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Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD
Nadia N Hansel1, Ingo Ruczinski, Nicholas Rafaels
1Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Human Genetics
|September 19, 2012
Summary
Researchers identified two novel genetic regions linked to accelerated lung function decline in mild Chronic Obstructive Pulmonary Disease (COPD). Genes near these regions are expressed in lung cells and associated with airflow limitation, suggesting new COPD susceptibility candidates.
Area of Science:
- Genetics
- Pulmonology
- Genomics
Background:
- Accelerated lung function decline is a significant phenotype in Chronic Obstructive Pulmonary Disease (COPD).
- The genetic underpinnings of this decline remain largely uncharacterized.
- Understanding genetic contributions is crucial for identifying COPD susceptibility factors.
Purpose of the Study:
- To conduct a genome-wide association study (GWAS) to identify genetic loci associated with accelerated lung function decline in mild COPD.
- To investigate the expression of candidate genes within identified regions in relevant lung tissues.
- To explore the relationship between gene expression levels and lung function parameters.
Main Methods:
- Genome-wide association study (GWAS) on 4,048 European American participants with mild COPD using Illumina Human660W-Quad v.1_A BeadChip.
- Generalized estimation equations (GEE) to analyze lung function decline over 5 years.
- Genotype imputation using HapMap II reference data.
- Immunohistochemistry for tissue expression studies of TMEM26, ANK3, and FOXA1.
- Replication attempts in independent cohorts.
Main Results:
- Two novel intergenic regions on chromosomes 10 and 14 showed genome-wide significance for association with lung function decline.
- Top associated single nucleotide polymorphisms (SNPs) included rs10761570, rs7911302, and rs177852.
- Genes TMEM26, FOXA1, and ANK3 were expressed in airway epithelium, lung parenchyma, and alveolar macrophages, respectively.
- Gene expression levels correlated with lung function and COPD status.
- Replication in general population cohorts and moderate-to-severe COPD cohorts was unsuccessful.
Conclusions:
- Two novel genetic regions associated with lung function decline in mild COPD were identified.
- Genes near these regions (TMEM26, ANK3, FOXA1) are expressed in key lung cells.
- Expression of these genes is related to airflow limitation, suggesting their potential role in COPD susceptibility.
- These findings highlight potential novel candidate genes for COPD.
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