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

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

SUBMITTER: Maggadottir SM

PROVIDER: S-EPMC4461447 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Maggadottir S Melkorka SM Li Jin J Glessner Joseph T JT Li Yun Rose YR Wei Zhi Z Chang Xiao X Mentch Frank D FD Thomas Kelly A KA Kim Cecilia E CE Zhao Yan Y Hou Cuiping C Wang Fengxiang F Jørgensen Silje F SF Perez Elena E EE Sullivan Kathleen E KE Orange Jordan S JS Karlsen Tom H TH Chapel Helen H Cunningham-Rundles Charlotte C Hakonarson Hakon H

The Journal of allergy and clinical immunology 20150210 6

<h4>Background</h4>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.<h4>Objective</h4>We sought to seek novel associations of genes and genetic variants with CVID.<h4>Methods</h4>We performed associat ...[more]

PMID: 25678086

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Project description:BACKGROUND:Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE:We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS:Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS:Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS:Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

Dataset Information

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

Publications

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

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