Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates

STUDY OBJECTIVE: To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN: Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING: Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS: Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS and MAIN RESULTS: Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS: Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.     

Study of alpha1-antitrypsin phenotypes frequencies in patients with primary antibody deficiency

Primary antibody deficiencies are the most frequent primary immunodeficiency disorders. Bronchiectasis as a feature of these disorders may be developed due to some factors such alpha-1- antitrypsin deficiency. In order to determine the prevalence of two common alpha-1-antitrypsin deficiency alleles (PI*Z and PI*S) in Iranian patients with antibody deficiency, this study was performed. The prevalence of PI*M, PI*S, and PI*Z allele combinations was determined in 40 patients with primary antibody deficiency (with and without bronchiectasis) and compared with 60 healthy control subjects. Phenotyping was performed by isoelectric focusing. The phenotype frequencies among patients were as follow: M in 92.5%, S in 2.5% and Z in 5%. There was not any significant difference in distribution of alleles or phenotypes between patients and control subjects. Moreover, no significant difference was found between patients with and without bronchiectasis. We did not find evidence to support an association between alpha-1-antitrypsin phenotypes and primary antibody deficiencies in a small, controlled study. Larger studies will be required to clarify the relationship between alpha-1-antitrypsin genotype and susceptibility to bronchiectasis in patients with antibody deficiency.     

Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease

BACKGROUND: Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. OBJECTIVE: The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. PATIENTS AND METHODS: Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genome through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq-1 (Z allele). RESULTS: Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. CONCLUSION: These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.     

Intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease in Yugoslavia.

As part of a larger investigation of factors associated with chronic obstructive pulmonary disease among Yugoslavian men, an attempt was made to measure the role played by alpha1-antitrypsin deficiency in the causation of those diseases. Almost 3,000 men from Tuzla, an industrial and mining center in central Bosnia, were screened for alpha1-antitrypsin deficiency. Twenty-six men heterozygous for the Pi MZ phenotype were found in this population. The men with the Pi MZ phenotype were compared with a random sample from the total population. The analysis of the data showed that there is an apparent physiologic impairment associated with Pi Z heterozygosity that produces a shift in the relationships between the different lung volumes without over-all hyperinflation, namely, an increase in residual volume at the expense of vital capacity. However, because of the low prevalence of the Pi Z gene, it does not appear to account for much of the high rate of chronic obstructive pulmonary disease found in this population.     

Chronic obstructive pulmonary disease, with and without alpha-1-antitrypsin deficiency: management practices in the U.K.

Alpha-1-antitrypsin deficiency is a common genetic defect associated with the development of severe and rapidly progressive lung disease. This study was undertaken to determine whether respiratory physicians manage patients with alpha-1-antitrypsin (AAT) deficiency differently from patients with chronic obstructive pulmonary disease (COPD) without alpha-1-antitrypsin deficiency. In addition we obtained physicians' views on who should be tested for AAT deficiency. A questionnaire was administered to 88 respiratory physicians based throughout the U.K. (44 in teaching hospitals). The main outcome measures were pulmonary function tests, radiological assessment, frequency of repeat testing, follow-up and screening protocol for alpha-1-antitrypsin deficiency. Subjects with homozygous (PiZ) AAT deficiency were more likely to: 1. have baseline and full pulmonary function testing including dynamic flow rates, static lung volumes, and gas transfer; 2. have more comprehensive assessment with high resolution computed tomography (HRCT) thorax and repeated radiological assessment (with annual chest radiography); 3. be followed-up routinely; and 4. have family members tested for alpha-1-antitrypsin deficiency. Testing remains limited for AAT deficiency and is mainly restricted to young patients with COPD. COPD assessment and management is influenced by the presence of AAT deficiency, which may reflect the poorer prognosis of such patients due to more rapid decline. Assessment and monitoring could be simplified to forced expired manoeuvres, although limited HRCT thorax and tests of gas transfer may prove more sensitive to progression of emphysema. Testing for AAT deficiency in the U.K. remains restricted, which will influence the detection rate for AAT deficiency. A wider policy of testing was advocated by the WHO will detect more patients and also influence our understanding of the natural history of the condition.     

Emphysema of early onset associated with a complete deficiency of alpha-1-antitrypsin (null homozygotes)

We have compared lung function in 3 subjects with no alpha 1-antitrypsin (alpha 1-protease inhibitor) (null homozygotes) with subjects having the typical deficiency, PIZZ. We identified a 31-yr-old woman, presenting with severe obstructive lung disease, who had no detectable plasma alpha 1-antitrypsin, indicating homozygosity for a "null" (or PI*QO) allele of alpha 1-antitrypsin. Two of her sisters have a similar deficiency, one with an onset of symptoms at 17 yr of age. Because of the likelihood that there are a number of different PI*QO alleles, the type in this family has been named null Mattawa (QOmattawa). All 3 homozygotes have shown a marked deterioration of lung function over a 7-yr period of follow-up. In contrast, lung function tests of 6 age-matched nonsmoking subjects with alpha 1-antitrypsin deficiency, PI type ZZ, showed no abnormalities of lung function. The 15 to 20% of the normal plasma concentration of alpha 1-antitrypsin associated with the PI*Z allele appears to provide some protection to the lung in comparison with a complete deficiency state.     

Clinical, epidemiologic, and pulmonary function studies in alpha,-antitrypsin-deficient subjects of Pi Z type.

The results of pulmonary function testing and systematic medical history and epidemiologic data collection are reported for 20 persons with alpha 1-antitrypsin deficiency of Pi Z phenotype. The most common symptom, reported in 19 subjects (95 per cent), was dyspnea on exertion; 16 subjects (80 per cent) gave a history of wheezing, and 8 (40 percent) reported chronic cough and sputum production. The 8 women who had been pregnant reported a miscarriage rate of 29 per cent for all pregnancies. Respiratory symptoms and disease were commonly reported in the children of study subjects. Pulmonary function testing revealed abnormalities for 18 of 20 subjects, all of those 26 or more years of age. The test that was most frequently abnormal was the 1-sec forced expiratory volume expressed as a per cent of the forced vital capacity. All pulmonary function studies demonstrated a trend toward increased impairment with increased age, which was evident by the fourth decade. Within this group of persons having severe alpha1-antitrypsin deficiency, there was no correlation between serum concentrations of antitrypsin and subjective or objective indices of pulmonary disease. A group of 7 subjects who were incidentally found to have Pi Z alpha1-antitrypsin deficiency exhibited symptoms and pulmonary function abnormalities comparable to those of 13 subjects who were originally referred for known or suspected pulmonary disease. These data suggest that if interventions such as smoking cessation and occupational counseling are to be effective, they should be initiated before the fourth decade of life.     

Alpha-1-antitrypsin replacement therapy: current status

PURPOSE OF REVIEW: Alpha-1-antitrypsin deficiency is a relatively common genetic disease that predisposes to the development of early-onset emphysema and, in some instances, liver disease. The use of alpha-1-antitrypsin replacement therapy in the treatment of alpha-1-antitrypsin deficiency related emphysema is much debated and the purpose of this review is to examine the results of recent studies. We will comment briefly on the pathogenesis and epidemiology of the disease together with new therapeutic approaches currently under intense research. RECENT FINDINGS: Several nonrandomized observational studies and one meta-analysis on the clinical effectiveness of alpha-1-antitrypsin replacement treatment showed a favourable result towards reducing forced expiratory volume in 1 s (FEV1) deterioration in alpha-1-antitrypsin-deficient individuals with moderate lung disease or accelerated FEV1 decline. Improved ways of monitoring disease progression, including computed tomography scanning and exacerbations, are being proposed as primary endpoints. Apart from one small randomized, placebo-controlled trial using computed tomography scanning, which showed a trend toward preservation of lung density on scanning with treatment, the literature lacks proof of effectiveness from large randomized trials. SUMMARY: There might be a possible, but so far unproven, role of alpha-1-antitrypsin augmentation therapy in reducing the progression of emphysema in subsets of patients with alpha-1-antitrypsin deficiency. Placebo-controlled, randomized clinical trials are required to draw firm conclusions. Recent advances in the understanding of the molecular pathology provide opportunities for development of new therapeutic targets for this genetic disorder.     

Urinary excretion of desmosine (elastin cross-links) in subjects with PiZZ alpha-1-antitrypsin deficiency, a phenotype associated with hereditary predisposition to pulmonary emphysema

To evaluate the concept that lung elastin degradation is accelerated in homozygous alpha-1-antitrypsin (AAT) deficient persons, we prepared acid hydrolysates of urine and used a radioimmunoassay for desmosine to measure urine concentrations of this elastin-specific cross-link in such persons and in control subjects. Excretion of desmosine in 17 homozygous AAT-deficient (PiZZ) patients with emphysema was compared with that in 27 patients with interstitial lung diseases (16 sarcoid, 5 idiopathic pulmonary fibrosis, 6 other interstitial lung diseases) and 26 healthy subjects. Both smokers and nonsmokers were present in all groups. Urinary desmosine concentration (microgram/100 mg creatinine) was 2.35 +/- 0.93 in the PiZZ patients, 2.49 +/- 1.01 in those with interstitial lung disease, and 2.05 +/- 0.54 in the healthy control subjects (p greater than 0.1, all comparisons). Because abnormal pulmonary elastolysis may be largely completed before symptoms of emphysema develop in AAT-deficient persons, we also tested 6 asymptomatic adults with homozygous AAT deficiency (PiZZ) and 5 PiZZ children. Urine desmosine (microgram/100 mg creatinine) was not significantly elevated in either group compared with that in the age-matched control subjects, although children (PiZZ and age-matched controls) showed higher excretions than did adults (6 asymptomatic PiZZ adults, 2.60 +/- 0.91; 5 PiZZ children, 3.27 +/- 0.62; 10 control children, 3.61 +/- 0.62). These data suggest that pathologic lung elastolysis in the PiZZ subject may constitute too small a fraction of total-body elastin turnover to be detected by this method.(ABSTRACT TRUNCATED AT 250 WORDS)     

alpha-1-antitrypsin deficiency in liver disease: the extent of the problem.

A prospective screening program was undertaken at the Royal Free Hospital, London, to ascertain the incidence of alpha-1-antitrypsin (AAT) deficiency in patients with liver disease. Quantitative determinations of serum alpha-1-antitrypsin were performed on 469 patients with hepatobiliary disease and 98 subjects with no known liver disease. Sera with low values of AAT were phenotyped. The homozygous state was rare and comprised only 1% of the patients with liver disease. All of the 5 homozygous deficient (ZZ phenotype) patients had a history of neonatal liver disease. Other phenotypes (partial deficiency) were found in 4.7% of patients with liver disease and 6.1% of subjects with normal liver function. Types of liver disease in the patients with other phenotypes were widely varied. Routine determination of serum AAT level and phenotype and special staining for AAT in liver biopsies in all adults with liver disease appears unnecessary. Investigation of possible AAT deficiency should be carried out, however, in children and young adults, in those with a history of neonatal liver disease, and possibly in all patients with liver disease of unknown aetiology.     

Study of familial alpha-1-proteinase inhibitor deficiency including a rare proteinase inhibitor phenotype (IZ). I. Alpha-1-phenotyping and clinical investigations

Proteinase inhibitor (PI) phenotyping and clinical investigations were performed on 20 persons in three generations of a family with alpha 1-antitrypsin deficiency. Two persons were homozygotes and 9 were heterozygotes for the Z allele; one is the first reported IZ phenotype; 11 were common M-types. Both homozygotes and 5 of the heterozygotes, including the IZ individual, had suffered from recurring or chronic respiratory diseases. However, only mild to moderate impairment in lung function tests was observed in some of these patients (DLCO steady state, 3 subjects; FEV1, 3 subjects; FEF25-75, 2 subject; elevation of RV, 2 subjects). The rare IZ type, a 35-year-old female, smoker, showed normal lung function except for an elevated RV. Our results indicate that PI deficiency is not necessarily associated with severe lung destruction if noxious inhalants are absent.     

Pulmonary function in heterozygotes for alpha,-antitrypsin deficiency: a case-control study.

In this paper we present the initial cross-sectional data from a prospective study of lung aging in heterozygotes for alpha 1-antitrypsin deficiency. Using a case-control design, our cases included 37 heterozygotes for alpha 1-antitrypsin deficiency, protease inhibitor phenotypes MZ and MS, selected because they were parents of children with homozygous alpha 1-antitrypsin deficiency identified in a statewide newborn screening program between 1971 and 1974. All of the heterozygotes were less than 40 yr of age. Our control subjects were selected from a random sample of a working population participating in a longitudinal study of lung aging, using a 2:1 match of control subjects to cases, matching age, sex, ethnic origin, and smoking. Using a respiratory symptom questionnaire, spirometry, and the single-breath N2 test, we found no significant difference between heterozygotes and control subjects in terms of respiratory symptoms or pulmonary function data. We conclude that to 40 yr of age, the heterozygous phenotype (Pi MZ and MS) is not a risk factor for impairment of pulmonary function.     

Physiologic characteristics of subjects exhibiting accelerated deterioration of ventilatory function

From a randomly selected community population sample followed with sequential surveys since 1972, 13 subjects who exhibited a mean annual decline in FEV1 greater than 60 ml/yr were drawn for detailed studies of lung function. These subjects had developed clinically significant airway obstruction during this period of follow-up. Clinical evaluation was not successful in characterizing the nature of the disorder. None of the subjects had alpha-1-antitrypsin deficiency. In a small proportion of subjects, elevated total serum immunoglobulin E may have played a role in the obstructive airway disorder. Some subjects exhibited loss of lung elastic recoil and diminished carbon monoxide diffusing capacity suggestive of developing emphysema. Others appeared to have intrinsic airway disease involving large and/or small airways, which may be fixed in some and responsive to bronchodilator in others. Thus, neither the site nor the nature of the disorder inferred from results of physiologic tests was uniform, illustrating the heterogeneous nature of chronic obstructive lung disease.     

A fast amplification-reverse hybridization assay kit to detect the most frequent deficient variants in the alpha-1-antitrypsin gene

BACKGROUND: There is worldwide growing awareness of alpha-1-antitrypsin deficiency (AATD), a major hereditary disorder in Caucasians. The gold standard for its laboratory diagnosis is thin-layer isoelectric focusing, which should be performed in reference laboratories. OBJECTIVES: The aim of this study was to check the characteristics of a commercially available amplification-reverse hybridization assay kit in detecting at a molecular level the alpha-1-antitrypsin (AAT) Z and S variants, i.e. the most frequent variants associated with AATD, by comparing its performance with DNA restriction fragment length polymorphism. METHODS: We studied samples from 36 subjects enrolled in the Italian National Registry for Severe Alpha-1-antitrypsin Deficiency. Based on previous plasma isoelectric focusing typing, we selected samples with the following phenotypes: MM (9 samples), MS (9 samples), SZ (3 samples), MZ (11 samples), ZZ (3 samples), and a rare variant (1 sample). DNA was extracted by the standard method. The presence of the AAT Z and S gene variants was determined by the amplification-reverse hybridization test kit, following the manufacturer's instructions, and by the restriction fragment length polymorphism technique, according to established procedures. RESULTS: We found that the identification of the AAT Z and S gene variants obtained by the amplification-reverse hybridization test kit was completely in agreement with that obtained by the restriction fragment length polymorphism technique. CONCLUSIONS: We conclude that the test kit provides a fast, easy and unambiguous identification of Z and S alleles. Because of its transferability to routine laboratories, the test kit may be useful in identifying cases of severe AATD, thus resulting in increasing awareness of this rare disorder.     

Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of emphysema

Background : Alpha-1-antitrypsin is the body's major inhibitor of human neutrophil elastase, a powerful proteolytic enzyme capable of degrading the common tissue components. There are over 70 genetic variants of alpha-1-antitrypsin, with the Z allele being of greatest clinical relevance. Individuals homozygous for this allele (approximately one in 2500 in Caucasians) have low serum alpha-1-antitrypsin levels (10–20% of normal) and are predisposed to emphysema, especially if they smoke. Much rarer are mutations which result in the complete or almost complete absence of alpha-1-antitrypsin in the serum.
Aim : To determine the cause of complete absence of alpha-1-antitrypsin in a patient who at age 27 years had both emphysema and idiopathic cardiomyopathy.
Methods : Molecular biology techniques were used to sequence the alpha-1-antitrypsin gene. Allele specific amplification was used to show the presence of the mutations in other family members.
Results : Investigation showed that the proband was homozygous for the Pi Null Bellingham variant of alpha-1-antitrypsin due to the mutation Lys 217 (AAG) to Stop (TAG). His grandmother was heterozygous for Pi Null Bellingham and the additional rare variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant that also results in alpha-1-antitrypsin deficiency.
Conclusion : Patients with complete absence of alpha-1-antitrypsin develop premature emphysema not having smoked or after only minimal exposure, and much earlier than the more common Pi Z individuals who have the usual form of alpha-1-antitrypsin deficiency.     

Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration

Background: Alpha-1-antitrypsin deficiency is associated with a high risk for the development of emphysema, particularly for phenotype Pi ZZ, which is both deficient and an abnormal inhibitor of the powerful proteolytic enzyme, human neutrophil elastase. The rare variant P_Lowell is also expressed at abnormally low levels, but its anti-elastase activity has not been described. Aim: To study the anti-elastase activity of alpha-1-antitrypsin P_Lowdl and compare it to the common M, S and Z proteins. Method: Alpha-1-antitrypsin from a female patient aged 75 years with the rare genotype P_LoweU Null_Bcllingham was studied for its ability to inhibit human neutrophil elastase in a time dependent manner. Results: P_Loweii has near normal function as an inhibitor of human neutrophil elastase with an association rate constant of 7.4 X 10⁶ M'V¹ at 25 °C, similar to that of M and S. Conclusion: Alpha-1-antitrypsin P_L is associated with a severe deficiency of alpha-1-antitrypsin similar to Z, but unlike that protein it has near normal function as an anti-elastase.     

Alpha-1-Antitrypsin Deficiency: Current Concepts

Since the condition was first described four decades ago, alpha-1-antitrypsin (A1AT) deficiency has served as a model for other disease processes. A1AT is the archetypal serpin designed to ensnare proteases, a process that involves significant conformational change within the molecule. Mutations in the A1AT gene lead to misfolding of the protein and accumulation within the endoplasmic reticulum of hepatocytes resulting in two different pathologic processes. First, the accumulation of mutant A1AT protein has a directly toxic effect on the liver, resulting in hepatitis and cirrhosis. Second, the resultant decrease in circulating A1AT results in protease-antiprotease imbalance at the lung surface and emphysema ensues. A1AT deficiency therefore can be seen as two distinct disease processes: a conformational disease of the liver and a protease-antiprotease imbalance of the lung. This two-stage model of disease in A1AT deficiency is elegant in its simplicity and goes a long way to explaining the clinical manifestations that occur in patients with the condition. However, some aspects of the disease are not readily explained. Recent findings suggest that there is more to the lung damage in A1AT deficiency than simple proteolytic insult and that the presence of the mutant protein itself is proinflammatory and may indeed cause chronic injury to the cells that produce it. This review discusses some of the emerging concepts in alpha-1-antitrypsin research and outlines the implications these new ideas may have for treatment of this condition.     

Primary hepatic tuberculosis in homozygous alpha-1-antitrypsin deficiency.

The case of a young female patient with homozygous alpha-1-antitrypsin deficiency (Pi-ZZ) associated chronic liver disease, who developed primary hepatic tuberculosis shortly after delivery of a healthy baby girl is reported. These findings emphasize that this rare disease should be considered even in patients with precirrhotic liver disease, while pointing out that the genetically determined deficiency of protease inhibitor alpha-1-antitrypsin (AAT) predisposes to hepatic infection.     

The ultrastructure of hepatocytes in alpha-1-antitrypsin deficiency with the genotype Pi--.

The ultrastructural appearance of the endoplasmic reticulum of the hepatocytes was found to be normal in a 5-year-old girl with alpha-1-antitrypsin deficiency with the genotype Pi--. The liver ultrastructure of this variant is therefore different from that of alpha-1-antitrypsin deficiency with the genotype PiZZ in which aggregates of an abnormal, unsecreted alpha-1-antitrypsin accumulate in the endoplasmic reticulum of the hepatocytes. The normal appearance of the endoplasmic reticulum in alpha-1-antitrypsin deficiency with the genotype Pi-- is compatible with the hypothesis, in this variant, synthesis of alpha-1-antitrypsin is completely, or nearly completely, absent; an alternative hypothesis would be that an abnormal alpha-1-antitrypsin is produced by the liver and secreted into the plasma, but disappears rapidly from the plasma.     

Genetics of chronic obstructive pulmonary disease

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.