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An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos

  1. Author:
    Gignoux, Chris R
    Torgerson, Dara G
    Pino-Yanes, Maria
    Uricchio, Lawrence H
    Galanter, Joshua
    Roth, Lindsey A
    Eng, Celeste
    Hu, Donglei
    Nguyen, Elizabeth A
    Huntsman, Scott
    Mathias, Rasika A
    Kumar, Rajesh
    Rodriguez-Santana, Jose
    Thakur, Neeta
    Oh, Sam S
    McGarry, Meghan
    Moreno-Estrada, Andres
    Sandoval, Karla
    Winkler, Cheryl
    Seibold, Max A
    Padhukasahasram, Badri
    Conti, David V
    Farber, Harold J
    Avila, Pedro
    Brigino-Buenaventura, Emerita
    Lenoir, Michael
    Meade, Kelley
    Serebrisky, Denise
    Borrell, Luisa N
    Rodriguez-Cintron, William
    Thyne, Shannon
    Joubert, Bonnie R
    Romieu, Isabelle
    Levin, Albert M
    Sienra-Monge, Juan-Jose
    Del Rio-Navarro, Blanca Estela
    Gan, Weiniu
    Raby, Benjamin A
    Weiss, Scott T
    Bleecker, Eugene
    Meyers, Deborah A
    Martinez, Fernando J
    Gauderman, W James
    Gilliland, Frank
    London, Stephanie J
    Bustamante, Carlos D
    Nicolae, Dan L
    Ober, Carole
    Sen, Saunak
    Barnes, Kathleen
    Williams, L Keoki
    Hernandez, Ryan D
    Burchard, Esteban G

  2. Author Address

    Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA. Electronic address: cgignoux@stanford.edu., Department of Medicine, University of California, San Francisco, San Francisco, CA., Department of Medicine, University of California, San Francisco, San Francisco, CA; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain., Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA; Department of Medicine, University of California, San Francisco, San Francisco, CA., Department of Medicine, Johns Hopkins University, Baltimore, Maryland., The Ann and Robert H. Lurie Children 39;s Hospital of Chicago; Feinberg School of Medicine, Northwestern University, Chicago, IL., Centro de Neumologia Pediatrica, San Juan, Puerto Rico., Department of Pediatrics, University of California, San Francisco, San Francisco, CA., Department of Genetics, Stanford University, Palo Alto, CA., Molecular Genetics Epidemiology Section, Frederick National Lab for Cancer Research, Frederick MD., Integrated Center for Genes, Environment, and Health; Department of Pediatrics; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO., Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI., Department of Preventative Medicine, University of Southern California, Los Angeles CA., Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children 39;s Hospital, Houston, TX., Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL., Department of Allergy & Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, CA., Bay Area Pediatrics, Oakland, CA., Children 39;s Hospital and Research Center Oakland, Oakland, CA., Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, NY., Department of Health Sciences, Graduate Program in Public Health, Lehman College, City University of New York, Bronx, NY., Veterans Caribbean Health Care System, San Juan, Puerto Rico., National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC., Nutritional Epidemiology Group, International Agency for Research on Cancer, Lyon, France., Departmento de Alergia e Inmunologia, Clinica Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico., Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, MD., Department of Medicine, Harvard Medical School, Boston, MA., Center for Genomics & Personalized Medicine Research, Wake Forest University, Winston-Salem, NC., BIO5 Institute, The University of Arizona, Tucson, AZ., Physical Sciences Division, Department of Statistics, University of Chicago, Chicago, IL., Department of Human Genetics, University of Chicago, Chicago, IL., Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, TN., Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI; Department of Internal Medicine, Henry Ford Health System, Detroit MI., Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA; Department of Medicine, University of California, San Francisco, San Francisco, CA.,
    1. Year: 2019
    2. Date: Mar
    3. Epub Date: 2018 09 07
  2. Journal: Journal of Allergy and Clinical Immunology
    1. 143
    2. 3
    3. Pages: 957-969
  4. Type of Article: Article
  5. ISSN: 0091-6749
  1. Abstract:

    Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. Perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. We leveraged the mixed ancestry of 3,902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3,774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of >500 individuals from 3 racial/ethnic groups. We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (p=6.8x10-6), where Native American ancestry was associated with increased risk of asthma (OR=1.20, 95% CI=1.07-1.34, p=0.002) and European ancestry with protection (OR=0.86, 95% CI=0.77-0.96, p=0.008). Our findings replicated in an independent childhood asthma study in Latinos (p=5.3x10-3, combined p=2.6x10-7). Fine mapping of 18q21 in 1,978 Latinos identified a significant association with multiple variants 5' of SMAD2 in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression, OR=3.93, 95% CI 2.12-7.28,p< 0.001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. Ancestry at 18q21 was significantly associated with asthma in Latinos, and implicated multiple ancestry-informative non-coding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations. Copyright © 2018. Published by Elsevier Inc.

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External Sources

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  2. DOI: 10.1016/j.jaci.2016.08.057
  3. PMID: 30201514
  4. View record in Web of Science®
  5. WOS: 000460272900016
  6. PII : S0091-6749(18)31274-0

Library Notes

  1. Fiscal Year: FY2017-2018
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