Molecular Genetics - Chronic Obstructive Pulmonary Disease - page 402

increased rate of decline in lung function and interacts with other familial
factors. Some of these familial factors could be genetic and others could be
environmental.
Investigators have also assessed the risk of the MZ genotype by study-
ing lung function in the general population (57,59-62). In these studies, a
population sample is phenotyped for a 1-AT variants and the prevalence of
COPD in those with the MZ phenotype is compared with those with the
MM phenotype. A weakness of many of these studies was that they were
based on small numbers of individuals and therefore had insufficient power
to detect an effect of the MZ or MS phenotype. In a large cohort study from
Denmark, Seersholm et al. (63) compared the prevalence of obstructive pul-
monary disease in 1551 MZ individuals vs. 14,484 controls from the general
population of unknown a 1-AT genotype. Obstructive pulmonary disease
was defined as a hospital discharge diagnosis of asthma or chronic bronchitis
or emphysema. The risk for obstructive pulmonary disease was significantly
increased in the MZ individuals compared with the controls (relative
risk ¼ 2.2). However, only first-degree relatives of ZZ COPD patients had
a significantly increased risk, suggesting that other genetic or environmental
factors were contributing to the increased risk in these patients. Dahl et al.
(64) performed a large cross-sectional study of 9187 individuals from the
general population of Copenhagen in Denmark. The study subjects under-
went pulmonary function testing (FEV 1 and FVC) and were genotyped for
the S and Z a 1-AT variants. Only the SZ and ZZ individuals in this popula-
tion showed an increased prevalence of COPD (FEV 1 < 80% predicted).
There was no association of either MS or MZ genotype with lower level of
lung function in individuals without clinically established COPD.
However, among the COPD patients, FEV 1 was < 655mL in MZ indi-
viduals compared with MM individuals (p < 0.05) after adjustment for con-
founding variables. The observation that the MZ genotype was associated
with airflow limitation only in those with COPD suggests that other predis-
posing factors exist, consistent with the results of Seersholm et al. (63). In
addition to this cross-sectional study, Dahl et al. (65) performed a longitudi-
nal study to test whether MZ genotype affects lung function decrease and
other clinical outcomes of COPD on the same study cohort. Three lung func-
tion measurements obtained from 1976 to 1978, 1981 to 1983, and 1991 to
1994 were used to calculate annual change in FEV1. The results showed that
the MZ genotype was more prevalent in subjects with airway obstruction and
COPD and was associated with more rapid decline rate in FEV1 than the
MM genotype. The author also concluded that the MZ genotype accounts
for almost the same proportion of COPD cases as the ZZ genotype (65).
a 1 -Antitrypsin Polymorphisms Not Associated with Deficiency: There
are several polymorphisms of the a 1-AT gene that are not associated with
a 1 -AT deficiency. The most extensively studied example is a polymorphism