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Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P <or= 0.001) and lower gas transfer (P = 0.02). There was no correlation of FEV(1) between siblings but KCO was significantly correlated (r = 0.42, P = 0.002). Quantitative analyses against lung function showed that a polymorphism in Surfactant protein B was associated with FEV(1) (P = 0.002). This result was replicated in a non-sibling group (P = 0.01). Our results show that clinical differences in families with alpha-1-antitrypsin deficiency are not solely explained by smoking or ascertainment bias and may be due to variation within genes involved in inflammatory pathways.

Original publication




Journal article



Publication Date





353 - 359


Forced Expiratory Volume, Genetic Variation, Humans, Phenotype, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Pulmonary Surfactant-Associated Protein B, Transforming Growth Factor beta, Vital Capacity, Vitamin D-Binding Protein, alpha 1-Antitrypsin Deficiency