This Article Full Text Full Text (PDF) All Versions of this Article: 200906-0963OCv1 181/1/17    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bækvad-Hansen, M. Articles by Nordestgaard, B. G. PubMed PubMed Citation Articles by Bækvad-Hansen, M. Articles by Nordestgaard, B. G.

Surfactant Protein-B 121ins2 Heterozygosity, Reduced Pulmonary Function, and Chronic Obstructive Pulmonary Disease in Smokers

¹ Department of Clinical Biochemistry and ² the Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital; ³ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital; and ⁴ the Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital; and ⁵ Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

Correspondence and requests for reprints should be addressed to Prof. Børge G. Nordestgaard, M.D., D.M.Sc., Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: brno{at}heh.regionh.dk

Rationale: Hereditary surfactant protein-B deficiency is an autosomal recessive disorder that causes fatal respiratory distress syndrome in newborns. Seventy percent of the cases of hereditary surfactant protein-B deficiency are caused by homozygosity for the 121ins2 mutation in the surfactant protein-B gene. Individuals heterozygous for this mutation have partial absence of surfactant protein-B and could be at risk of lung disease when exposed to additional risk factors for impaired surfactant function such as tobacco smoking.

Objectives: To test whether individuals heterozygous for the 121ins2 mutation have reduced lung function and increased risk for chronic obstructive pulmonary disease (COPD) among smokers.

Methods: We genotyped 47,600 individuals from the adult Danish general population and recorded smoking habits, spirometry, and hospital admissions due to COPD. The study and findings are limited to Danes/Europeans.

Measurements and Main Results: We identified 85 individuals heterozygous for the 121ins2 mutation. Smoking interacted statistically with the 121ins2 genotype in predicting FEV₁ % predicted (P = 0.006), FVC % predicted (P = 0.02) and FEV₁/FVC (P = 0.002), indicating that the effect of genotype differ by smoking status. Among smokers, 121ins2 heterozygous individuals had 9% reduced FEV₁% predicted (P = 0.0008), 6% reduced FVC % predicted (P = 0.01) and 6% reduced FEV₁/FVC (P = 0.00007), compared with wild-types. Also among smokers, 121ins2 heterozygous individuals had odds ratios of 2.4 (95% CI, 1.2–4.8) for spirometry-defined COPD and 2.2 (1.0–5.1) for hospitalization due to COPD. Among never-smokers, 121ins2 heterozygous individuals did not differ from wild-types in lung function or risk of COPD.

Conclusions: Surfactant protein-B 121ins2 heterozygosity is associated with reduced lung function and increased risk for COPD among smokers.

Key Words: COPD • genetics • surfactant protein SP-B • smoking

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Hereditary surfactant protein-B deficiency is an autosomal recessive disorder that causes fatal respiratory distress syndrome in newborns. Adult heterozygotes with partial absence of surfactant protein-B could be at risk of lung disease when exposed to additional risk factors for impaired surfactant function such as tobacco smoking. What This Study Adds to the Field We screened 47,600 individuals for the most important mutation leading to absence of surfactant protein-B (121ins2), and we show that among smokers, heterozygotes have markedly reduced lung function and a twofold greater risk of chronic obstructive pulmonary disease.