Biomedical Engineering Reference
In-Depth Information
high mineral dust exposure was associated with reduced FEV1 and chronic
cough, independent of smoking history. Although genotype-environment
interactions have not been formally demonstrated, occupational and other
environmental exposures may also be important determinants of the devel-
opment of lung disease in PI Z subjects.
However, the rate of decline of lung function in ZZ subjects who are
lifelong nonsmokers is also highly variable (44). In studies in which index
and nonindex cases have been compared, many nonindex ZZ subjects show
normal lung function (48) and a survival similar to the normal population
(49) if they are nonsmokers. Therefore, the effect of the ZZ genotype in
increasing the risk of clinically significant airflow limitation is likely to have
been overestimated in some studies due to selection bias. It is possible that
other genetic factors influence the clinical course in ZZ homozygotes. Poly-
morphisms in the endothelial nitric oxide synthase (NOS3) gene were shown
to contribute to the development of COPD in ZZ individuals (50), although
this association has not been confirmed in an independent study.
Intermediate
a
1
-Antitrypsin Deficiency:
With the clear association
of severe
a
1
-AT deficiency with COPD, it was a natural question to ask
whether individuals with intermediate deficiency were also at risk for airflow
limitation. Individuals who have one copy of either S or Z alleles are present
in Caucasian populations at
10% or 3%, respectively. These MS and MZ
heterozygotes have reductions in
a
1
-AT levels to
80% and 60% of normal,
respectively. The SZ compound heterozygotes are rare but have levels even
lower at
40% of normal. In one study, SZ heterozygotes were shown to
have an increased risk for COPD if they smoked (51). However, in a study
from Spain, no association between SZ phenotype and COPD was found
(52). To date, there have been no studies to convincingly demonstrate that
MS heterozygotes are at increased risk of airflow limitation.
The results of many case-control studies have shown an increased
prevalence of MZ heterozygotes in COPD patients compared with controls
(53-57). In such studies, the odds ratio (OR) for MZ typically ranges from
1.5 to 5.0. However, in some of these studies, the controls were not selected
from the same population as the cases, and this may lead to spurious associa-
tions of the MZ genotype with COPD due to differences in MZ frequency
between populations. In addition, some of these case-control study. results
were not adjusted for confounding variables such as smoking history and
age. Recently, the MZ genotype was investigated as a risk factor for
increased rate of decline of lung function in smokers (58). The study group
consisted of 283 smokers with rapid decline of lung function (mean DFEV
1
¼
154mL
=
year) and 308 smokers with no decline (mean DFEV
1
¼þ
15mL
=
year). Rapid decline of FEV1 was associated with the MZ (OR
¼
2.8) and
the association was stronger for a combination of a family history of COPD
with MZ (OR
¼
9.7). These data suggest that the MZ genotype results in an
