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J Allergy Clin Immunol. 2019 Mar;143(3):957-969. doi: 10.1016/j.jaci.2016.08.057. Epub 2018 Sep 7.

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

Author information

1
Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif. Electronic address: chris.gignoux@ucdenver.edu.
2
Department of Medicine, University of California, San Francisco, San Francisco, Calif.
3
Department of Medicine, University of California, San Francisco, San Francisco, Calif; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
4
Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif.
5
Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif; Department of Medicine, University of California, San Francisco, San Francisco, Calif.
6
Department of Medicine, Johns Hopkins University, Baltimore, Md.
7
Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
8
Centro de Neumologia Pediatrica, San Juan, Puerto Rico.
9
Department of Pediatrics, University of California, San Francisco, San Francisco, Calif.
10
Department of Genetics, Stanford University, Palo Alto, Calif.
11
Molecular Genetics Epidemiology Section, Frederick National Laboratory for Cancer Research, Frederick, Md.
12
Integrated Center for Genes, Environment, and Health, Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colo.
13
Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich.
14
Department of Preventative Medicine, University of Southern California, Los Angeles, Calif.
15
Department of Pediatrics, Section of Pulmonology, Baylor College of Medicine and Texas Children's Hospital, Houston, Tex.
16
Division of Allergy-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
17
Department of Allergy & Immunology, Kaiser Permanente-Vallejo Medical Center, Vallejo, Calif.
18
Bay Area Pediatrics, Oakland, Calif.
19
Children's Hospital and Research Center Oakland, Oakland, Calif.
20
Pediatric Pulmonary Division, Jacobi Medical Center, Bronx, NY.
21
Department of Health Sciences, Graduate Program in Public Health, Lehman College, City University of New York, Bronx, NY.
22
Veterans Caribbean Health Care System, San Juan, Puerto Rico.
23
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
24
Nutritional Epidemiology Group, International Agency for Research on Cancer, Lyon, France.
25
Departmento de Alergia e Inmunologia, Clinica Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
26
Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Md.
27
Department of Medicine, Harvard Medical School, Boston, Mass.
28
Center for Genomics & Personalized Medicine Research, Wake Forest University, Winston-Salem, NC.
29
BIO5 Institute, University of Arizona, Tucson, Ariz.
30
Physical Sciences Division, Department of Statistics, University of Chicago, Chicago, Ill.
31
Department of Human Genetics, University of Chicago, Chicago, Ill.
32
Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis, Tenn.
33
Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Mich; Department of Internal Medicine, Henry Ford Health System, Detroit, Mich.
34
Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif.
35
Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, Calif; Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, Calif; Department of Medicine, University of California, San Francisco, San Francisco, Calif.

Abstract

BACKGROUND:

Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.

OBJECTIVE:

We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.

METHODS:

We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.

RESULTS:

We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (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 < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma.

CONCLUSION:

Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

KEYWORDS:

Asthma; Latinos; SMAD2; admixture mapping; asthma exacerbations; gene expression; meta-analysis; rare variation; targeted sequencing

PMID:
30201514
DOI:
10.1016/j.jaci.2016.08.057

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