Mutations in the DENND1B gene leads to enhanced cytokine release, according to paper in NEJM.

A group of researchers have implicated a gene known as DENND1B in the development of childhood asthma. Their research suggests the gene’s protein is involved in the release of cytokines.

The study is published in the New England Journal of Medicine in a paper titled “Variants of DENND1B Associated with Asthma in Children.” 

The team, led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia, carried out genome-wide association studies to compare the genomes of children suffering persistent asthma with those of healthy controls. The studies were carried out on separate cohorts of children of North American descent, European background, and African American ethnicity.

“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,” Dr. Hakonarson notes.

Back in 2007, genome-wide association studies by U.K. researcher William O. C. Cookson, M.D., identified the asthma-susceptibility gene ORMDL3 on chromosome 17. The Children’s Hospital research, on which Dr. Cookson also collaborated, highlighted ORMDL3 but also found a new location on chromosome 1q31, in which eight SNPs appeared to show clear association with asthma. 

The putative gene within the 1q31 region was DENND1B, which is expressed by natural killer cells and dendritic cells, and encodes a protein that interacts with the TNF-alpha receptor. “We know that the DENND1B gene and its protein are involved in the release of cytokines,” Dr. Harkonarson continues. “In asthma, patients have an inappropriate immune response. The gene mutations in DENND1B appear to lead to overproduction of cytokines that subsequently drive this oversensitive response in asthma patients.”

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