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1.  IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe α1-Antitrypsin Deficiency 
Severe α1-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV1) and the ratio of FEV1/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV1 ⩽ 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005–0.05) and 3 of 5 SNPs in TNF (P = 0.01–0.05) were associated with FEV1 and/or FEV1/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.
PMCID: PMC2176135  PMID: 17690329
chronic obstructive pulmonary disease; genetic modifiers; interleukin 10; family-based association analysis
2.  Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels 
PLoS Genetics  2013;9(8):e1003585.
Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.
We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.
Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.
Author Summary
Low levels of alpha1-antitrypsin (AAT) in the blood are a well-established risk factor for accelerated loss in lung function and chronic obstructive pulmonary disease. While a few infrequent genetic polymorphisms are known to influence the serum levels of this enzyme, the role of common genetic variants has not been examined so far. The present genome-wide scan for associated variants in approximately 1400 Swiss inhabitants revealed a chromosomal locus containing the functionally established variants of AAT deficiency and variants previously associated with lung function and emphysema. We used dense genotyping of this genetic region in more than 5500 individuals and subsequent conditional analyses to unravel which of these associated variants contribute independently to the phenotype's variability. All associations of common variants could be attributed to the rarer functionally established variants, a result which was then replicated in an independent population-based Danish cohort. Hence, this locus represents a textbook example of how a large part of a trait's heritability can be hidden in infrequent genetic polymorphisms. The attempt to transfer these results to lung function furthermore suggests that effects of common variants in this genetic region in ever-smokers may also be explained by rarer variants, but only in individuals with hampered pulmonary health.
PMCID: PMC3749935  PMID: 23990791
3.  Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency 
Respiratory Research  2012;13(1):16.
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).
We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.
The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD.
Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.
IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.
PMCID: PMC3306733  PMID: 22356581
CHRNA3; Chronic obstructive pulmonary disease; Genetic association analysis; Genetic modifiers; IREB2
4.  Plasma levels of alpha1-antichymotrypsin and secretory leukocyte proteinase inhibitor in healthy and chronic obstructive pulmonary disease (COPD) subjects with and without severe α1-antitrypsin deficiency 
Individuals with severe Z α1-antitrypsin (AAT) deficiency have a considerably increased risk of developing chronic obstructive lung disease (COPD). It has been hypothesized that compensatory increases in levels of other protease inhibitors mitigate the effects of this AAT deficiency. We analysed plasma levels of AAT, α1-antichymotrypsin (ACT) and secretory leukocyte protease inhibitor (SLPI) in healthy (asymptomatic) and COPD subjects with and without AAT deficiency.
Studied groups included: 71 asymptomatic AAT-deficient subjects (ZZ, n = 48 and SZ, n = 23, age 31 ± 0.5) identified during Swedish neonatal screening for AAT deficiency between 1972 and 1974; age-matched controls (MM, n = 57, age 30.7 ± 0.6); older asymptomatic ZZ (n = 10); healthy MM (n = 20, age 53 ± 9.6); and COPD patients (ZZ, n = 10, age 47.4 ± 11 and MM, n = 10, age 59.4 ± 6.7). Plasma levels of SLPI, AAT and ACT were analysed using ELISA and immunoelectrophoresis.
No significant difference was found in plasma ACT and SLPI levels between the healthy MM and the ZZ or SZ subjects in the studied groups. Independent of the genetic variant, subjects with COPD (n = 19) had elevated plasma levels of SLPI and ACT relative to controls (n = 153) (49.5 ± 7.2 vs 40.7 ± 9.1 ng/ml, p < 0.001 and 0.52 ± 0.19 vs 0.40 ± 0.1 mg/ml, p < 0.05, respectively).
Our findings show that plasma levels of ACT and SLPI are not elevated in subjects with genetic AAT deficiency compared MM controls and do not appear to compensate for the deficiency of plasma AAT.
PMCID: PMC1800898  PMID: 17261175
5.  Circulating monocytes from healthy individuals and COPD patients 
Respiratory Research  2003;4(1):11.
Chronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of α1-antitrypsin (AAT), an inhibitor of serine proteases.
We investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency.
After 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patient's monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFα (by 2.3-fold, p < 0.03).
The basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.
PMCID: PMC239032  PMID: 14624669
6.  Circulating alpha1-antitrypsin in the general population: Determinants and association with lung function 
Respiratory Research  2008;9(1):35.
Severe alpha1-antitrypsin (AAT) deficiency associated with low AAT blood concentrations is an established genetic COPD risk factor. Less is known about the respiratory health impact of variation in AAT serum concentrations in the general population. We cross-sectionally investigated correlates of circulating AAT concentrations and its association with FEV1.
In 5187 adults (2669 females) with high-sensitive c-reactive protein (CRP) levels ≤ 10 mg/l from the population-based Swiss SAPALDIA cohort, blood was collected at the time of follow-up examination for measuring serum AAT and CRP.
Female gender, hormone intake, systolic blood pressure, age in men and in postmenopausal women, as well as active and passive smoking were positively, whereas alcohol intake and BMI inversely correlated with serum AAT levels, independent of CRP adjustment. We observed an inverse association of AAT with FEV1 in the total study population (p < 0.001), that disappeared after adjustment for CRP (p = 0.28). In addition, the AAT and FEV1 association was modified by gender, menopausal status in women, and smoking.
The results of this population-based study reflect a complex interrelationship between tobacco exposure, gender related factors, circulating AAT, systemic inflammatory status and lung function.
PMCID: PMC2413219  PMID: 18439253
7.  Genes and COPD 
The marked variability in individual susceptibility to the detrimental effects of smoking on lung function and findings suggest a significant genetic contribution to COPD, which has been demonstrated in several studies. The only known genetic risk factor for COPD, severe alpha 1 antitrypsin (AAT) deficiency, explains only 1–2% of cases of this disease. Screening for severe AAT should be conducted in all cases of COPD. Intravenous augmentation therapy should be combined with currently recommended treatment modalities for COPD when treating patients with COPD due to severe AAT deficiency. There is considerable interest in identifying susceptibility genes for COPD unrelated to severe AAT deficiency, as this could greatly enhance current efforts to prevent, diagnose and treat this disease by yielding novel insights into its pathogenesis. Genome-wide association studies (GWAS) of COPD and its intermediate phenotypes (e.g., lung function measures) have identified novel susceptibility loci for COPD. Some of these susceptibility loci may also influence lung function in the general population (e.g., HHIP and FAM13A), while others may affect not only COPD but other diseases related to smoking behavior (e.g., CHRNA3/CHRNA5). Although much work remains to be done, recent advances and the implementation of novel approaches to study COPD genetics (e.g., sequencing) and epigenetics are promising, and could have a profound impact on COPD management.
PMCID: PMC3399759  PMID: 22793939
COPD; genetics; alpha 1 antitrypsin deficiency
8.  Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency. 
Environmental Health Perspectives  2003;111(14):1749-1752.
Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.
PMCID: PMC1241718  PMID: 14594626
9.  SERPINA1 PiZ and PiS Heterozygotes and Lung Function Decline in the SAPALDIA Cohort 
PLoS ONE  2012;7(8):e42728.
Severe alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study.
Methodology and Principal Findings
The SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p = 0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio.
We suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation.
PMCID: PMC3418297  PMID: 22912729
10.  Relationship between frequency, length, and treatment outcome of exacerbations to baseline lung function and lung density in alpha-1 antitrypsin-deficient COPD 
Diary cards are useful for analyzing exacerbations in chronic obstructive pulmonary disease (COPD), although factors influencing the length and frequency of each episode are poorly understood. This study investigated factors that influence the features of exacerbations in patients with alpha-1 antitrypsin (AAT) deficiency (PiZ phenotype) and COPD.
Daily diary cards were collected over 2 years. Patients had emphysema visualized and quantified by computed tomography scan, and had at least one documented exacerbation in the previous year.
The patients (n = 23) had a mean age of 52.5 years, forced expiratory volume in one second (FEV1) of 1.2 L (38.4% predicted), corrected gas transfer (KCO) of 0.90 mmol/min/kPa/L (59.7% predicted), and 15th percentile lung density of 44.55 g/L. Two hundred and sixty-three exacerbations (164 treated) were identified. The frequency of treated exacerbations correlated negatively with KCO% predicted (r = −0.432; P = 0.022). Exacerbation length (determined for 17 of the patients for whom diary card data through the episode were available) correlated negatively with baseline 15th percentile lung density (r = −0.361; P = 0.003), and increased the longer treatment was delayed (r = 0.503; P < 0.001). Treatment delay was shorter with higher day 1 symptom score, lower baseline FEV1, FEV1/forced vital capacity, and lower 15th percentile lung density (r = −0.368, 0.272, 0.461, and 0.786; P = 0.004, 0.036, <0.001, and <0.001, respectively). Time to resolution of exacerbation after treatment initiation was not affected by treatment delay, but correlated negatively with KCO% predicted (r = −0.647; P = 0.007).
In alpha-1 antitrypsin deficiency, the frequency and length of resolution of exacerbation were related to baseline gas transfer. Treatment delay adversely affected exacerbation length, and lung density was the best independent predictor of delay in starting treatment.
PMCID: PMC3514009  PMID: 23226015
alpha-1 antitrypsin deficiency; antibiotic; exacerbation; gas transfer; lung density; lung function
11.  A novel alpha1-antitrypsin null variant (PiQ0Milano) 
World Journal of Hepatology  2013;5(8):458-461.
Alpha1-antitrypsin deficiency is an autosomal recessive disease characterized by reduced serum levels of alpha1-antitrypsin (AAT) due to mutations in the SERPINA1 gene causing early onset pulmonary emphysema and, occasionally, chronic liver disease. We report an incidental finding of a novel null AAT allele, Q0Milano, consisting of a 17 nucleotides deletion in exon 3 of SERPINA1 gene, in an Italian child with persistently increased liver enzymes, a mild decrease in circulating AAT levels and without any pulmonary disease. Q0Milano variant results in an unfunctional protein lacking of AAT active site, as the resultant protein is truncated near PiS locus involved in AAT protein stability.
PMCID: PMC3767846  PMID: 24023986
Alpha1-antitrypsin deficiency; Rare variant; Alpha1-antitrypsin null mutation; Liver disease
12.  Wood Smoke Exposure and Gene Promoter Methylation Are Associated with Increased Risk for COPD in Smokers 
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
PMCID: PMC3001253  PMID: 20595226
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA
13.  Development of Predictive Models for Airflow Obstruction in Alpha-1-Antitrypsin Deficiency 
American Journal of Epidemiology  2009;170(8):1005-1013.
Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV1 and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV1 explained 50% of the variance in FEV1, and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).
PMCID: PMC2765363  PMID: 19726494
alpha-1-antitrypsin deficiency; genetics; polymorphism, single nucleotide; pulmonary disease, chronic obstructive
14.  Effect of age and occupational exposure to airway irritants on lung function in non-smoking individuals with alpha 1-antitrypsin deficiency (PiZZ) 
Thorax  1997;52(3):244-248.
BACKGROUND: Severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is associated with an increased risk of lung emphysema, especially in smokers. The aim of this study was to identify risk factors other than smoking for declining lung function. METHODS: Lung function was studied in 225 self-reported never-smoking PiZZ individuals included in the Swedish AAT deficiency register. RESULTS: Lung function was poorer in men than in women (mean (SD) forced expiratory volume in one second (FEV1) 80 (30) versus 88 (17)% predicted) despite the fact that the men were younger (mean (SD) age 45 (18) versus 51 (17) years), and poorer in those aged 50 or older than in those aged under 50 (mean (SD) FEV1 70 (30) versus 98 (16)% predicted). Self-reported occupational exposure to gas, fumes, or dust occurred more frequently in men than in women. In those aged 50 or older lung function was lower in individuals exposed to airway irritants than those who were not exposed (mean (SD) FEV1 63 (29) versus 76 (31)% predicted). Male sex, increasing age, and previous symptoms of wheezing were independent risk factors for lung function impairment, and male sex, wheeziness, and occupational exposure to airway irritants were independent risk factors in the subjects aged 50 years or more. CONCLUSIONS: In non-smoking PiZZ individuals lung function declines with increasing age, especially after 50. Men are at greater risk of lung function deterioration than women. Asthmatic symptoms and occupational exposure to airway irritants appear to constitute additional risk factors. 

PMCID: PMC1758519  PMID: 9093340
15.  Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a meta-analysis 
Thorax  2004;59(10):843-849.
Background: Severe α1-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial.
Methods: A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV1) in heterozygotes.
Results: In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV1 as a continuous outcome there was no difference in mean FEV1 between PI MM and PI MZ individuals.
Conclusions: Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.
PMCID: PMC1746834  PMID: 15454649
16.  Is an integrative laboratory algorithm more effective in detecting alpha-1-antitrypsin deficiency in patients with premature chronic obstructive pulmonary disease than AAT concentration based screening approach? 
Biochemia Medica  2014;24(2):293-298.
Alpha-1-antitrypsin deficiency (AATD), genetic risk factor for premature chronic obstructive pulmonary disease (COPD), often remains undetected. The aim of our study was to analyse the effectiveness of an integrative laboratory algorithm for AATD detection in patients diagnosed with COPD by the age of 45 years, in comparison with the screening approach based on AAT concentration measurement alone.
Subjects and methods:
50 unrelated patients (28 males/22 females, age 52 (24–75 years) diagnosed with COPD before the age of 45 years were enrolled. Immunonephelometric assay for alpha-1-antitrypsin (AAT) and PCR-reverse hybridization for Z and S allele were first-line, and isoelectric focusing and DNA sequencing (ABI Prism BigDye) were reflex tests.
AATD associated genotypes were detected in 7 patients (5 ZZ, 1 ZMmalton, 1 ZQ0amersfoort), 10 were heterozygous carriers (8 MZ and 2 MS genotypes) and 33 were without AATD (MM genotype). Carriers and patients without AATD had comparable AAT concentrations (P = 0.125). In majority of participants (48) first line tests were sufficient to analyze AATD presence. In two remaining cases reflex tests identified rare alleles, Mmalton and Q0amersfoort, the later one being reported for the first time in Serbian population. Detection rate did not differ between algorithm and screening both for AATD (P = 0.500) and carriers (P = 0.063).
There is a high prevalence of AATD affected subjects and carriers in a group of patients with premature COPD. The use of integrative laboratory algorithm does not improve the effectiveness of AATD detection in comparison with the screening based on AAT concentration alone.
PMCID: PMC4083581  PMID: 24969923
alpha-1-antitrypsin deficiency; diagnostic techniques and procedures; pulmonary disease, chronic obstructive
17.  Prevalence of α-1-Antitrypsin Gene Mutations in Saudi Arabia 
α-1 antitrypsin (AAT) deficiency results from mutations of the protease inhibitor (PI). The AAT gene is mapped on chromosome 14 and has been associated with chronic liver disease and chronic obstructive pulmonary disease (COPD).
To determine the frequency of AAT mutations on S and Z carrier alleles in healthy Saudi individuals from Qassim Province in Saudi Arabia.
Patients and Methods:
A total of 158 healthy, unrelated participants from Qassim Province were recruited. They were genotyped for the two AAT-deficiency alleles, PI*S and PI*Z, using polymerase chain reaction, with primers designed throughout to mediate site-directed mutagenesis.
Of the 158 subjects, 11.39% were carriers for the S mutation (i.e., had the MS genotype), whereas 2.53% were carriers for the Z mutation (i.e., had the MZ genotype). The SZ genotype was present in 3.8% of subjects, while the homozygous genotype SS was present in 1.9% of subjects. No subjects showed the ZZ mutant genotype. Accordingly, frequency of the mutant S and Z alleles of AAT gene was 9.49% and 3.19%, respectively.
The results obtained showed a high prevalence of the AAT deficiency allele in the Saudi population. This probably warrants adoption of a screening program for at-risk individuals, so that they might initiate adequate prophylactic measures.
PMCID: PMC3133983  PMID: 21727732
α-1 antitrypsin; Saudi Arabia; S allele; Z allele
18.  Identification of Clinical Phenotypes Using Cluster Analyses in COPD Patients with Multiple Comorbidities 
BioMed Research International  2014;2014:420134.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies.
PMCID: PMC3934315  PMID: 24683548
19.  Alpha-1 antitrypsin gene polymorphism in Chronic Obstructive Pulmonary Disease (COPD) 
Genetics and Molecular Biology  2010;33(1):23-26.
Alpha-1-antitrypsin (AAT) plays an important role in the pathogenesis of emphysema, the pathological lesion underlying the majority of the manifestations of Chronic Obstructive Pulmonary Disease (COPD). In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val), PiM2 (Arg101His), PiM3 (Glu376Asp), PiS (Glu264Val) and PiZ (Glu342Lys) SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3) and the emphysematous type of COPD. In addition, FEV1 annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms.
PMCID: PMC3036098  PMID: 21637600
alpha-1 antitrypsin; SERPINA1 polymorphisms; COPD; emphysema; lung function
20.  Environmental correlates of impaired lung function in non-smokers with severe α1-antitrypsin deficiency (PiZZ) 
Thorax  1998;53(11):939-943.
BACKGROUND—Active smoking is the most important risk factor for pulmonary emphysema in subjects with severe α1-antitrypsin (AAT) deficiency. The aim of this study was to analyse the effects of environmental risk factors other than active smoking on lung function and on respiratory symptoms in non-smoking PiZZ individuals.
METHODS—Lifetime exposure to passive smoking, domiciliary use of a kerosene (paraffin) heater or gas cooker, and all occupations since leaving school were reported by 205 non-smoking PiZZ individuals (95 men and 110 women) included in the Swedish AAT deficiency register. Lung function test results and histories of respiratory symptoms (chronic bronchitis, recurrent wheezing, and exertional dyspnoea) were elicited from the AAT register records.
RESULTS—After adjustment for age, agricultural employment and domiciliary kerosene heater usage, but not gas cooker usage or passive smoking, were both associated with significantly decreased lung function. Multiple linear regression analysis showed age, sex, kerosene heater usage, and agricultural employment to be independent determinants of lung function impairment. Age and passive smoking for 10 years or more, both at home and at the work place, were associated with the presence of chronic bronchitis. Age and agricultural employment for ⩾10 years were associated with recurrent wheezing and exertional dyspnoea.
CONCLUSIONS—Domiciliary kerosene heater usage and an agricultural occupation therefore appear to be environmental factors associated with decreased lung function in non-smoking PiZZ individuals, and passive smoking is associated with an increased frequency of chronic bronchitis, but not with impaired lung function.

PMCID: PMC1745103  PMID: 10193391
21.  Prolastin, a pharmaceutical preparation of purified human α1-antitrypsin, blocks endotoxin-mediated cytokine release 
Respiratory Research  2005;6(1):12.
α1-antitrypsin (AAT) serves primarily as an inhibitor of the elastin degrading proteases, neutrophil elastase and proteinase 3. There is ample clinical evidence that inherited severe AAT deficiency predisposes to chronic obstructive pulmonary disease. Augmentation therapy for AAT deficiency has been available for many years, but to date no sufficient data exist to demonstrate its efficacy. There is increasing evidence that AAT is able to exert effects other than protease inhibition. We investigated whether Prolastin, a preparation of purified pooled human AAT used for augmentation therapy, exhibits anti-bacterial effects.
Human monocytes and neutrophils were isolated from buffy coats or whole peripheral blood by the Ficoll-Hypaque procedure. Cells were stimulated with lipopolysaccharide (LPS) or zymosan, either alone or in combination with Prolastin, native AAT or polymerised AAT for 18 h, and analysed to determine the release of TNFα, IL-1β and IL-8. At 2-week intervals, seven subjects were submitted to a nasal challenge with sterile saline, LPS (25 μg) and LPS-Prolastin combination. The concentration of IL-8 was analysed in nasal lavages performed before, and 2, 6 and 24 h after the challenge.
In vitro, Prolastin showed a concentration-dependent (0.5 to 16 mg/ml) inhibition of endotoxin-stimulated TNFα and IL-1β release from monocytes and IL-8 release from neutrophils. At 8 and 16 mg/ml the inhibitory effects of Prolastin appeared to be maximal for neutrophil IL-8 release (5.3-fold, p < 0.001 compared to zymosan treated cells) and monocyte TNFα and IL-1β release (10.7- and 7.3-fold, p < 0.001, respectively, compared to LPS treated cells). Furthermore, Prolastin (2.5 mg per nostril) significantly inhibited nasal IL-8 release in response to pure LPS challenge.
Our data demonstrate for the first time that Prolastin inhibits bacterial endotoxin-induced pro-inflammatory responses in vitro and in vivo, and provide scientific bases to explore new Prolastin-based therapies for individuals with inherited AAT deficiency, but also for other clinical conditions.
PMCID: PMC549028  PMID: 15683545
α1- antitrypsin; Prolastin; monocytes; neutrophils; inflammation; endotoxin
22.  Postoperative outcome after coronary artery bypass grafting in chronic obstructive pulmonary disease 
It is uncertain if the presence and severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is predictive of surgical morbidity and mortality after coronary artery bypass grafting (CABG).
Retrospective study of patients who underwent CABG between 1998 and 2003 in a university-affiliated hospital for whom a preoperative spirometry was available. COPD was diagnosed in smokers or ex-smokers 50 years of age or older in the presence of irreversible airflow obstruction. Patients were divided into three groups depending on the spirometry: controls (forced expiratory volume in 1 s [FEV1] 80% or more, FEV1/forced vital capacity [FVC] greater than 0.7), mild to moderate COPD (FEV1 50% or more and FEV1/FVC 0.7 or less) and severe COPD (FEV1 less than 50% and FEV1/FVC 0.7 or less).
Among the 411 files studied, 322 (249 men, 68±8 years of age) were retained (controls, n=101; mild to moderate COPD, n=153; severe COPD, n=68). The mortality rate (3.0%, 2.6% and 0%, respectively) was comparable among the three groups. Patients with severe COPD had a slightly longer hospital stay than controls (mean difference 0.7±1.4 days, P<0.05). Pulmonary infections were more frequent in severe COPD (26.5%) compared with mild to moderate COPD (12.4%) and controls (12.9%), P<0.05. Atrial fibrillation tended to be more frequent in severe COPD than in the other two groups.
Mortality rate associated with CABG surgery is not influenced by the presence and severity of airflow obstruction in patients with COPD. The incidence of pulmonary infections and length of hospital stay were increased in patients with severe COPD.
PMCID: PMC2690441  PMID: 17315054
COPD; Coronary artery bypass; Heart surgery; Postoperative complications
23.  Autophagy master regulator TFEB induces clearance of toxic SERPINA1/α-1-antitrypsin polymers 
Autophagy  2013;9(7):1094-1096.
Deficiency of SERPINA1/AAT [serpin peptidase inhibitor, clade A (α-1 antiproteinase, antitrypsin), member 1/α 1-antitrypsin] results in polymerization and aggregation of mutant SERPINA1 molecules in the endoplasmic reticulum of hepatocytes, triggering liver injury. SERPINA1 deficiency is the most common genetic cause of hepatic disease in children and is frequently responsible for chronic liver disease in adults. Liver transplantation is currently the only available treatment for the severe form of the disease. We found that liver-directed gene transfer of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, results in marked reduction of toxic mutant SERPINA1 polymer, apoptosis and fibrosis in the liver of a mouse model of SERPINA1 deficiency. TFEB-mediated correction of hepatic disease is dependent upon increased degradation of SERPINA1 polymer in autolysosomes and decreased expression of SERPINA1 monomer. In conclusion, TFEB gene transfer is a novel strategy for treatment of liver disease in SERPINA1 deficiency. Moreover, this study suggests that TFEB-mediated cellular clearance may have broad applications for therapy of human disorders due to intracellular accumulation of toxic proteins.
PMCID: PMC3722318  PMID: 23584152
TFEB; autophagy; gene transfer; lysosome; α-1-antitrypsin deficiency
24.  Krüppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency 
Chronic obstructive pulmonary disease (COPD) is influenced by environmental and genetic factors. An important fraction of COPD cases harbor a major genetic determinant, inherited ZZ (Glu342Lys) α1-antitrypsin deficiency (AATD). A study was undertaken to investigate gene expression patterns in end-stage COPD lungs from patients with and without AATD.
Explanted lungs of end-stage ZZ AATD-related (treated and non-treated with AAT augmentation therapy) and “normal” MM COPD, and liver biopsies from patients suffering from liver cirrhosis with and without ZZ AATD were used for gene expression analysis by Affymetrix microarrays or RT-PCR.
A total of 162 genes were found to be differentially expressed (p-value ≤ 0.05 and |FC| ≥ 2) between MM and ZZ COPD patients. Of those, 134 gene sets were up-regulated and 28 were down-regulated in ZZ relative to MM lung tissue. A subgroup of genes, zinc finger protein 165, snail homolog 1 (Drosophila) (SNAI1), and Krüppel-like transcription factors (KLFs) 4 (gut), 9 and 10, perfectly segregated ZZ and MM COPD patients. The higher expression of KLF 9 and KLF10 has been verified in the replication cohort with AATD-related end-stage lung emphysema and liver cirrhosis. Furthermore, higher expression of KLF9, SNAI1 and DEFA1 was found in ZZ COPD lungs without augmentation therapy relative to MM COPD or ZZ COPD with augmentation therapy.
These results reveal the involvement of transcriptional regulators of the zinc-finger family in COPD pathogenesis and provide deeper insight into the pathophysiological mechanisms of COPD with and without AATD.
PMCID: PMC3517304  PMID: 22621770
Alpha 1-antitrypsin; COPD; Gene expression, Krüppel-like zinc finger proteins, Affymetrix gene chips
25.  Real time PCR detection of the PI*Z and PI*S mutations associated with alpha-1 antitrypsin deficiency 
Alpha-1 antitrypsin (A1AT or AAT) is a serine protease inhibitor (PI) which, when present at low levels, can cause chronic obstructive pulmonary disease (COPD) and liver disease in both children and adults. Several mutations within the SERPINA1 gene have been found to cause this deficiency. The most common variants are PI*Z and PI*S, each caused by a single nucleotide polymorphism (SNP). We describe a real time polymerase chain reaction (PCR) assay for the rapid genotyping of these polymorphisms. DNA was extracted from fourteen EDTA-anticoagulated whole blood samples using the Qiagen EZ1 blood extraction kit. SNP genotyping was performed using primer/probe sets purchased from Applied Biosystems. These were evaluated for performance and assay conditions on the Applied Biosystems 7500 FAST System. The genotypes of these samples were compared with their phenotype results from isoelectric focusing assays, which were performed by an independent reference laboratory. In addition, twenty samples that were previously genotyped at another laboratory were obtained for accuracy studies. Thirty-four samples were tested; five genotypes were represented and the assay was able to discriminate these successfully. Only one genotype could not be correlated with its phenotype result, as the phenotype was reported as an “unidentified allele”. All other genotyping results were concordant with previously determined genotypes and phenotypes. We describe a rapid real time PCR assay that is suitable for clinical use in genotyping AAT alleles and which can be used as the initial step in A1AT testing algorithms.
PMCID: PMC2780033  PMID: 19956452
Real-time PCR; alpha-1 antitrypsin; molecular diagnostics; serine protease inhibitor; chronic obstructive pulmonary disease (COPD); single nucleotide polymorphism (SNP); genotyping

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