 and Angiotensin
Converting Enzyme Polymorphisms in Mild/Moderate
and Fatal/Near-Fatal Asthma
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Allele 2 of the polymorphism at position 
308 in the promoter of the tumor necrosis factor 
(TNF-)
gene, and the D allele of the angiotensin converting enzyme (ACE) gene, have been associated with
asthma. We hypothesized that genotypes containing these alleles would show an increased prevalence in asthmatic as compared with nonasthmatic individuals, and would be associated with asthma severity. Polymerase chain reaction-based assays were developed to determine TNF- and ACE genotypes among subjects with mild/moderate asthma (n = 92), fatal/near-fatal asthma (n = 159), no
asthma (n = 43), and random population controls (n = 252). The TNF- 308 polymorphism was increased in both subjects with mild/moderate (p = 0.03) and those with fatal/near fatal asthma (p = 0.02) versus those without asthma, and in all subjects with asthma versus random population controls (p = 0.02). The mild/moderate group was subdivided into subjects with mild (n = 43) and those
with moderate (n = 33) asthma. TNF- 308 was increased in the moderately asthmatic versus the
nonasthmatic subjects (p = 0.003), and in the mildly asthmatic subjects (p = 0.01). However, TNF-
308 was not significantly more prevalent in the fatal/near-fatal than in the mild/moderate asthmatic group. The ACE-D allele did not show an association with either asthma or asthma severity. We
conclude that the TNF- 308 polymorphism may be a risk factor for asthma but does not increase
the risk of a fatal or a near-fatal asthma attack, whereas the ACE polymorphism is not associated with
asthma in this population.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Asthma is a common multifactorial disease of widely varying severity, the etiology of which is attributable to both environmental and genetic factors. Airway inflammation is a hallmark of asthma; the inflammation is caused by the release of cytokines and mediators from a variety of cells, and is characterized by increased vascular permeability, mucus hypersecretion, and smooth-muscle contraction and proliferation (1).
Several candidate genes are implicated in the pathogenesis
of asthma, one of which is the tumor necrosis factor- (TNF-) gene. The TNF- gene lies within the Class III region of the
major histocompatibility complex (MHC), on chromosome 6p
(2). TNF- is a potent proinflammatory cytokine expressed by
mast cells, alveolar and tissue macrophages, and bronchial epithelial cells (3). The expression of TNF- is upregulated in
asthmatic individuals, as shown by its increased secretion in
the airways (4) and bronchoalveolar lavage fluid (BALF) of
symptomatic subjects (5). TNF- production by alveolar macrophages (AM) and blood monocytes from subjects with allergic asthma is enhanced after an allergen challenge in vitro (6).
A TNF- polymorphism, consisting of a G
A transition at
position 308 in the promoter of the gene, has a prevalence of
about 5% in the general population (7). Allele 2 (308 A) of
the TNF- 308 promoter polymorphism was shown in an in
vitro study to be associated with increased secretion of TNF-
from macrophages (8). Results of a previous study have shown
a higher prevalence of the TNF- 308 allele 2 in asthmatic than in nonasthmatic subjects (9).
Another plausible candidate gene proposed as being involved in the pathogenesis of asthma is the angiotensin converting enzyme (ACE) gene. ACE is a zinc metallopeptidase whose main function is to catabolize the proinflammatory mediator bradykinin, and to thus exert an antiinflammatory effect (10). On the other hand, ACE converts angiotensin I into the vasoactive compound angiotensin II, which could contribute to the pathogenesis of asthma by causing proliferation and increased contractility of airway smooth-muscle, thus favoring excessive airflow obstruction (11). In vitro studies have shown that ACE is expressed by human pulmonary endothelial cells, monocytes, and T lymphocytes. (12). An ACE polymorphism has been reported that is caused by a 287-bp insertion (I) or deletion (D) in intron 16 of the ACE gene on chromosome 17q23 (13). The D allele of this polymorphism is associated with increased expression of ACE and higher circulating (14) and cellular levels of this enzyme (15). In a previous study it was demonstrated that the D allele of the ACE gene has an increased prevalence in asthmatic as compared with nonasthmatic individuals (16).
Although, previous studies have shown an association of
genotypes bearing the TNF- 308 allele 2 and the D allele of
the ACE gene, with asthma, it is not known whether the presence of these genotypes is a risk factor for asthma severity. We
hypothesized that the TNF- 308 allele 2 and the D allele of
the ACE gene affect the severity of asthma either in the form
of near-fatal exacerbations of asthma or the likelihood of
death from an asthma attack.
To test this hypothesis, we investigated the prevalence of
the TNF- 308 and the ACE-D polymorphisms in a population of individuals with mild/moderate asthma who had not
experienced a life-threatening asthma attack in the preceding
year, and in individuals with fatal/near-fatal asthma who died
or nearly died during an asthma attack. Polymerase chain reaction (PCR)-based assays were designed to genotype the TNF- and ACE variants. The prevalence of these polymorphisms was compared with that in a group of nonasthmatic individuals and with a random population sample.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
The study subjects were divided into four groups. The first group consisted of subjects with mild/moderate asthma (n = 92) who had no history of hospital admission for an asthma attack in the year before the
study and were not taking oral steroids. This group was further subdivided into: (1) Subjects with mild asthma (n = 43) whose FEV1 was > 75% predicted and/or who took 
400 µg/d of inhaled beclomethasone or an equivalent dose of another inhaled corticosteroid preparation; and (2) subjects with moderate asthma (n = 33) whose FEV1
was < 75% predicted and/or who took > 400 µg/d of inhaled beclomethasone or equivalent. Sixteen subjects with mild/moderate asthma
could not be categorized as either having mild or moderate asthma
specifically, owing to unavailability of phenotypic data.
The second study group consisted of subjects with fatal/near-fatal asthma (n = 159). Subjects with fatal asthma (n = 132) were defined as those who were under the age of 50 yr and had a history of recent deterioration of asthma symptoms leading to a terminal asthmatic episode. In addition, two pathologists independently confirmed airway histopathologic findings characteristic of asthma on autopsy specimens from these subjects. Subjects with near-fatal asthma either had a history of hospital admission requiring intubation and ventilation for an acute exacerbation of asthma symptoms (n = 25), or had hypercapnic respiratory failure (n = 2) with a PaCO2 > 45 mm Hg during an acute asthmatic episode.
The third study group consisted of nonatopic nonasthmatic subjects (n = 42) who had no personal or family history of asthma or allergy and had negative skin prick tests (wheal < 1 mm greater than with saline) with six common allergens (cat and dog dander, grass, molds, house dust mite, and trees).
The fourth study group consisted of a random population sample of subjects (n = 252) recruited from a blood donor clinic.
All asthmatic and nonasthmatic subjects were Caucasians and gave informed consent to participate in the study. Ethics approval was obtained from the University of British Columbia Institutional Review Board.
Genotyping
For subjects with mild/moderate and near-fatal asthma, DNA was extracted from peripheral blood samples (17). Because the lung tissue
samples for subjects with fatal asthma were obtained at autopsy, DNA
was extracted from formalin-fixed, paraffin-embedded tissue blocks
(18). The TNF- 308 polymorphism was detected by PCR amplification of the fragment of interest, followed by restriction enzyme digestion. A primer was designed with a single mismatch to create a StyI restriction enzyme site in the wild-type allele (TNF- 308 allele 1).
The G A nucleotide substitution abolishes the StyI site in the mutant
allele (TNF- 308 allele 2). PCR was conducted with the novel
primers: 5'-AGGCAATAGGTTTTGAGGGCCATGG-3' (the mismatched nucleotide is underlined) and 5'-ACACACAAGCATCAAGGATACC-3' which generated a 143-bp product. Two-hundred
nanograms (2 µl) of genomic DNA was added to 18 µl of reaction
mixture containing 2 µmol of each primer, 200 µmol of each deoxynucleotide triphosphate (dNTP), 1.5 mM MgCl2, 20 mM (NH4)2SO4, 75 mM Tris-HCl (pH 8.8 at 25° C), 0.01% Tween 20, and one unit of
DNA polymerase (Ultra Therm thermophilic DNA polymerase; BIO/
CAN Scientific, Mississauga, ON, Canada). Amplification conditions
were 40 cycles of denaturation at 94° C for 30 s, annealing at 59° C for
30 s, and extension at 72° C for 1 min. A final extension for 10 min at
72° C was included. Following amplification, each PCR reaction was
digested with 15 units of StyI restriction enzyme and incubated overnight at 37° C. TNF- 308 allele 1 was identified by 123-bp and 20-bp fragments, and allele 2 was identified by a single 143-bp fragment (Figure 1).
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The ACE-D polymorphism was also detected by PCR amplification. For the DNA samples extracted from peripheral blood, the reaction was run with a sense primer (ACEF) from the published sequence (19) and a novel antisense primer called ACER with the sequence 5'-GCTGGAATAAAATTGGCGAAACCAC-3'. The PCR reaction mixture was the same as described above except the total volume was 30 µl. Thirty-five cycles of amplification were performed with denaturation at 94° C for 1 min, annealing at 55° C for 1 min and extension at 72° C for 30 s. The PCR products were 376-bp and 89-bp in length for the I and D alleles, respectively (Figure 2). Because the DNA samples obtained from paraffin-embedded tissue blocks were often degraded, we designed a novel sense primer called ACEI from within the insertion, which amplified a smaller product. The sequence of ACEI is as follows: 5'-GTTTTAGCCGGGATGGTCTCGATC-3'. The PCR reaction mixture contained 5 µmol each of the ACEF and ACER primers and 1.5 µmol of the ACEI primer. The remaining constituents were at the same concentrations as described earlier with the addition of 10% dimethylsulfoxide. The amplification cycles consisted of an initial step at 94° C for 5 min, followed by 35 cycles at 94° C for 30 s and 59° C for 30 s. The combination of the three primers yielded a 122-bp fragment in the case of the I allele, and an 89-bp fragment in the case of the D allele (Figure 3). Ten control samples were initially genotyped according to this method, and there was no discrepancy with the results obtained with the original method.
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The amplified PCR products were resolved on 3% agarose gels
stained with ethidium bromide. Known controls of each genotype were included with each set of samples for both the TNF- 308 and
ACE-D polymorphisms. All of the genotypes were checked independently by two individuals.
Statistical Analysis
The genotype frequencies among all the subsets of asthmatic and control subjects were compared by means of a chi-squared test for 2 × 2 contingency tables. All values of p < 0.05 were considered significant.
Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated as a measure of the association of each genotype with asthma.
The genotype distributions of the TNF- 308 and ACE-D polymorphisms for all of the study groups were found to be in Hardy-Weinberg equilibrium.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We successfully genotyped 251 asthmatic subjects for the
TNF- 308 polymorphism and 231 asthmatic subjects for the
ACE-D polymorphism. Forty-two nonasthmatic subjects were
genotyped for both polymorphisms. In addition, 252 subjects
from a random population sample were genotyped for the
TNF 308 and 249 for the ACE-D polymorphism. The ACE
gene failed to amplify in 20 DNA samples from the asthmatic
population and in three from the random population.
The genotype frequency of the TNF- 308 polymorphism
in asthmatic and nonasthmatic subjects is shown in Table 1. In
a previously reported Caucasian, nonasthmatic control population (9), the number of individuals with the TNF- 308
polymorphism (33%) was higher than that observed in our
nonasthmatic control population (21%), but this difference
was not significant (p = 0.1). The TNF- 308 polymorphism
was significantly more common in both the groups with mild/
moderate asthma and fatal/near-fatal asthma than in the nonasthmatic controls (Table 1). Comparison of all the asthmatic
subjects with the nonasthmatic group indicated a significant
association of the TNF- 308 polymorphism with asthma (p = 0.02; OR: 3.07; 95% CI: 1.1 to 5.3). Contrary to our hypothesis, we were unable to show an increased prevalence of
this polymorphism in subjects with fatal/near-fatal asthma as
compared with those with mild/moderate asthma (p = 0.95).
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When the mild/moderate asthma group was subdivided
into subjects with mild and those with moderate asthma, there
was a higher prevalence of the TNF- 308 polymorphism in
the moderately asthmatic subjects than in the nonasthmatic
controls (Table 2). There was also a statistically significant increase in the prevalence of the TNF- 308 polymorphism in
the moderately asthmatic as compared with the mildly asthmatic subjects (Table 2).
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We also compared the frequency of the TNF- 308 polymorphism in the asthma groups with its frequency in the random population sample (Table 3). We found a greater frequency of this polymorphism in the group with fatal/near-fatal
asthma and in all asthma subjects combined than in the random population sample (Table 3). The moderately asthmatic
subgroup demonstrated a higher prevalence of this polymorphism than did the random population (Table 3).
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The frequency of ACE-D-containing genotypes in the nonasthmatic control population (84%) in this study was in agreement with the data previously reported (16) for another Caucasian, nonasthmatic control population (86%). In contrast to
the TNF- 308 polymorphism, the ACE-D polymorphism
did not show an increased frequency in the asthmatic as compared with either the nonasthmatic subjects (p = 0.15) or the
random population sample (p = 0.31) (Table 4). Therefore,
there was no relationship of this polymorphism to asthma in
any of the study groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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To date there have been several linkages of allergy and
asthma phenotypes with different regions of the human genome (1). Despite this, no specific polymorphisms within candidate genes in these regions have been definitely implicated
in the pathogenesis of allergic diseases or asthma. It is likely
that asthma and allergy are polygenic disorders with considerable genetic heterogeneity. We reasoned that individuals who
have asthma might carry genes that modify the severity of inflammation, and which could therefore, influence the phenotypic manifestations of this disorder. Among the many gene
products involved in the production and modulation of airway
inflammation, TNF- and ACE are potential candidates.
The results of this study show an increased prevalence of
the TNF- 308 promoter polymorphism in asthmatic subjects than in nonasthmatic subjects or a random population
sample. Although there was no difference in genotype frequency between subjects with mild/moderate asthma and fatal/near-fatal asthma, there was a higher prevalence of allele 2 in the subgroup of moderately asthmatic subjects than in those
who had mild asthma. There were no significant differences in
the prevalence of the ACE-D allele.
The present study is the first to examine the prevalence of
the TNF- 308 promoter polymorphism in subjects with fatal and near-fatal asthma (9). The study revealed two previously unknown findings. First, the association of the TNF-
308 polymorphism with moderate versus mild asthma suggests that the presence of this polymorphism produces a
greater severity of asthma. Second, the prevalence of this
polymorphism was not increased in subjects with fatal/near-
fatal asthma as compared with those with mild/moderate asthma.
A possible explanation for this is that the subjects with fatal/
near-fatal asthma were not intrinsically different from those
with moderate asthma in terms of their steroid use, degree of
airway obstruction, or asthma-associated structural changes in
the lungs. However, because of unavailability of data, we
could not determine whether the subjects with fatal asthma
would have been categorized as "moderate" in terms of their
steroid use and FEV1. Thus, the presence of TNF- 308 allele 2 may create an increased risk for the development of
severe asthma, but may not contribute to the risk of a fatal
asthma attack. Alternatively, TNF- 308 allele 2 may increase the risk of fatal asthma, whereas our sample size was
not large enough to detect this.
The TNF- 308 polymorphism could influence asthma
severity by augmenting airway inflammation. There is evidence that the 308 allele 2 is associated with a variety of infectious and immunologic diseases (20), and that it may exert
its effect by enhancing TNF- secretion in response to inflammatory stimuli. In vitro studies (8) have shown that the 308
variant displays increased gene transcription as compared
with the wild-type allele. The TNF- 308 polymorphism is
also strongly associated with celiac disease of the small intestine (21) and with an increased risk for cerebral malaria (22).
However, the relevance of the 308 allele 2 for exaggerated TNF- gene expression has not been uniformly supported (23, 24). No association was found between the severity of sepsis and the 308 variant (23), and there was no
association of the 308 allele 2 with increased TNF- gene
transcription in vitro (23, 24).
These inconsistent results suggest that the association of
the TNF- 308 polymorphism with asthma may not be expressed through the influence of the polymorphism on TNF
secretion. The TNF- gene lies within the Class III region of
the MHC. The TNF locus is 250 kb centromeric of the human
leukocyte antigen (HLA)-B1 locus and 350 kb telomeric of the
Class III cluster (2). Thus, the TNF- 308 polymorphism could
be in linkage disequilibrium with HLA variants associated
with asthma. There is a strong association of the TNF- 308
promoter polymorphism and the HLA-A1, -B8, and -DR3 alleles (25).
Despite the observed association of the TNF- 308 polymorphism with asthma severity in terms of lung function and
steroid use, it is puzzling not to see an association of this polymorphism with fatal and near-fatal asthma. Paradoxically, fatal or near-fatal asthma may not be good markers of asthma
severity. This may be attributed to factors related to the physician, the patient, and the environment. Physician-related factors include the appropriateness and timeliness of medical
care, failure to objectively evaluate the severity of an asthma
attack, and failure to suggest avoidance strategies for important triggering factors. Patient-related factors include perception of dyspnea, compliance with a therapeutic regime, socioeconomic status, and male gender. Environmental factors
include the frequency and intensity of exposure to pertinent
allergens (26). Therefore, although fatal or near-fatal asthma
is a well-defined clinical endpoint, it may not represent a homogeneous phenotype, since several factors other than the intrinsic severity of asthmatic airway inflammation can be important contributors to its expression.
The deletion mutation in the ACE gene has been shown to be associated with an increase in the circulating ACE level (14). This increase could conceivably have both beneficial and detrimental effects on airway inflammation and remodeling in asthma. Increased ACE activity could have beneficial effects by yielding more complete metabolism of bradykinin, a potent proinflammatory mediator. High levels of bradykinin in plasma (27) and bronchoalveolar lavage fluid (28) have been reported in asthmatic individuals. However, increased ACE could also result in an increased angiotensin level. Angiotensin II is a potent vascular and airway smooth-muscle contractile agonist and mitogen (11). The level of angiotensin II is increased in acute severe asthma, and causes bronchoconstriction either by a direct effect on the airway smooth muscle, or by an indirect effect through the release of other mediators of bronchoconstriction such as endothelin (29).
We were unable to confirm the previously reported association of asthma with the ACE polymorphism (16) despite our use of a larger sample size. Our negative results may reflect the involvement of variable combinations of risk alleles in different populations. Genetic heterogeneity in this complex disease may have contributed to the difficulty of replicating this finding.
In summary, the results of this study suggest that the TNF-
308 promoter polymorphism is a risk factor for asthma and
that it augments asthma severity. Although we had hypothesized that there would be a gradient in the prevalence of this
proinflammatory polymorphism from subjects with mild to
moderate to severe asthma, we did not see the highest prevalence of this polymorphism in those who had fatal or near fatal
asthma. Factors other than intrinsic severity of disease may be
important risk factors for fatal or near-fatal asthma.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. A. J. Sandford, UBC Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6 Canada. E-mail: asandford{at}prl.pulmonary.ubc.ca
(Received in original form August 7, 1998 and in revised form January 6, 1999).
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References |
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ABSTRACT
INTRODUCTION
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DISCUSSION
REFERENCES
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H. Bilolikar, A. R. Nam, M. Rosenthal, J. C. Davies, D. C. Henderson, and I. M. Balfour-Lynn Tumour necrosis factor gene polymorphisms and childhood wheezing Eur. Respir. J., October 1, 2005; 26(4): 637 - 646. [Abstract] [Full Text] [PDF]
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A. G. Randolph, C. Lange, E. K. Silverman, R. Lazarus, and S. T. Weiss Extended Haplotype in the Tumor Necrosis Factor Gene Cluster Is Associated with Asthma and Asthma-related Phenotypes Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 687 - 692. [Abstract] [Full Text] [PDF]
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E. R. McFadden Jr. Acute Severe Asthma Am. J. Respir. Crit. Care Med., October 1, 2003; 168(7): 740 - 759. [Abstract] [Full Text] [PDF]
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A. J. SANDFORD, T. CHAGANI, T. D. WEIR, J. E. CONNETT, N. R. ANTHONISEN, and P. D. PARÉ Susceptibility Genes for Rapid Decline of Lung Function in the Lung Health Study Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 469 - 473. [Abstract] [Full Text]
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W. O.C. Cookson and M. F. Moffatt Genetics of asthma and allergic disease Hum. Mol. Genet., October 1, 2000; 9(16): 2359 - 2364. [Abstract] [Full Text] [PDF]
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