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Therapeutic Advances in Respiratory Disease
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Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency

Christopher J. McAloon

Lung Investigation Unit, University Hospital Birmingham, Birmingham, UK

Alice M. Wood

Division of Medical Sciences, University of Birmingham, Birmingham, UK

Stephen C. Gough

Division of Medical Sciences, University of Birmingham, Birmingham, UK

Robert A. Stockley

Division of Medical Sciences, University of Birmingham, Birmingham, UK, rob.stockley{at}uhb.nhs.uk

Alpha-1-antitrypsin deficiency (AATD) is associated with variable development of emphysema and other features of chronic obstructive pulmonary disease (COPD). Matrix metalloproteinases (MMPs) are believed to be important in the pathophysiology of COPD, and may therefore confer susceptibility to this phenotype in patients with AATD.

Objectives: to assess the role of polymorphism of MMP1, MMP3 and MMP12 in AATD phenotypes.

Methods: 424 PiZZ subjects from the UK AATD Registry were assessed for history of chronic bronchitis (CB), post-bronchodilator lung function impairment and decline of lung function. Tag single nucleotide polymorphisms (SNPs) for MMP1, MMP3 and MMP12 were chosen using HapMap (r2>0.8, MAF>0.05) and were genotyped using TaqMan® genotyping technologies. Quantitative genetic association was assessed using regression modelling to correct for covariates.

Results: in patients with AATD, carriers of the G allele of rs678815 (MMP3) had lower gas transfer (KCO) (P = 0.025, B =-7.766) than the homozygous wild type, while carriers of the T allele of rs470358 (MMP1) had higher KCO (P = 0.025, B = 6.130).

Conclusions: variations in MMP1 and MMP3 are associated with gas transfer in AATD, supporting a previous family study showing linkage of KCO to this gene region. Replication of these preliminary data is now required particularly if MMP inhibitors are to be considered as a therapeutic option.

Key Words: matrix-metalloproteinase • alpha-1-antitrypsin • chronic obstructive pulmonary disease • genotyping

Therapeutic Advances in Respiratory Disease, Vol. 3, No. 1, 23-30 (2009)
DOI: 10.1177/1753465809102263
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