December 23, 2009 — A novel gene linked to moderate-to-severe childhood-onset asthma may suggest new therapeutic targets, according to the results of a study reported online December 23 in the New England Journal of Medicine.
The DENND1B gene, located on chromosome 1, affects cells and signaling molecules thought to play a key role in immune system hyperactivity seen in asthma.
"By analyzing a large cohort of children with moderate to severe asthma, all of whom require controller medications on a regular basis, we managed to enrich our study for genetic signals and achieve sufficient statistical power to uncover and replicate a novel asthma gene," senior author Hakon Hakonarson, MD, PhD, from the Center for Applied Genomics at the Children's Hospital of Philadelphia, Pennsylvania, said in a news release.
"We now know that the DENND1B gene and its protein are involved in the release of cytokines, which are signaling molecules that in this case tell the body how it should respond to foreign particles. Many of these particles are well-known triggers of asthma."
Geneticists believe that a large number of genes, most of which are still undiscovered, interact with each other and with environmental factors to produce airway hyperresponsiveness and inflammation, resulting in wheezing, coughing, and shortness of breath associated with asthma. The heterogeneity of asthma results in different presentations in different patients and in different manifestations in childhood-onset vs adult-onset asthma.
"The gene mutations in DENND1B appear to lead to overproduction of cytokines that subsequently drive this oversensitive response in asthma patients," Dr. Hakonarson said.
Genomewide association study (GWAS), which uses automated genotyping tools to scan the entire human genome and to identify gene variants contributing to disease risk, previously identified only 1 other asthma-susceptibility gene, ORMDL3, located on chromosome 17.
The present study compared GWAS findings in 793 white North American children with persistent asthma requiring daily inhaled glucocorticoid therapy with those in a control group of 1988 children without asthma. The investigators replicated their findings in a separate group of 2400 white children with asthma (n = 917) and controls (n = 1546), as well as in a third group of 3700 black children.
In addition to confirming findings regarding ORMDL3 on chromosome 17, the investigators identified 8 single nucleotide polymorphisms associating robustly with asthma in a new location on chromosome 1q31. The same gene for asthma susceptibility was present in study samples from both white and black children.
Limitations of this study include the inability to differentiate a genetic effect of DENND1B on age of onset from an effect on severity.
The DENND1B gene on chromosome 1q31, now identified as a genetic risk factor for asthma, was previously implicated in the immune response because the DENND1B protein is active in specific dendritic cells and T lymphocytes, including natural killer cells.
Via the antigen-presenting synapse, cross-talks between these immune cell subtypes regulate immune response to foreign particles including viruses, bacteria, and allergens. DENND1B protein, which interacts with the tumor necrosis factor alpha receptor, is therefore a potential therapeutic target for development of new asthma drugs affecting this signaling pathway.
"Because this gene seems to regulate many different cytokines, intervening in this pathway has great potential for treating asthma," Dr. Hakonarson concluded. "Other asthma-related genes remain to be discovered, but finding a way to target this common gene variant could benefit large numbers of children."
The Children's Hospital of Philadelphia, the state of Pennsylvania, the Cotswold Foundation, the Lundbeck Foundation, and the National Institutes of Health supported this study. The study authors have disclosed no relevant financial relationships.
