Περίληψη:
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 FEV1 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 FEV1 and
FEV1/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
FEV1 decrease suggested for nonasthmatic participants in the discovery
phase was replicated (discovery, P = 4.8 x 10(-6); replication, P =
.03), and additional sensitivity analyses point to a relation to growth.
The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio
decrease in asthmatic participants (P = 5.3 x 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. (J
Allergy Clin Immunol 2012;129:1218-28.)
Συγγραφείς:
Imboden, Medea
Bouzigon, Emmanuelle
Curjuric, Ivan
Ramasamy,
Adaikalavan
Kumar, Ashish
Hancock, Dana B.
Wilk, Jemma B.
and Vonk, Judith M.
Thun, Gian A.
Siroux, Valerie
Nadif,
Rachel
Monier, Florent
Gonzalez, Juan R.
Wjst, Matthias and
Heinrich, Joachim
Loehr, Laura R.
Franceschini, Nora
North,
Kari E.
Altmueller, Janine
Koppelman, Gerard H.
Guerra,
Stefano
Kronenberg, Florian
Lathrop, Mark
Moffatt, Miriam F.
and O'Connor, George T.
Strachan, David P.
Postma, Dirkje S. and
London, Stephanie J.
Schindler, Christian
Kogevinas, Manolis and
Kauffmann, Francine
Jarvis, Debbie L.
Demenais, Florence and
Probst-Hensch, Nicole M.
