Biomedical Engineering Reference
In-Depth Information
was referred as ''fast allele'' because it caused the His
139
!
Arg substitution
and 25% increase of enzyme activity (89).
However, similar correlation between the polymorphisms and the
mEH activity were not shown in liver tissue samples (91). The slow allele
of mEH was found in a higher proportion of patients with emphysema
(22%) and COPD (19%) than in control subjects (6%), yielding an OR of
5 (92). In a smaller Japanese study, the slow allele of mEH was associated
with more severe COPD (93). These results were not confirmed in a Korean
population (94). However, the slow allele was found associated with rapid
rate of decline of lung function in smokers (58) and COPD in Caucasians
(95). Therefore, despite the one inconsistent study, overall these data suggest
that genetic variation in the mEH gene does modify an individual's risk of
COPD.
Glutathione S-Transferases:
Glutathione S-transferases (GSTs) are
members of a family of enzymes critically involved in detoxification of
various toxic substances found in cigarette smoke, including polycyclic
aromatic hydrocarbons that have been implicated in the pathogenesis of
COPD. Most GSTs exist as soluble enzymes and can be divided into four
main classes: alpha(A), mu (M), pi (P), and theta (T) (96). The GST genes
are polymorphic. Homozygous deletion of the GSTM1 gene occurs in
50% of Caucasians and therefore results in complete absence of this
enzyme in these individuals. Homozygous deficiency for GSTM1 was asso-
ciated with emphysema in Caucasian patients who had lung cancer
(OR
¼
2.1) (97) and severe chronic bronchitis in heavy smokers (OR
¼
2.8)
(98). However, in a Korean study, there was no association of the GSTM1
deletion with COPD (94). These discrepant results may be due to differences
in the ethnicity of the study subjects. Certain genetic variants may be asso-
ciated with disease only in certain ethnic groups due to interactions with
population-specific environmental factors or other genetic factors.
A null polymorphism has also been identified in the GSTT1 gene (99),
as well as two single nucleotide polymorphisms in the GSTP1 gene. The
polymorphism in exon 5 of GSTP1 at nucleotide 313 (Ile
105
!
Val) was
shown to result in altered enzyme activity (100,101). Homozygotes for the
isoleucine allele were significantly increased in Japanese patients with COPD
compared with the controls (OR
¼
3.5) (102), However, this result was not
replicated in a larger study of Korean COPD patients and controls (103).
In a recent study, He et al. (104) investigated the association between the
polymorphisms of the GSTM1, GSTT1, and GSTP1 gene and accelerated
decline rate in FEV
1
in a Caucasian population. They found that none of
the polymorphisms individually had a significant effect on the decline of
lung function. However, a significant association was observed for concur-
rent deletion of the GSTM1 and GSTT1 genes and presence of homozygous
GSTP1 Ile allele (OR
¼
2.83, P
¼
0.03). These data suggest that individuals
