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

• Published in: Biochimica et biophysica acta Vol. 1860; no. 11; pp. 2656 - 2663
• Main Authors: Li, Jin, Wei, Zhi, Li, Yun R., Maggadottir, S. Melkorka, Chang, Xiao, Desai, Akshatha, Hakonarson, Hakon
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2016
• Subjects: autoimmunity; Common Variable Immunodeficiency - genetics; Common variable immunodeficiency disorder; Copy number variation; disease incidence; environmental factors; Epigenesis, Genetic - genetics; Epigenetic; epigenetics; Epigenomics - methods; etiology; genes; Genetic Predisposition to Disease - genetics; Genome-wide association study; Genome-Wide Association Study - methods; Genomics - methods; Humans; immunosuppression; loci; Meta-analysis; translation (genetics); WGS; GWAS; HMM; CNV; Epigenetic; SVM; IIBDGC; aCGH; Meta-analysis; BCR; CVID; CNPs; Copy number variation; Common variable immunodeficiency disorder; Genome-wide association study; SNPs; pAID
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.06.014

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. 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. 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. 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. •GWAS and meta-analysis revealed several significant CVID susceptibility loci.•CNV in ORC4L gene is significantly associated with CVID based on SNP array intensity data.•High-throughput sequencing identified mutations, genes and pathways associated with CVID.•Epigenomic study demonstrated defects in demethylation during B-cell development of CVID.•Other omics studies suggested molecular defects in CVID at mRNA and protein levels.