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Am J Respir Crit Care Med. 2016 Dec 15;194(12):1465-1474.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

Author information

1
1 Channing Division of Network Medicine and.
2
2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
3
3 Bloomberg School of Public Health and.
4
4 School of Medicine, Johns Hopkins University, Baltimore, Maryland.
5
5 National Jewish Health and Research Center, Denver, Colorado.
6
6 Children's Hospital Colorado and.
7
7 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Denver, Colorado.
8
8 Boston Children's Hospital, Boston, Massachusetts.
9
9 Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, and.
10
10 School of Biological Sciences, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
11
11 Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts.
12
12 Genome Sciences, School of Medicine, University of Washington, Seattle, Washington.
13
13 University of Colorado, Denver, Colorado.
14
14 Department of Pediatrics, University of California at San Diego, La Jolla, California.
15
15 Kaiser Permanente Southern California Region, San Diego, California.
16
16 ASTHMA, Inc., Clinical Research Center and Northwest Asthma & Allergy Center, Seattle, Washington.
17
17 University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
18
18 Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada.
19
19 Department of Epidemiology.
20
20 Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, and.
21
21 Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands.
22
22 Program in Molecular and Integrative Physiological Sciences, Departments of Environmental Health and Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; and.
23
23 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
24
24 Division of Allergy, Immunology, and Pulmonary Medicine, Washington University School of Medicine, St. Louis, Missouri.

Abstract

RATIONALE:

Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease.

OBJECTIVES:

To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.

METHODS:

We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.

MEASUREMENTS AND MAIN RESULTS:

An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.

CONCLUSIONS:

Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

KEYWORDS:

CSMD3; asthma; chronic obstructive pulmonary disease; genome-wide association studies; longitudinal lung function patterns

Comment in

PMID:
27367781
PMCID:
PMC5215031
DOI:
10.1164/rccm.201602-0250OC
[Indexed for MEDLINE]
Free PMC Article

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