 1-Antitrypsin Heterozygotes
of Phenotype PiMZ
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Whether subjects heterozygous for 
1-antitrypsin (1-AT) deficiency are at risk for development of
obstructive pulmonary disease (OPD) has been discussed for the past three decades. Both cohort and
case-control studies have reached different conclusions, with the major problems being small sample sizes. A cohort of heterozygotes with the phenotype PiMZ was retrieved from the Danish Alpha1-Antitrypsin Deficiency Registry. Ten matched controls for each PiMZ subject were identified from the
files of the Danish Central Population Registry. Cases and controls were subsequently linked to the
files of the Danish Hospital Discharge Registry, and relative risk for OPD was calculated. In the cohort
of 1,551 PiMZ subjects (11,678 person-years), we identified 47 subjects with a discharge diagnosis of
OPD, as compared with 206 subjects with this diagnosis in the control group (109,748 person-years),
yielding a relative risk (RR) of 2.2 (95% confidence interval [CI]: 1.5 to 3.0). This increased risk was
present in both men and women and in all age groups; however, it was significant only in the age
group from 40 to 79 yr. Of the 1,551 PiMZ subjects, 565 (36%) were first-degree relatives of PiZ index cases, and it appeared that only this group was at increased risk of hospital admission for OPD
(RR: 3.4, 95% CI: 2.2 to 5.3). We conclude that 1-AT heterozygotes of phenotype PiMZ are at increased risk of hospital admission for OPD if they are first-degree relatives of PiZ index cases only,
and that other, yet unknown genetic or environmental factors contribute to the development of
lung disease. Seersholm N, Wilcke JTR, Kok-Jensen A, Dirksen A. Risk of hospital admission
for obstructive pulmonary disease in 1-antitrypsin heterozygotes of phenotype PiMZ.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The increased risk for development of emphysema at an early
age is well known for subjects homozygous for the inherited
disorder alpha1-antitrypsin (1-AT) deficiency. Heterozygotes
with the phenotype PiSZ also have an increased risk for pulmonary disease, but to a much lesser degree (1). With a prevalence of 4% in persons of Northern European descent, the
heterozygous PiMZ phenotype as a risk factor for obstructive
pulmonary disease (OPD) has been subject to discussion for
the past 30 yr. A number of case-control studies (2), cohort
studies (9), and studies of family members to PiZZ patients (15, 16) have dealt with the issue of OPD risk, but no
clear-cut conclusions have been derived, and many of the
studies have been criticized for being too small (17).
The aim of the present study was to estimate the risk of OPD in a cohort of 1,551 PiMZ subjects selected from a registry who were followed for up to 18 yr.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The study was a prospective record-linkage study based on the Danish Alpha1-Antitrypsin Deficiency Registry, the Danish Central Population Registry (CPR), and the Danish Hospital Discharge Registry (HDR).
Since 1978, patients with 1-AT deficiency of phenotypes PiZ and
PiSZ have been reported to the Danish Alpha1-Antitrypsin Deficiency Registry by physicians throughout Denmark. Once a patient is
registered, a family record is obtained and relatives at risk of having a
Z-gene are offered an examination of their Pi type. Determination of
1-AT Pi type is performed by the Department of Clinical Chemistry
at Bispebjerg Hospital in Copenhagen, through isoelectric focusing as
described by Fagerhol and Cox (18). Thus, the registry contains subjects of PiZ and PiSZ phenotype identified on the basis of respiratory
symptoms (index cases), as well as other subjects of PiZ, PiSZ, and
PiMZ phenotype; some rare phenotypes; and the nondeficient PiMM
phenotype, ascertained through family studies (nonindex cases). Subjects of PiMZ phenotype identified in this way were the subjects of the
present study.
The CPR was initiated on April 1, 1968, when all Danish citizens were assigned a unique 10-digit personal identification number that includes information on date of birth and gender. The registry records place of residence and date of death or emigration. From the CPR we identified 10 controls for each PiMZ subject, who were matched for date of birth, gender, and county of resident. PiMZ subjects and controls were subsequently linked to the files of the HDR through their unique ID number. The HDR was initiated in 1977, and apart from psychiatric departments, holds information on hospitalizations at all hospital departments in Denmark. The information in the HDR includes date of admission and discharge, and up to 20 discharge diagnoses. From 1977 to 1994, the International Classification of Disease, Revision 8 (ICD8) was used for discharge diagnoses, and from 1995 onwards ICD10 was used.
To identify PiMZ subjects and controls discharged with a diagnosis of OPD, we used ICD8 codes from 490 to 493 and ICD10 codes from J41 to J46.
The study was approved by the local ethics committee of Copenhagen.
Statistical Analysis
The follow-up period for each PiMZ subject and matching control was from the date on which the PiMZ status was established (entry date) to December 31, 1995, the date of death or emigration, or the date of first occurrence of OPD (or other diagnoses of interest) in the HDR files, whichever came first. Controls who died before the entry date were excluded from the analysis, and hospital admissions before the entry date were ignored. Subjects who had been discharged more than once with a diagnosis of OPD were counted only once.
Rate ratios for the incidence of OPD were calculated as the ratio of nPiMZ subjects/pyPiMZ subjects to ncontrols/pycontrols, where n is the number of patients discharged with a diagnosis of OPD and py is the person-years of follow up. These rate ratios are referred to as relative risks (RRs) in this report. Confidence intervals (CIs) (95%) were calculated with the formula described by Breslow and Day (19), and if 1 was not included in a confidence interval, the results were considered significant. For calculation of cumulative probability of OPD, the life-table method was used.
Multivariate analysis (i.e., Poisson regression analysis) was done through use of the software package PROC GENMOD (SAS Institute, Cary, NC) (20).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The study population comprised 1,551 MZ subjects and 15,506 controls (for one MZ subject, only six controls could be matched). In the control group, 1,022 subjects died before the entry date, leaving 14,484 controls for analysis. The total number of person-years of follow-up was 11,678 for the PiMZ subjects and 109,748 for the controls, and the average follow-up times for the two groups were 7.5 yr (range: 0.2 to 18 yr) and 7.6 yr (range: 0.0 to 18 yr), respectively. The mean age at entry was 37.1 yr (range: 0 to 86.5 yr) for PiMZ subjects and 35.7 yr (range: 0 to 86.5 yr) for controls (t test: p < 0.01). The percentages of men in the two groups were 48.7% and 48.2% (chi-square test: p = 0.6), respectively. This slight difference in age and gender was due to a number of controls dying before the entry date.
During the follow-up period, 99 PiMZ subjects and 804 controls died, yielding an RR of 1.2 (95% CI: 0.9 to 1.4).
Among the PiMZ subjects 47 were discharged with a diagnosis of OPD, compared with 206 such subjects in the control group, giving an RR of 2.2 (95% CI: 1.5 to 3.0). In Table 1, OPD is divided into the diagnoses of emphysema, chronic bronchitis, and asthma. All three diagnoses were significantly more frequent in the PiMZ group. Table 2 shows the risk for OPD in different age groups and by gender. In all age groups there was an increased risk for OPD among PiMZ subjects; however, this was significant only in the age group of 40 to 79 yr. Figure 1 shows the cumulative probability of being discharged with a diagnosis of OPD by age. By age 70 yr the cumulative risk for being discharged with a diagnosis of OPD among PiMZ subjects was 20%, compared with 8% in the control group.
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Because the control group was on average younger than the PiMZ group, we performed Poisson regression analysis to adjust for this age difference and to analyze whether there was any gender difference in the risk of hospital admission for OPD. With five age groups and gender included in the model, the RR of hospital admission for OPD in the PiMZ group was 1.9 (95% CI: 1.4 to 2.7). The RR for men compared with women was 1.1 (95% CI: 0.8 to 1.4).
Because different smoking habits in the PiMZ group and the control group could have confounded the results, we analyzed whether the PiMZ subjects had an increased risk for smoking-related cancers (mouth, esophagus, airways, bladder, and pelvis of the kidney), and used this as a proxy for smoking habits. There were 13 of these cancers in the PiMZ group and 109 in the control group (RR = 1.1; 95% CI: 0.6 to 2.0).
To analyze whether the increased risk for OPD among the PiMZ subjects, all of whom were relatives of PiZ patients with severe emphysema, was due to other, unexplained familial factors, we performed a similar analysis for PiMM subjects identified in the same way. There were 1,014 PiMM subjects representing 6,919 person-years, and 9,404 controls representing 64,344 person-years (736 controls died before the study entry date). Eighteen PiMM subjects and 134 controls were discharged with a diagnosis of OPD, yielding an RR of 1.2 (95% CI: 0.7 to 2.1).
The percentage of first-degree relatives (parents, siblings, and offspring) of PiZ index cases in the PiMZ group was 36%, compared with 12% in the PiMM group (p < 0.001). We therefore reanalyzed the data with the PiMZ group divided into two subgroups: (1) first-degree relatives of PiZ index cases; and (2) the remainder of the PiMZ group. The risk of hospital admission for OPD was 3.4 (95% CI: 2.2 to 5.3) in the first group and 1.3 (95% CI: 0.7 to 2.2) in the second group. There was no difference between these subgroups in the risk for smoking-related cancers. A similar analysis of the PiMM group did not reveal any significant difference in hospital admission for OPD.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This longitudinal cohort study of 1,551 PiMZ subjects followed for an average of 7.5 yr showed that subjects heterozygous for 1-AT deficiency were at increased risk of hospital
admission for OPD only if they were first-degree relatives of
PiZ index cases.
The study was based on a nationwide hospital discharge registry, and hence had certain limitations. Evaluation of the registry has shown a correct discharge diagnosis for 75% to 90% of PiMZ subjects, with surgical procedures and cancer being the most accurate discharge diagnoses (21). OPD includes asthma, emphysema, and chronic bronchitis, and it is often difficult to correctly classify a patient as having one of these diseases even in a clinical setting. By lumping all the diagnoses of OPD together, we overcame classification bias to some extent.
Previous studies have analyzed the risk for OPD in PiMZ subjects in three ways (17): (1) case-control studies have estimated the frequency of PiMZ in populations of patients with OPD, and compared this frequency with that in control populations; (2) cohort studies have identified populations of PiMZ subjects, matched them to PiMM subjects, and analyzed differences in lung function; and (3) studies have been done of the incidence of OPD in PiMZ relatives of PiZZ subjects with severe emphysema.
Some case-control studies have estimated the prevalence of PiMZ subjects in OPD populations as being from 1.5 to 4 times the prevalence in the respective control groups (2, 6), whereas other such studies have found no significant difference in the prevalence of PiMZ and PiMM phenotypes in OPD and control populations (5, 7, 8). Although these studies have involved fairly large groups of OPD patients, the prevalences of PiMZ were rather small, which can explain these discrepant findings, as can the inherent problem in case-control studies of recruiting proper control groups.
There are also inconsistencies among the cohort studies conducted so far, with the major problem having been small sample sizes. The largest study was a collaborative study by Bruce and colleagues (10), who failed to show any difference in lung function of 143 PiMZ subjects and matching PiMM subjects. A later study, by Eriksson and coworkers (14), of 32 PiMZ and 31 PiMM subjects, showed that only PiMZ subjects who were smokers had a significantly faster decline in lung function.
The studies of PiMZ relatives of PiZZ subjects have more consistently favored PiMZ as a risk factor for OPD but can be criticized for selecting for other genetic or environmental factors (16, 17, 22, 23).
Rather than comparing our PiMZ subjects with PiMM subjects identified from the population of relatives of PiZZ index cases, we matched our PiMZ subjects with a large group from the general population, and thus increased the statistical power of our study and overcame problems with age and sex as confounders. The drawback of the latter approach is potential bias caused by other, unknown genetic or environmental factors, since the study sample was identified as having been relatives of a PiZZ population, who may be at greater risk for OPD than would a population-based sample. The study showed that there must be other genetic or environmental factors that together with the PiMZ genotype increase the risk for OPD, since only first-degree relatives of index PiZ patients had a significantly increased risk for OPD. In this context, the inconsistent results in previous studies become more comprehensible, because both the case-control and family studies assessed the combined risk for PiMZ phenotype and other unknown factors, whereas the cohort studies assessed the risk for PiMZ alone. The results of the present study are further in accord with our previous studies of index and nonindex PiZ subjects (24, 25), in which we found large differences in lung function impairment and survival.
Another serious confounder that could have hampered the results of our study is smoking habit, of which we had no knowledge. The percentage of smokers in the study population, and particularly among the first-degree relatives of index cases, may have been higher than in the general population, because the subjects were related to PiZZ index cases, of whom 92% were smokers (24). However, the analysis of smoking- related cancers did not show any increased risk in either the first-degree relatives of index cases or in the remaining group, and we assume that there were no major differences in smoking habits that could explain the increased risk of hospital admission for OPD in the PiMZ group. However, the validity of this assumption is uncertain, because the smoking histories of PiMZ and control subjects were not assessed directly.
From a biologic viewpoint, it is reasonable to assume that
smokers of PiMZ phenotype are at increased risk for OPD
from an altered protease-antiprotease imbalance. Ostrow and
associates (26) suggest the possibility of changes in lung elasticity in smokers of PiMZ phenotype, and Tattersall and colleagues (27) found reduced elastic recoil in four of 12 PiMZ
subjects. These changes in the lungs are caused by reduced
1-AT in the blood, and explain why the risk of OPD is further
increased in subjects of PiSZ phenotype and very high but not
absolute in those of PiZZ phenotype (25).
The increased risk of hospital admission for OPD in younger individuals demonstrated in the present study was in eight of nine cases due to asthma. This is rather surprising, since there is no firm evidence for increased childhood asthma in PiZZ subjects, and since the risk was not significantly increased, this finding may have been due to chance. However, Lindmark and associates (28) found a more severe course in asthmatic subjects of either PiMZ or PiSZ phenotype, and Townley and coworkers observed an increased risk for bronchial hyperreactivity in subjects of PiMS and to a lesser degree in those of PiMZ phenotype. Another study, of male subjects aged 48 to 50 yr, failed to demonstrate bronchial hyperractivity in PiMZ subjects (29).
Smoking is the most significant risk factor for OPD, but
only about 20% of smokers develop the disease, and these susceptible individuals could also be genetically predisposed to
OPD. Persons with severe 1-AT deficiency (PiZZ phenotype) are often recognized because they develop emphysema
at an early age, whereas asthmatic individuals and older people with OPD are rarely tested for their 1-AT status. The
only known approach to preventing OPD is abstention from
smoking, and this may justify screening younger persons with OPD for 1-AT deficiency in order to encourage smoking cessation or to prevent young asthmatic individuals from starting
to smoke.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Niels Seersholm, Respiratory Department Y, Gentofte Hospital, Niels Andersens Vej 65, DK-2900 Hellerup, Denmark. E-mail: seersholm{at}dadlnet.dk
(Received in original form December 23, 1998 and in revised form June 22, 1999).
Acknowledgments: Supported by the Danish Lung Foundation.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Seersholm, N., and A. Kok-Jensen. 1998. Intermediate alpha-1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema? Respir. Med. 92: 241-245 [Medline].
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