title: 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 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.
authors.affiliation: 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.
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: 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.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Thibault
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Andy
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.affiliation: Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, Mo.
authors.forename: Robert
authors.initials: R
authors.lastname: Strunk
authors.affiliation: Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, Mo.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Diette
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Becky M
authors.initials: BM
authors.lastname: Vonakis
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: N Franklin
authors.initials: NF
authors.lastname: Adkinson
authors.affiliation: Hospital Nacional de Niños, San José, Costa Rica.
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.affiliation: Hospital Nacional de Niños, San José, Costa Rica.
authors.forename: Manuel
authors.initials: M
authors.lastname: Soto-Quiros
authors.affiliation: National Institute of Public Health of Mexico, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
authors.forename: Albino
authors.initials: A
authors.lastname: Barraza-Villareal
authors.affiliation: Division of Allergy and Immunology, Department of Medicine, University of Wisconsin, Madison, Wis.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Ill.
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.affiliation: Department of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, Ill.
authors.forename: Jerry
authors.initials: J
authors.lastname: Krishnan
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, Ill.
authors.forename: Steven R
authors.initials: SR
authors.lastname: White
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Jinshui
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Meher Preethi
authors.initials: MP
authors.lastname: Boorgula
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Ill.
authors.forename: Dan
authors.initials: D
authors.lastname: Nicolae
authors.affiliation: Division of Environmental and Occupational Health, Department of Medicine, University of Southern California, Los Angeles, Calif.
authors.forename: Frank
authors.initials: F
authors.lastname: Gilliland
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Barnes
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
authors.affiliation: Arizona Respiratory Center, University of Arizona, Tucson, Ariz.
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Ill.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Carey
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: 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.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
mesh_terms: D001249:Asthma / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003364:Costa Rica; D004311:Double-Blind Method; D044943:Fatty Acid Desaturases / Q000235:genetics / Q000276:immunology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D048809:alpha-N-Acetylgalactosaminidase / Q000235:genetics / Q000276:immunology
chemical_list: D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human; C482722:NAGA protein, human; D048809:alpha-N-Acetylgalactosaminidase
keywords: Asthma; CD4(+) lymphocytes; expression quantitative trait locus; haplotype; integrative genomics; regulatory variants