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

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• 作者：Medea Imboden ; PhD^a ; ^b ; ^&lowast ; ; Emmanuelle Bouzigon ; MD ; PhD^c ; ^d ; ^e ; ^&lowast ; ; Ivan Curjuric ; MD^a ; ^b ; Adaikalavan Ramasamy ; PhD^f ; Ashish Kumar ; MSc^a ; ^b ; ^g ; Dana B. Hancock ; PhD^h ; ⁱ ; Jemma B. Wilk ; DSc^j ; Judith M. Vonk ; PhD^k ; Gian A. Thun ; MSc^a ; ^b ; Valerie Siroux ; PhD^l ; ^m ; Rachel Nadif ; PhDⁿ ; ^o ; Florent Monier ; MSc^c ; ^d ; ^e ; Juan R. Gonzalez ; PhD^p ; ^q ; Matthias Wjst ; MD ; MD^r ; Joachim Heinrich ; PhD^r ; Laura R. Loehr ; MD ; PhD^s ; Nora Franceschini ; MD ; MPH^s ; Kari E. North ; PhD^t ; Janine Altmü ; ller ; MD^u ; Gerard H. Koppelman ; MD ; PhD^k ; Stefano Guerra ; MD ; PhD^p ; ^q ; ^v ; ^cc ; Florian Kronenberg ; MD^w ; Mark Lathrop ; PhD^d ; ^x ; Miriam F. Moffatt ; DPhil^y ; George T. O&rsquo ; Connor ; MD ; MSc^z ; ^aa ; David P. Strachan ; MD^bb ; Dirkje S. Postma ; MD ; PhD^k ; Stephanie J. London ; MD ; DrPH^h ; Christian Schindler ; PhD^a ; ^b ; Manolis Kogevinas ; MD^p ; ^q ; ^cc ; ^dd ; Francine Kauffmann ; MDⁿ ; ^o ; Debbie L. Jarvis ; MD^f ; Florence Demenais ; MD^c ; ^d ; ^e ; Nicole M. Probst-Hensch ; PhD^a ; ^b ; ^{Nicole.Probst@unibas.ch}
• 关键词：Asthma ; cohort studies ; genome-wide association ; lung function decline ; heterogeneity
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 期刊代码：158_00916749
• 类别：med
• 出版时间：May, 2012
• 卷：129
• 期：5
• 页码：1218-1228
• 文件大小：756 K

摘要

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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聽= 4.8 脳 10^鈭?; replication, P聽= .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聽= 5.3 脳 10^鈭?), 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.