title: 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.
authors.affiliation: Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.forename: Denise
authors.initials: D
authors.lastname: Daley
authors.forename: Alla
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authors.lastname: Malinina
authors.forename: Lili
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authors.lastname: Huang
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authors.lastname: Sandford
authors.forename: Tanda
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authors.lastname: Murray
authors.forename: Yoonhee
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authors.forename: Candelaria
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authors.lastname: Vergara
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.forename: Bruce M
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authors.forename: Guo
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authors.lastname: Li
authors.forename: W Mark
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authors.forename: Farzian
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authors.lastname: Dupuis
authors.forename: George T
authors.initials: GT
authors.lastname: O'Connor
authors.forename: Kimberly
authors.initials: K
authors.lastname: Doheny
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.forename: H Marike
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authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Joanna
authors.initials: J
authors.lastname: Smolonska
authors.forename: Pieter
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authors.lastname: Zanen
authors.forename: Firdaus A
authors.initials: FA
authors.lastname: Mohamed Hoesein
authors.forename: Harry J
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authors.lastname: de Koning
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
authors.forename: Toshiko
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authors.lastname: Tanaka
authors.forename: Luigi
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authors.lastname: Ferrucci
authors.forename: Edwin
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authors.lastname: Silverman
authors.forename: Emily
authors.initials: E
authors.lastname: Wan
authors.forename: Jorgen
authors.initials: J
authors.lastname: Vestbo
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: John
authors.initials: J
authors.lastname: Connett
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.forename: Enid R
authors.initials: ER
authors.lastname: Neptune
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
mesh_terms: D000328:Adult; D017487:Ankyrins / Q000235:genetics* / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D008565:Membrane Proteins; C578535:TMEM26 protein, human