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Familial aggregation of FEF_25–75 and FEF_25–75/FVC in families with severe, early onset COPD

¹ Channing Laboratory, Brigham and Women’s Hospital, Boston, MA, USA
² Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
³ Harvard Medical School, Boston, MA, USA
⁴ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
⁵ Cardiovascular Research Institute, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA

Correspondence to:
Correspondence to:
Dr D L DeMeo
Channing Laboratory, Pulmonary & Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Ave, Boston, MA 02115, USA; redld{at}channing.harvard.edu

Background: The Boston Early-Onset COPD study showed that current or ex-smoking first degree relatives of severe early onset COPD probands have significantly lower forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) values than current or ex-smoking control subjects, which suggests the existence of genetic risk factors for the development of COPD in response to cigarette smoking. We hypothesised that first degree relatives of early onset COPD probands may also have lower values of spirometric parameters such as forced expiratory flow at the mid-portion of forced vital capacity (FEF_25–75) and FEF_25–75/FVC.

Methods: Using generalised estimating equations, FEF_25–75 and FEF_25–75/FVC were analysed in 333 first degree relatives of probands with severe early onset COPD and 83 population based controls; analyses were also performed on data stratified by smoking status. Narrow sense heritability estimates were calculated using a variance component approach.

Results: Significantly lower FEF_25–75 and FEF_25–75/FVC were observed in smoking (FEF_25–75: ß –0.788 l/s (95% CI –1.118 to –0.457), FEF_25–75/FVC: ß –20.4% (95% CI –29.3 to –11.6, p<0.0001 for both phenotypes) and non-smoking (FEF_25–75: ß –0.357 l/s (95% CI –0.673 to –0.041, p = 0.0271), FEF_25–75/FVC: ß –9.5% (95% CI –17.1 to –1.9, p = 0.0145)) first degree relatives of early onset COPD probands. Narrow sense heritability estimates for FEF_25–75 (h² = 0.38) and FEF_25–75/FVC (h² = 0.45) were similar to those for FEV₁ and FEV₁/FVC.

Conclusion: Lower values of FEF_25–75 and FEF_25–75/FVC in non-smoking first degree relatives of early onset COPD probands than in controls suggest a genetic susceptibility to develop obstructive lung disease, independent of smoking, which is magnified by exposure to deleterious environments as suggested by the further decrements in FEF_25–75 and FEF_25–75/FVC seen in smoking first degree relatives. FEF_25–75 and FEF_25–75/FVC have high heritability and are important intermediate phenotypes for inclusion in genetic epidemiological studies of COPD.

Keywords: chronic obstructive pulmonary disease; smoking; genetics; lung function

Abbreviations: FEF_25–75, forced expiratory flow at the mid-portion of forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity

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