Rare Gene Variant Associated with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality.

CVID can first occur early or later in life, and the symptoms are highly variable and frequent respiratory infections may lead to permanent lung damage. Patients may also suffer joint inflammation, stomach and bowel disorders, and a higher risk of cancers.


A team of investigators led by those at the Children's Hospital of Philadelphia (PA, USA) performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They used a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases, to pinpoint single nucleotide polymorphisms (SNPs) associated with CVID, followed by meta-analysis.

All patients with CVID and all control subjects were genotyped on the Immuno BeadChip (iCHIP) platform (Illumina; San Diego, CA, USA), with 196,524 single nucleotide polymorphisms (SNPs) and small indels targeting genes implicated in patients with autoimmune and inflammatory diseases based on previous genome-wide association study (GWASs). The novel array was designed to provide dense coverage of rare polymorphisms and strong candidate genes for major autoimmune and inflammatory diseases from prior GWASs. The scientists sought to associate these rare immune gene SNPs with CVID, as well as with clinical phenotypes, to address the heterogeneity of CVID in an ongoing study aimed at identifying susceptibility loci for CVID.

The team found 11 single nucleotide polymorphisms (SNPs) on the 16p11.2 locus of chromosome 16. SNPs are changes in one letter of DNA, compared to the more typical sequence at a given location. Of particular interest, the study team found variants in the gene Integrin, Alpha M (Complement Component 3 Receptor 3 Subunit (ITGAM), carrying codes for an integrin protein, which regulates cellular contact and adhesion. They also found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts.

Hakon Hakonarson, MD, PhD, the director of the Center for Applied Genomics, and senior author of the study said, “This association is of high biological relevance, because ITGAM plays an important role in normal immune responses. Other scientists have shown that mice in which this gene has been knocked out have immune deficiencies. These findings may have broader implications for patients who do not have these specific rare variants, because the integrin protein affects many important pathways in immune function.” The study was published online on February 10, 2015, in the Journal of Allergy and Clinical Immunology.

Related Links:
Children's Hospital of Philadelphia
Illumina