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SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung Development
- Source :
- American Journal of Respiratory and Critical Care Medicine. 183:1482-1489
- Publication Year :
- 2011
- Publisher :
- American Thoracic Society, 2011.
-
Abstract
- Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified. Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD. Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice. Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis. Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
- Subjects :
- Male
Pulmonary and Respiratory Medicine
Chronic bronchitis
Candidate gene
Extracellular matrix component
Genome-wide association study
Single-nucleotide polymorphism
Critical Care and Intensive Care Medicine
Polymorphism, Single Nucleotide
A. Chronic Obstructive Pulmonary Disease
Mice
Pulmonary Disease, Chronic Obstructive
Animals
Humans
Medicine
SNP
Genetic Predisposition to Disease
Aged
COPD
Lung
business.industry
Middle Aged
medicine.disease
respiratory tract diseases
Disease Models, Animal
medicine.anatomical_structure
Case-Control Studies
Immunology
Female
business
SOXD Transcription Factors
Subjects
Details
- ISSN :
- 15354970 and 1073449X
- Volume :
- 183
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....6c41e3565355a8ba9323d49bf42f5bce