Rare variants at 16p11.2 are associated with common variable immunodeficiency - 05/06/15
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.
Le texte complet de cet article est disponible en PDF.Key words : Immunodeficiency, immunogenetics, genome-wide association study, ITGAM, rare variants
Abbreviations used : CR3, CVID, DC, FUS, GWAS, IIBDGC, ITGAM, LD, Mac-1, MAF, NF-κB, OR, QC, SLE, SNP
Plan
| Supported by an Institute Development Fund from CHOP, U01HG006830, and a donation from the Kubert Estate Foundation. |
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| Disclosure of potential conflict of interest: Y. R. Li is supported by the Paul and Daisy Soros Fellowship for New Americans and the NIH F30 Individual NRSA Training Grant. E. E. Perez has received consultancy fees from Baxter and CSL Behring; research support from CSL Behring; lecture fees from the Eastern Allergy Conference and the American College of Allergy, Asthma & Immunology (ACAAI); and royalties from UpToDate. K. E. Sullivan has received consultancy fees from the Immune Deficiency Foundation and UpToDate, research support from Baxter, and royalties from UpToDate. J. S. Orange has received consultancy fees from CSL Behring, Baxter, Atlantic Research, Viracor, Octapharma, BPL, Cangene, and Amerisource Bergen; research support from CSL Behring; lecture fees from Baxter; and royalties from UpToDate and Unimed Publishing. H. Chapel is a board member for Baxter Healthcare and has received consultancy fees from Biotest, LFB. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 135 - N° 6
P. 1569-1577 - juin 2015 Retour au numéro
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