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Genome-wide association study of lung function decline in adults with and without asthma.

TitleGenome-wide association study of lung function decline in adults with and without asthma.
Publication TypeJournal Article
Year of Publication2012
AuthorsImboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB, Wilk JB, Vonk JM, Thun GA, Siroux V, Nadif R, Monier F, Gonzalez JR, Wjst M, Heinrich J, Loehr LR, Franceschini N, North KE, Altmüller J, Koppelman GH, Guerra S, Kronenberg F, Lathrop M, Moffatt MF, O'Connor GT, Strachan DP, Postma DS, London SJ, Schindler C, Kogevinas M, Kauffmann F, Jarvis DL, Demenais F
Secondary AuthorsProbst-Hensch NM
JournalJ Allergy Clin Immunol
Volume129
Issue5
Pagination1218-28
Date Published2012 May
ISSN1097-6825
KeywordsAdult, Asthma, Chromosomes, Human, Pair 13, Europe, Female, Follow-Up Studies, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Lung, Male, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins, Vital Capacity, Young Adult
Abstract

BACKGROUND: Genome-wide association studies have identified determinants of chronic obstructive pulmonary disease, asthma, and lung function level; however, none have addressed decline in lung function.

OBJECTIVE: We conducted the first genome-wide association study on the age-related decrease in FEV(1) and its ratio to forced vital capacity (FVC) stratified a priori by asthma status.

METHODS: Discovery cohorts included adults of European ancestry (1,441 asthmatic and 2,677 nonasthmatic participants: the Epidemiological Study on the Genetics and Environment of Asthma, the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults, and the European Community Respiratory Health Survey). The associations of FEV(1) and FEV(1)/FVC ratio decrease with 2.5 million single nucleotide polymorphisms (SNPs) were estimated. Thirty loci were followed up by in silico replication (1,160 asthmatic and 10,858 nonasthmatic participants: Atherosclerosis Risk in Communities, the Framingham Heart Study, the British 1958 Birth Cohort, and the Dutch Asthma Study).

RESULTS: Main signals identified differed between asthmatic and nonasthmatic participants. None of the SNPs reached genome-wide significance. The association between the height-related gene DLEU7 and FEV(1) decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10(-6); replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV(1)/FVC ratio decrease in asthmatic participants (P = 5.3 × 10(-8)), did not replicate. SNPs previously associated with cross-sectional lung function were not prominently associated with decline.

CONCLUSIONS: Genetic heterogeneity of lung function might be extensive. Our results suggest that genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status.

DOI10.1016/j.jaci.2012.01.074
Alternate JournalJ Allergy Clin Immunol
PubMed ID22424883
PubMed Central IDPMC3340499
Grant ListP30 ES007048 / ES / NIEHS NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
G0000934 / MRC_ / Medical Research Council / United Kingdom
R01HL086694 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
G1001799 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100009I / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
Z01 ES043012-09 / ImNIH / Intramural NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
G1000758 / MRC_ / Medical Research Council / United Kingdom
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 MH062633 / MH / NIMH NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
068545/Z/02 / WT_ / Wellcome Trust / United Kingdom
HHSN268201100007C / HL / NHLBI NIH HHS / United States
G0901214 / MRC_ / Medical Research Council / United Kingdom
R01 HL62633-01 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
/ DH_ / Department of Health / United Kingdom
HHSN268201100006C / HL / NHLBI NIH HHS / United States
097117 / WT_ / Wellcome Trust / United Kingdom
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
Z01 ES043012-10 / ImNIH / Intramural NIH HHS / United States
Z01 ES043012 / ImNIH / Intramural NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
WT084703MA / WT_ / Wellcome Trust / United Kingdom
076113/B/04/Z / WT_ / Wellcome Trust / United Kingdom