J Allergy Clin Immunol. 2014 Jun 13. pii: S0091-6749(14)00585-5. doi: 10.1016/j.jaci.2014.04.011. [Epub ahead of print]
A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes.
Sharma S1, Zhou X2, Thibault DM3, Himes BE3, Liu A4, Szefler SJ4, Strunk R5, Castro M5, Hansel NN6, Diette GB6, Vonakis BM7, Adkinson NF Jr7, Avila L8,Soto-Quiros M8, Barraza-Villareal A9, Lemanske RF Jr10, Solway J11, Krishnan J12, White SR11, Cheadle C7, Berger AE7, Fan J7, Boorgula MP7, Nicolae D13,Gilliland F14, Barnes K7, London SJ15, Martinez F16, Ober C13, Celedón JC17, Carey VJ3, Weiss ST3, Raby BA2.
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.
We evaluated 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+lymphocytes for association with asthma.
eSNPs were tested for association with asthma in 359 asthmatic patients and 846 control subjects from the Childhood Asthma Management Program, with verification by 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 using formaldehyde-assisted isolation of regulatory elements (FAIRE) quantitative PCR and chromatin immunoprecipitation PCR in lung-derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes.
Cis-acting eSNPs demonstrated associations with asthma in both cohorts. We confirmed the previously reported association of ORMDL3/GSDMB variants with asthma (combined P = 2.9 × 10-8). Reproducible associations were also observed for eSNPs in 3 additional genes: fatty acid desaturase 2 (FADS2; P = .002), N-acetyl-α-D-galactosaminidase (NAGA; P = .0002), and Factor XIII, A1 (F13A1; P = .0001). Subsequently, we demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatic patients and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity.
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.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Asthma; CD4(+) lymphocytes; expression quantitative trait locus; haplotype; integrative genomics; regulatory variants
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