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

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

Author information

1
Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa; Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
2
Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
3
Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa; Medical Scientist Training Program, Perelman School of Medicine Philadelphia, University of Pennsylvania, Philadelphia, Pa.
4
Department of Computer Science, New Jersey Institute of Technology, Newark, NJ.
5
K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
6
Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of South Florida, St Petersburg, Fla.
7
Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa.
8
Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Houston, Tex.
9
Nuffield Department of Medicine, University of Oxford and Oxford Radcliffe Hospital, Oxford, United Kingdom.
10
Institute of Immunology and Department of Medicine, Mount Sinai School of Medicine, New York, NY.
11
Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine Philadelphia, University of Pennsylvania, Philadelphia, Pa. Electronic address: Hakonarson@email.chop.edu.

Abstract

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

PMID:
25678086
PMCID:
PMC4461447
DOI:
10.1016/j.jaci.2014.12.1939
[Indexed for MEDLINE]
Free PMC Article

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