Researchers Identify Novel Gene for Childhood-Onset Asthma

Pediatric researchers have identified a novel gene involved in childhood asthma, in one of the largest gene studies to date of the common respiratory disease. Because the gene, called DENND1B, affects cells and signaling molecules thought to be instrumental in the immune system overreaction that occurs in asthma, the discovery may have singled out an important target for new treatments.

A research team led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia, implicated a location on chromosome 1 associated with moderate-to-severe, childhood-onset asthma. The study appeared on Dec. 23 on the Online First Web site of the New England Journal of Medicine. It will be published in the journal's print issue on Jan. 7.

Asthma is a complex disease, in which a large number of genes, as yet mostly undiscovered, are thought to interact with each other and with environmental factors to produce asthma's characteristic wheezing, coughing, and shortness of breath. It also is highly heterogeneous, manifesting differently in different patients, and appears to operate differently in childhood-onset asthma compared to adult-onset asthma.

Previously, researchers had identified only one other asthma-susceptibility gene using a genome-wide association study (GWAS), in which automated genotyping tools scan the entire human genome seeking gene variants that contribute to disease risk. That gene, ORMDL3, on chromosome 17, was discovered in 2007 by U.K. researcher William O.C. Cookson, M.D., who collaborated with Hakonarson in the current study.

In this current study, Hakonarson's team performed GWAS on a sample of 793 white North American children with persistent asthma, compared to control group of 1,988 children. They replicated the study in a separate group of 2,400 European subjects and controls, then did further analyses on a third group of 3,700 African American children.

"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," Hakonarson said.

In addition to observing the previous results for chromosome 17, his group found a novel location on chromosome 1q31, with eight single nucleotide polymorphisms (SNPs) associating robustly with asthma. A SNP (pronounced "snip") is a change to a single chemical base along the DNA helix. Unlike other studies, here the researchers found the same gene for asthma susceptibility in children of both European and African-American ancestries.

Within this region on chromosome 1q31 the gene with an apparent role in asthma is DENND1B, already suspected as a player in the body’s immune response. DENND1B expresses a protein of the same name, which is active in particular types of dendritic cells and specific T lymphocytes, including natural killer cells. Both of these immune cell subtypes form cross-talks between them (commonly referred to as the antigen presenting synapse) and regulate how the body responds to foreign material such as viruses, bacteria, and allergens.

"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," said Hakonarson, who is a pulmonologist. "Many of these particles are well-known triggers of asthma. In asthma, patients have an inappropriate immune response in which they develop airway inflammation and overreaction of the airway muscle cells, referred to as airway hyper responsiveness. The gene mutations in DENND1B appear to lead to overproduction of cytokines that subsequently drive this oversensitive response in asthma patients."

By identifying an asthma susceptibility gene with a compelling link to the pathobiology of asthma, Hakonarson said, his team may also have pinpointed a tempting therapeutic target, if researchers can develop drugs to contain this signaling pathway.

"Because this gene seems to regulate many different cytokines, intervening in this pathway has great potential for treating asthma," he added. "Other asthma-related genes remain to be discovered, but finding a way to target this common gene variant could benefit large numbers of children."

For more information, visit www.chop.edu.

Product Showcase

  • Glove Guard® Clip

    Safety should never be compromised, especially when it comes to proper glove usage. The Glove Guard® clip enhances safety by encouraging employees to keep their gloves with them at all times. This reduces the risk of accidents and injuries on the job. By ensuring everyone has their gloves readily available, we help promote a culture of safety and efficiency. The Glove Guard® clip is designed to withstand the toughest work environments. Constructed from robust materials made in the USA, it can endure extreme conditions, including harsh weather, and rigorous activities. Read More

  • The MGC Simple Plus

    The MGC Simple Plus is a simple-to-use, portable multi gas detector that runs continuously for three years without being recharged or routinely calibrated after its initial charge and calibration during manufacturing. The detector reliably tests a worksite’s atmosphere for hydrogen sulfide, carbon monoxide, oxygen and combustible gases (LEL). Its durability enables the detector to withstand the harshest treatment and environments, hence earning it an IP 68 rating. The MGC Simple Plus is also compatible with a variety of accessories, such as the GCT External Pump. Visit gascliptech.com for more information. Read More

  • Magid® D-ROC® GPD412 21G Ultra-Thin Polyurethane Palm Coated Work Gloves

    Magid’s 21G line is more than just a 21-gauge glove, it’s a revolutionary knitting technology paired with an advanced selection of innovative fibers to create the ultimate in lightweight cut protection. The latest offering in our 21G line provides ANSI A4 cut resistance with unparalleled dexterity and extreme comfort that no other 21-gauge glove on the market can offer! Read More

Featured