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

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 5; pp. 1153 - 1162
• Main Authors: Sharma, Sunita, Zhou, Xiaobo, Thibault, Derek M., Himes, Blanca E., Liu, Andy, Szefler, Stanley J., Strunk, Robert, Castro, Mario, Hansel, Nadia N., Diette, Gregory B., Vonakis, Becky M., Adkinson, N. Franklin, Avila, Lydiana, Soto-Quiros, Manuel, Barraza-Villareal, Albino, Lemanske, Robert F., Solway, Julian, Krishnan, Jerry, White, Steven R., Cheadle, Chris, Berger, Alan E., Fan, Jinshui, Boorgula, Meher Preethi, Nicolae, Dan, Gilliland, Frank, Barnes, Kathleen, London, Stephanie J., Martinez, Fernando, Ober, Carole, Celedón, Juan C., Carey, Vincent J., Weiss, Scott T., Raby, Benjamin A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2014; Elsevier; Elsevier Limited
• Subjects: Allergy and Immunology; alpha-N-Acetylgalactosaminidase - genetics; alpha-N-Acetylgalactosaminidase - immunology; Asthma; Asthma - epidemiology; Asthma - genetics; Asthma - immunology; Asthma - pathology; Biological and medical sciences; CD4+ lymphocytes; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Child; Child, Preschool; Chronic obstructive pulmonary disease, asthma; Costa Rica; Disease; Double-Blind Method; Epidemiology; expression quantitative trait locus; Families & family life; Fatty Acid Desaturases - genetics; Fatty Acid Desaturases - immunology; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Genome-Wide Association Study; Genomes; haplotype; Hospitals; Humans; Immunopathology; integrative genomics; Lymphocytes; Male; Medical sciences; Pneumology; Polymorphism, Single Nucleotide; regulatory variants; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Studies; Costa Rica; CD4+ lymphocytes; integrative genomics; haplotype; GWAS; Asthma BRIDGE; PUFA; regulatory variants; F13A1; NAGA; eQTL; ChIP; Asthma; FADS2; expression quantitative trait locus; SNP; FDR; FAIRE; LD; qPCR; CAMP; FADS1; eSNP; Linkage disequilibrium; Fatty acid desaturase 2; Formaldehyde-assisted isolation of regulatory elements; Fatty acid desaturase 1; Asthma Biorepository for Integrative Genomic Exploration; Genome-wide association study; N-acetyl-α-D-galactosaminidase; CD4 + lymphocytes; Chromatin immunoprecipitation; Childhood Asthma Management Program; Polyunsaturated fatty acid; Quantitative PCR; Factor XIII, A1; False discovery rate; Single nucleotide polymorphism; Expression-associated variant; Genetic variability; Quantitative character; Genomics; Immunology; Gene; T-Lymphocyte; Bronchus disease; Genetics; Obstructive pulmonary disease; Locus; Haplotype; Lung disease; Immunopathology; lymphocytes; Respiratory disease; Genetic variant; Genotype; Survey; CD4; Surveillance; Genome; CD4(+) lymphocytes
• ISSN: 0091-6749; 1097-6825; 1085-8725; 1097-6825
• DOI: 10.1016/j.jaci.2014.04.011

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.