your own DNA samples from target groups — an expensive and time-consuming process.
Minority groups also tend to have more varied ancestral origins than European or Asian populations — adding an additional level of scientific complexity. “‘Latino’ means more than one founder population,” said Angel Mak, a UCSF geneticist who helped lead the albuterol study. “It’s three – European, Native American, and African. So you need a bigger sample size to reach a conclusion. That will cost more money.”
With a series of grants from the National Institutes of Health, since the early 2000s Burchard collected and studied DNA data from a variety of Latino and African-American populations, putting it in the context of other risk factors. The albuterol study is the latest product of that effort.
In those with albuterol resistance, he and his team found common mutations in genes related to lung capacity and immune response. The most prominent was a variant in a gene known as NFKB1, which is associated with smooth muscle response in the lungs. It’s the sudden constriction of these particular cells that albuterol targets. People of African ancestry – including both African-Americans and Puerto Ricans in the study – with low albuterol response were much more likely to have this mutation.
“NFKB1 is part of a signaling pathway affecting a lot of things; one is allergic response,” Mak said. “Asthma is an allergic-related disease; airways become irritated, inflamed, and the drug helps you open up airways so you can breathe. This actually makes a lot of sense.”
Only recently has the cost of DNA sequencing dropped enough to make the idea of applying such findings directly in medical diagnoses seem feasible. But there is increasing hope that precision medicine, currently a mostly theoretical form of treatment available mostly to the well-off, could reach into urban asthma clinics.
“This is the direction the field is going,” said Kathleen Barnes, director of the University of Colorado’s Division of Biomedical Informatics and Personalized Medicine, who was not involved with the UCSF study. “First the cost of whole genome sequencing went from $10,000 to $5,000. We were still paying $2,000 per genome until recently. Today, it’s under $1,000. The price of whole genome sequencing continues dropping.”