Study of Rare Disease Reveals Gene Crucial to Immune Defense

Mar 13 2015

Study of Rare Disease Reveals Gene Crucial to Immune Defense

rare diseaseGenomics researchers from the Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia investigating a serious, rare disease called common variable immunodeficiency (CVID) have discovered a gene linked to immune defense. Children with the challenging disorder have difficulty fighting off infections.

CVID affects one in 25,000 to one in 50,000 people worldwide, and they may start experiencing signs and symptoms of the disorder anytime between childhood and adulthood. Researchers suspect that mutations in the genes associated with CVID result in a shortage of antibodies that leaves the body vulnerable to infections from bacteria and viruses. Recurrent respiratory infections can lead to chronic lung disease, and patients also may have joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They compared regions of the genome using a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases.

The researchers found 11 single nucleotide polymorphisms (SNPs) associated with CVID on the 16p11.2 locus of chromosome 16. SNPs are changes in a single DNA building block (A,T, C, or G), compared to the more typical sequence in a certain stretch of DNA. Of particular interest, the study team found variants in the gene ITGAM, which carries codes for an integrin protein that regulates cellular contact and adhesion.

“This association is of high biological relevance because ITGAM plays an important role in normal immune responses,” said Hakon Hakonarson, MD, PhD, director of the CAG, who led the study team. “Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies.”

The new findings may promote better understanding of ITGAM’s functional role and eventually lead to targeted therapies for patients with CVID. Dr. Hakonarson added that the research may have broader implications for other patients who do not have these novel gene variants because the integrin protein affects many important pathways in immune function.

“This discovery fits well with the ‘precision medicine’ concept that is currently in its infancy but represents the future of genomic medicine,” said Dr. Hakonarson, who is also on the faculty of Perelman School of Medicine at the University of Pennsylvania.

The study team reported their findings in the Journal of Allergy and Clinical Immunology. Funds from the National Institutes of Health, the Kubert Estate Foundation, and CHOP’s Institute Development Fund supported this research.