A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

Abstract

Background Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective We evaluated 6,706 cis-acting expression-associated variants (eSNP) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods eSNP were tested for association with asthma in 359 asthma cases and 846 controls from the Childhood Asthma Management Program, with verification using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE)-qPCR and Chromatin-Immunoprecipitation (ChIP)-PCR in lung derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results Cis-acting eSNP demonstrated associations with asthma in both cohorts. We confirmed the previously-reported association of ORMDL3/GSDMB variants with asthma (combined p=2.9 × 108). Reproducible associations were also observed for eSNP in three additional genes: FADS2 (p=0.002), NAGA (p=0.0002), and F13A1 (p=0.0001). We subsequently demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatics, and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes, and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma.

Global gene regulation during activation of immunoglobulin class switching in human B cells

“…Genes with a H2H orientation are prone to co-expression and co-functionality33. Disturbed expression of the FADS genes has previously been reported in several IgE-mediated diseases, including asthma34 and atopic dermatitis3536, but this is the first such association with the direct cellular processes leading to IgE production. Variation in FADS gene expression during the activation time course is shown in supplementary Figure S3.…”

Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control

“…Gene expression profiles in CAMP CD4 have been used successfully to identify novel genetic susceptibility loci for asthma (23). Notably, the distributions of chronic or acute asthma control scores in the three replication cohorts differed from that observed in the discovery cohort (Figure 2), requiring cohort-specific definitions of optimal asthma control (see the METHODS and supplemental METHODS sections).…”

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

“…14–17 Genome-wide association studies of patients with asthma have shown that polymorphisms in IL33 and IL1RL1 (i.e., ST2, the IL-33 receptor) are associated with an increased susceptibility to asthma. 18–21 IL-33 activates a variety of cell types that are implicated in allergic airway diseases, such as Th2-type CD4 + T cells, type 2 innate lymphoid cells (ILC2s), mast cells, and eosinophils. 22 In the murine model of asthma, IL-33 induces Th2-type differentiation of naïve CD4 + T cells and promotes production of IL-5 and IL-13, hence amplifying airway hyperresponsiveness and eosinophilic airway inflammation.…”