Packard, Stanford Researchers Uncover Gene Family Critical To Asthma Development

Asthma researchers have known for years that the disease has a genetic component, but efforts to pinpoint specific genes have been stymied by the complexity of the disease, which involves more than a dozen independently acting genes. When the Stanford researchers used a special technique to look at the effects of only small stretches of DNA at a time, however, they identified a previously unknown group of nearby genes, called the Tim family, as primary culprits.

"It was only by using this mouse model that we could identify a locus and some potential candidate genes that could be inducing this phenomenon," said Rosemarie DeKruyff, PhD, senior author of the study, published in the December issue of Nature Immunology. "It was especially interesting when we found that the gene we homed in on encoded the hepatitis A receptor gene."

Infection with hepatitis A protects against asthma for reasons that have not been well understood. The newly discovered link between family member TIM-1 and the hepatitis A virus may help explain the association between the two diseases. Researchers speculate that binding of the virus to the hepatitis A receptor gene, TIM-1 somehow interferes with disease development in these infected individuals. If so, their finding may provide a clue as to why asthma rates have increased where hepatitis A infection rates have dropped over the past two decades.

"It may be that when hepatitis A binds to this receptor it somehow brings about a deletion of those cells that bias the immune response toward asthma," says DeKruyff, a professor of pediatrics at Packard. "But there are also other possible scenarios."

To carry out the research, Jennifer McIntire, an MD/PhD student working in DeKruyff's lab in collaboration with Dale Umetsu, MD, PhD, chief of the division of allergy and immunology, bred together two sets of mice. One set develops airway hyperreactivity, or AHR, after being exposed to an allergen, and another is resistant to AHR, which causes the shortness of breath, chest tightening, wheezing and coughing that are hallmarks of human asthma attacks.

Using a technique known as backcrossing, McIntire and her colleagues generated mice that were genetically identical to the susceptible mice, other than for small segments of DNA from the resistant group. They then looked for mice in the group that did not develop AHR when exposed to an allergen.

They found that mice containing a small segment of DNA similar to an asthma susceptibility region on human chromosome 5 were significantly less likely to develop AHR than the susceptible group, even though the two groups shared the rest of their genomes.

The region on human chromosome 5 contained some likely candidate genes, including several encoding proteins called cytokines that regulate the immune response leading to asthma. Many researchers had assumed that these cytokine genes were responsible for the increased asthma susceptibility conferred by the region. However, when McIntire and her colleagues analyzed the stretch of DNA more closely they found that the development of AHR was actually linked to a nearby group of genes, which they named the Tim family.

The researchers are now investigating whether this gene family is also linked to the development of asthma in humans.

DeKruyff's and McIntire's Stanford colleagues on the study include undergraduate Sarah Umetsu; Omid Akbari, PhD; and Dale Umetsu, MD, PhD, all in the division of allergy and immunology in the Department of Pediatrics; and Gregory Barsh, MD, PhD, in the Howard Hughes Institute and Departments of Pediatrics and Genetics.

Lucile Salter Packard Children's Hospital at Stanford is a 240-bed hospital devoted entirely to the care of children and expectant mothers that is celebrating its tenth anniversary in 2001. Providing pediatric medical and surgical services associated with Stanford University Medical Center, Packard offers patients locally, regionally and nationally with the full range of health care programs and services - from preventive and routine care to the diagnosis and treatment of serious illness and injury. To learn more about Lucile Packard Children's Hospital, please visit our Web site at www.lpch.org.