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

TitleGenome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.
Publication TypeJournal Article
Year of Publication2013
AuthorsHansel, NN, Ruczinski, I, Rafaels, N, Sin, DD, Daley, D, Malinina, A, Huang, L, Sandford, A, Murray, T, Kim, Y, Vergara, C, Heckbert, SR, Psaty, BM, Li, G, W Elliott, M, Aminuddin, F, Dupuis, J, O'Connor, GT, Doheny, K, Scott, AF, H Boezen, M, Postma, DS, Smolonska, J, Zanen, P, Hoesein, FAMohamed, de Koning, HJ, Crystal, RG, Tanaka, T, Ferrucci, L, Silverman, E, Wan, E, Vestbo, J, Lomas, DA, Connett, J, Wise, RA, Neptune, ER, Mathias, RA, Paré, PD, Beaty, TH, Barnes, KC
JournalHum Genet
Volume132
Issue1
Pagination79-90
Date Published2013 Jan
ISSN1432-1203
KeywordsAdult, Ankyrins, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 14, Cohort Studies, Female, Genome-Wide Association Study, Hepatocyte Nuclear Factor 3-alpha, Humans, Linkage Disequilibrium, Lung, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
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.

DOI10.1007/s00439-012-1219-6
Alternate JournalHum. Genet.
PubMed ID22986903
PubMed Central IDPMC3536920
Grant ListAG-023629 / AG / NIA NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
AG-15928 / AG / NIA NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
G0901786 / / Medical Research Council / United Kingdom
HHSN268201200036C / / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
HL095406-01 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01 HC 25195 / HC / NHLBI NIH HHS / United States
N01 HC-15103 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
N01 HC085084 / HC / NHLBI NIH HHS / United States
N01 HC085085 / HC / NHLBI NIH HHS / United States
N01 HR046002 / HR / NHLBI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
N01-HR-46002 / HR / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
R01 CA047006 / CA / NCI NIH HHS / United States
R01 CA085180 / CA / NCI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R03 HL095406 / HL / NHLBI NIH HHS / United States
U01 HG004438 / HG / NHGRI NIH HHS / United States
U01 HG004438 / HG / NHGRI NIH HHS / United States
U01 HG004738 / HG / NHGRI NIH HHS / United States
U01HG 004738 / HG / NHGRI NIH HHS / United States
UL 1TR000124 / TR / NCATS NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States