Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches.

BACKGROUND: Common variable immunodeficiency disorder (CVID) is the most frequently encountered symptomatic primary immunodeficiency, characterized by highly heterogeneous immunological features and clinical presentations. As better targeted therapies are importantly needed for CVID, improved understanding of the genetic and epigenetic basis for the development of CVID presents the most promising venue for improvement. SCOPE OF REVIEW: Several genomic and epigenomic studies of CVID have recently been carried out on cohorts of sporadic cases of CVID. Using high-throughput array and sequencing technologies, these studies identified several loci associated with the disease. Here, we review the omics approaches used in these studies and resulting discoveries. We also discuss how these findings lead to improved understanding of the molecular basis of CVID and possible future directions to pursue. MAJOR CONCLUSIONS: High-throughput omics approaches have been productive in genetic and epigenetic studies of CVID, leading to the identifications of several significantly associated loci of different variant types, as well as genes and pathways elucidating the shared genetic basis of CVID and autoimmunity. Complex polygenic model of inheritance together with interplay between genetic components and environmental factors may account for the etiology of CVID and various associated comorbidities. GENERAL SIGNIFICANCE: The genetic and epigenetic basis of CVID when further translated through functional studies will allow for improved understanding of the CVID etiology and will provide new insights into the development of potential new therapeutic approaches for this devastating condition. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang.

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

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.

Are genetic tests informative in predicting food allergy?

PURPOSE OF REVIEW: Food allergy is common among children and adults worldwide. Recent studies have improved our understanding of the genetic mechanism of food allergy and further studies may result in clinical application through genetic testing. RECENT FINDINGS: Genetic factors are important in the development of food allergy. An increasing number of genes have been associated with food allergy in recent years. These include mutations and genetic variants in the filaggrin gene, the association of human leukocyte antigen DR and DQ regions with food allergy, copy number variation impacting CTNNA3 and RBFOX1, DNA methylation that partially mediates single nucleotide polymorphism association at the HLA-DR and DQ loci, as well as other genes. Several studies have implicated differences in gut microbiota composition in food allergy. SUMMARY: With the advance of high-throughput genotyping and sequencing techniques together with improved analytical methods, the contributions of genetic and environmental factors in development of food allergy are being clarified. Yet much remains to be explored and more studies with larger sample sizes, better phenotyping, and improved quality control genomics methods are needed. The ultimate goal is the development of a panel of reliable markers for genetic testing in food allergy to improve overall patient care.

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10,999 controls across 123,127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P=2.0 × 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P=4.8 × 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition.

Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.