Sunita Sharma1, Xiaobo Zhou2, Derek M Thibault3, Blanca E Himes3, Andy Liu4, Stanley J Szefler4, Robert Strunk5, Mario Castro5, Nadia N Hansel6, Gregory B Diette6, Becky M Vonakis7, N Franklin Adkinson7, Lydiana Avila8, Manuel Soto-Quiros8, Albino Barraza-Villareal9, Robert F Lemanske10, Julian Solway11, Jerry Krishnan12, Steven R White11, Chris Cheadle7, Alan E Berger7, Jinshui Fan7, Meher Preethi Boorgula7, Dan Nicolae13, Frank Gilliland14, Kathleen Barnes7, Stephanie J London15, Fernando Martinez16, Carole Ober13, Juan C Celedón17, Vincent J Carey3, Scott T Weiss3, Benjamin A Raby2. 1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address: sunita.sharma@channing.harvard.edu. 2. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Mass. 3. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass. 4. Department of Pediatrics, National Jewish Health, Denver, Colo. 5. Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, Mo. 6. Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. 7. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. 8. Hospital Nacional de Niños, San José, Costa Rica. 9. National Institute of Public Health of Mexico, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico. 10. Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, Madison, Wis. 11. Department of Pediatrics, University of Chicago, Chicago, Ill. 12. Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, Ill. 13. Department of Human Genetics, University of Chicago, Chicago, Ill. 14. Division of Environmental and Occupational Health, Department of Medicine, University of Southern California, Los Angeles, Calif. 15. National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC. 16. Arizona Respiratory Center, University of Arizona, Tucson, Ariz. 17. Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pa.
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.
RCT Entities:
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.
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