Molecular Genetics - Chronic Obstructive Pulmonary Disease - page 404

pulmonary emphysema (80). The MMPl2 knockout mice did not develop
emphysema following exposure to cigarette smoke compared to wild-type
mice (81), suggesting that the presence of MMP12 is critical in smoke-
induced lung injury. Smokers with airway obstruction show increased
expression of MMPl and MMP9 compared with smokers without COPD
and nonsmokers (82,83).
A promoter polymorphism in the MMPl gene (G-1607GG) was asso-
ciated with rate of decline of lung function in smokers (84). In the same
study, polymorphisms of MMP9 and MMPl 2 were not individually asso-
ciated with rate of decline of lung function (84). However, combination of
alleles (i.e., haplotypes) from the MMPl G-1607GG and MMP12 Asn357Ser
polymorphisms revealed an association with rate of decline of lung function
(p ¼ 0.0007). These data suggest that the polymorphisms in the MMPl and
MMP12 genes investigated by Joos et al. are either causative factors in
smoking related lung injury or are associated with causative polymorphisms.
Minematsu et al. (85) examined the association between a MMP9
promoter polymorphism (C-l 562T) and the development of emphysema in
Japanese smokers. They demonstrated that the T allele frequency was higher
in subjects with distinct emphysema on chest CT-scans than in those without
it (p ¼ 0.02). In addition, the diffusing capacity of the lung for carbon mon-
oxide per liter of alveolar volume was lower (p ¼ 0.02) and emphysematous
changes were more conspicuous (p ¼ 0.03) in subjects with C = TorT = T than
those with the C = C genotype (85). These data are consistent with the higher
level of gene expression associated with the T allele in an in vitro assay (86).

2. Xenobiotic Metabolizing Enzymes

Xenobiotic metabolizing enzymes are a class of molecules that play an
important role in detoxifying potentially damaging organic compounds
found in cigarette smoke (87,88). There is considerable interindividual
variation in the catalytic efficiencies of these enzymes in many, if not all,
human populations. Therefore, these molecules have been studied to deter-
mine whether genetically determined deficiencies in xenobiotic metabolism
may predispose an individual to the development of airflow limitation in
response to cigarette smoke.

Microsomal Epoxide Hydrolase: Microsomal epoxide hydrolase
(mEH) is an enzyme that plays a critical role in the lung's ability to metabo-
lize highly reactive epoxide intermediates which may be found in cigarette
smoke. Microsomal epoxide hydrolase is expressed in a variety of different
cell types including hepatocytes and bronchial epithelial cells. In the coding
region of the mEH gene, two relatively common genetic polymorphisms
have been identified (89,90). The polymorphism in exon 3 resulted in the
Tyr 113 ! His substitution and a 40-50% decrease in mEH activity, and was
named the ''slow allele.'' Conversely, another polymorphism in exon 4