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

Sunita Sharma, Xiaobo Zhou, Derek M. Thibault, Blanca E. Himes, Andy Liu, Stanley J. Szefler, Robert Strunk, Mario Castro, Nadia N. Hansel, Gregory B. Diette, Becky M. Vonakis, N. Franklin Adkinson, Lydiana Avila, Manuel Soto-Quiros, Albino Barraza-Villareal, Robert F. Lemanske, Julian Solway, Jerry Krishnan, Steven R. White, Chris CheadleAlan E. Berger, Jinshui Fan, Meher Preethi Boorgula, Dan Nicolae, Frank Gilliland, Kathleen Barnes, Stephanie J. London, Fernando Martinez, Carole Ober, Juan C. Celedón, Vincent J. Carey, Scott T. Weiss, Benjamin A. Raby

Research output: Contribution to journalArticle

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 6706 cis-acting expression-associated variants (eSNPs) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods 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. Results 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. 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.

Original languageEnglish (US)
Pages (from-to)1153-1162
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume134
Issue number5
DOIs
StatePublished - Nov 1 2014

Keywords

  • Asthma
  • CD4 lymphocytes
  • expression quantitative trait locus
  • haplotype
  • integrative genomics
  • regulatory variants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Sharma, S., Zhou, X., Thibault, D. M., Himes, B. E., Liu, A., Szefler, S. J., Strunk, R., Castro, M., Hansel, N. N., Diette, G. B., Vonakis, B. M., Adkinson, N. F., Avila, L., Soto-Quiros, M., Barraza-Villareal, A., Lemanske, R. F., Solway, J., Krishnan, J., White, S. R., ... Raby, B. A. (2014). A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes. Journal of Allergy and Clinical Immunology, 134(5), 1153-1162. https://doi.org/10.1016/j.jaci.2014.04.011