Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD
| Autor: | W. Mark Elliott, David A. Lomas, John E. Connett, Ingo Ruczinski, Guo Li, Josée Dupuis, Kimberly F. Doheny, Rasika A. Mathias, George T. O'Connor, Robert A. Wise, Yoonhee Kim, Joanna Smolonska, Tanda Murray, Nicholas Rafaels, Dirkje S. Postma, Firdaus A. A. Mohamed Hoesein, Alla Malinina, Terri H. Beaty, Susan R. Heckbert, Edwin K. Silverman, H. Marike Boezen, Harry J. de Koning, Peter D. Paré, Alan F. Scott, Kathleen C. Barnes, Farzian Aminuddin, Enid Neptune, Candelaria Vergara, Jørgen Vestbo, Ronald G. Crystal, Andrew J. Sandford, Emily S. Wan, Pieter Zanen, Luigi Ferrucci, Bruce M. Psaty, Denise Daley, Lili Huang, Don D. Sin, Toshiko Tanaka, Nadia N. Hansel |
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| Přispěvatelé: | Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Erasmus School of Social and Behavioural Sciences, Public Health |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Candidate gene EARLY INTERVENTION Linkage Disequilibrium Cohort Studies Pulmonary Disease Chronic Obstructive 0302 clinical medicine POPULATION-BASED COHORTS International HapMap Project Lung Genetics (clinical) BRONCHODILATOR Genetics GENERAL-POPULATION 0303 health sciences education.field_of_study COPD Middle Aged RAPID DECLINE 3. Good health Female HEALTH SMOKING SMOKERS Adult Ankyrins Hepatocyte Nuclear Factor 3-alpha Population Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide OBSTRUCTIVE PULMONARY-DISEASE Article 03 medical and health sciences medicine SNP Humans education POLYMORPHISMS 030304 developmental biology Chromosomes Human Pair 14 Chromosomes Human Pair 10 Membrane Proteins medicine.disease Human genetics respiratory tract diseases 030228 respiratory system Imputation (genetics) Genome-Wide Association Study |
| Zdroj: | HUMAN GENETICS, 132(1), 79-90. SPRINGER Human Genetics, 132(1), 79-90. Springer-Verlag Human Genetics; Vol 132 |
| ISSN: | 0340-6717 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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