Rare variants at 16p11.2 are associated with common variable immunodeficiency

J Allergy Clin Immunol. 2015 Jun;135(6):1569-77. doi: 10.1016/j.jaci.2014.12.1939. Epub 2015 Feb 10.


Background: 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. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients.

Objective: We sought to seek novel associations of genes and genetic variants with CVID.

Methods: We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis.

Results: We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10(-9)), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10(-5)) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts.

Conclusion: We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.

Keywords: ITGAM; Immunodeficiency; genome-wide association study; immunogenetics; rare variants.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • CD11b Antigen / genetics*
  • CD11b Antigen / immunology
  • Case-Control Studies
  • Child, Preschool
  • Chromosomes, Human, Pair 16*
  • Cohort Studies
  • Common Variable Immunodeficiency / diagnosis
  • Common Variable Immunodeficiency / genetics*
  • Common Variable Immunodeficiency / immunology
  • Common Variable Immunodeficiency / pathology
  • Enhancer Elements, Genetic
  • Female
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Humans
  • Immunologic Memory
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / immunology


  • CD11b Antigen
  • FUS protein, human
  • ITGAM protein, human
  • RNA-Binding Protein FUS