Dataset Information

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.

ABSTRACT: Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

SUBMITTER: Hansel NN

PROVIDER: S-EPMC3536920 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.

Hansel Nadia N NN Ruczinski Ingo I Rafaels Nicholas N Sin Don D DD Daley Denise D Malinina Alla A Huang Lili L Sandford Andrew A Murray Tanda T Kim Yoonhee Y Vergara Candelaria C Heckbert Susan R SR Psaty Bruce M BM Li Guo G Elliott W Mark WM Aminuddin Farzian F Dupuis Josée J O'Connor George T GT Doheny Kimberly K Scott Alan F AF Boezen H Marike HM Postma Dirkje S DS Smolonska Joanna J Zanen Pieter P Mohamed Hoesein Firdaus A FA de Koning Harry J HJ Crystal Ronald G RG Tanaka Toshiko T Ferrucci Luigi L Silverman Edwin E Wan Emily E Vestbo Jorgen J Lomas David A DA Connett John J Wise Robert A RA Neptune Enid R ER Mathias Rasika A RA Paré Peter D PD Beaty Terri H TH Barnes Kathleen C KC

Human genetics 20120918 1

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions mee ...[more]

PMID: 22986903

Similar Datasets

Project description:BackgroundBoth allergen-specific IgE and total IgE in serum play a major role in asthma. However, the role of IgE in chronic obstructive pulmonary disease (COPD) is poorly understood. It was the aim of this study to systematically analyze the relationship between serum IgE levels and disease characteristics in large COPD cohorts.MethodsCOSYCONET is a comprehensively characterized cohort of patients with COPD: total IgE and IgE specific to common aeroallergens were measured in serum of 2280 patients, and related to clinical characteristics of the patients. WISDOM is another large COPD population (2477 patients): this database contains the information whether total IgE in serum was elevated (≥ 100 IU/l) or normal in patients with COPD.ResultsBoth in COSYCONET and WISDOM, total IgE was elevated (≥ 100 IU/l) in > 30% of the patients, higher in men than in women, and higher in currently than in not currently smoking men. In COSYCONET, total IgE was elevated in patients with a history of asthma and/or allergies. Men with at least one exacerbation in the last 12 months (50.6% of all men in COSYCONET) had higher median total IgE (71.3 IU/l) than men without exacerbations (48.3 IU/l): this difference was also observed in the subgroups of not currently smoking men and of men without a history of asthma. Surprisingly, a history of exacerbations did not impact on total IgE in women with COPD. Patients in the highest tertiles of total IgE (> 91.5 IU/ml, adjusted OR: 1.62, 95% CI 1.12-2.34) or allergen-specific IgE (> 0.19 IU/ml, adjusted OR: 2.15, 95% CI 1.32-3.51) were at risk of lung function decline (adjusted by: age, gender, body mass index, initial lung function, smoking status, history of asthma, history of allergy).ConclusionThese data suggest that IgE may play a role in specific COPD subgroups. Clinical trials using antibodies targeting the IgE pathway (such as omalizumab), especially in men with recurrent exacerbations and elevated serum IgE, could elucidate potential therapeutic implications of our observations.

Dataset Information

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.

Publications

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure