Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency.
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.


OBJECTIVE
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 [r(2)>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.
McAloon
Christopher J
CJ
Lung Investigation Unit, University Hospital Birmingham, Birmingham, UK.
Wood
Alice M
AM
Gough
Stephen C
SC
Stockley
Robert A
RA
D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics; D005260:Female; D005541:Forced Expiratory Volume / Q000502:physiology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D053508:Matrix Metalloproteinase 12 / Q000235:genetics*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics*; D008875:Middle Aged; D010101:Oxygen Consumption / Q000502:physiology*; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications / Q000235:genetics* / Q000378:metabolism
D004247:DNA; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12; D020781:Matrix Metalloproteinase 1