Serum Levels Of Alpha-1 Antitrypsin Research Articles

Alpha-1 antitrypsin, a diagnostic and prognostic marker of vernal keratoconjunctivitis.

A major chunk of ocular allergies in humans involve the conjunctiva, of which Vernal Keratoconjunctivitis (VKC) appears to be more common. VKC, a chronic allergic conjunctivitis, frequently affects young males and is characterized by intense inflammation of the limbal and/or tarsal conjunctiva. The etiology and immuno-pathogenesis of VKC still remain unclear. Alpha-1 antitrypsin (AAT), a member of serine proteinase inhibitor (SERPIN) superfamily, is an acute phase protein whose concentration in blood increases in response to inflammation. AAT deficiency is one of the many factors that may be involved in several abnormalities such as liver disease, emphysema, inflammatory joint diseases and inflammatory eye diseases. In the present study, the role played by this protein in VKC was analyzed in a selective case/control study to assess its diagnostic and prognostic value. The case control study included 50 patients of VKC reporting to Ophthalmology out patient department (OPD). Age and sex matched 40 healthy subjects served as control. Serum AAT level of both the cases and controls were evaluated and compared. Moreover the serum AAT levels of the patients at presentation were compared with their serum AAT level after three weeks post treatment. Levels of AAT in the serum of VKC patients at presentation (2.80 ± 0.42 mg/ml) were significantly higher as compared to controls (2.31 ± 0.21 mg/ml) whereas no significant difference was observed between the serum level of post treatment VKC patients (2.48 ± 0.26 mg/ml) and controls. AAT is a potent acute phase protein whose concentration rises significantly in VKC, irrespective of the age and sex of the patient. Moreover, the serum level of AAT declined significantly post treatment; therefore it might be used as a prognostic marker.

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

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.

438. Development of a Myeloid Cell-Binding Adenovirus for the Potential Gene Therapy of Alpha-1 Anti-Trypsin Deficiency

Alpha-1 anti-trypsin (A1AT) deficiency lung disease represents an ideal candidate for definitive gene therapy treatment. As the liver is the major locale for A1AT synthesis, the majority of gene therapy approaches have been directed towards induction of functional wild type A1AT within hepatocytes. Despite the diverse range of gene therapy strategies applied, the levels of serum A1AT achieved have not been sufficient to correct the elastase/anti-elastase balance within the lung. To this end, we hypothesized that in vivo gene delivery to pulmonary endothelium could provide A1AT augmentation of Epithelial Lining Fluid (ELF) more effectively than liver-based transduction methods. To re-target the expression of transgene in the lung, the knob domain of Ad5 has been successfully modified genetically in our lab. We have identified a novel peptide sequence called myeloid binding peptide (MBP) which increases the lung targeting. Based on this we created a recombinant adenovirus expressing A1AT with MBP in the fiber protein (AdMBPA1AT). When we injected this Ad systemically in mice we saw a high expression of the transgene in the serum in comparison to the control Ad expressing A1AT without MBP in the fiber protein. In order to confirm that the AdMBPA1AT localizes to the lung, we analyzed viral copy number using total DNA extracted from the organs of mice by qPCR and the expression of the protein in serum and ELF. Our strategy will test the hypothesis that A1AT deriving from the pulmonary endothelium can augment more effectively ELF A1AT to provide a corrective anti-elastase screen.

A novel alpha1-antitrypsin null variant (PiQ0Milano)

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.

Alpha-1 antitrypsin deficiency in patients with chronic hepatitis

Alpha-1 antitrypsin deficiency causes accumulation of mutant alpha-1 antitrypsin molecules in hepatocytes, and is attributed to severe liver injury even in heterozygous state. However, there is a question as to whether alpha-1 antitrypsin deficiency is only a cause of liver injury or has a worsening effect on the underlying liver disease. We aimed to determine the role of alpha-1 antitrypsin deficiency in the ongoing chronic hepatitic process. Fifty-four patients with the diagnosis of chronic hepatitis by liver biopsy (36 chronic hepatitis B virus, 8 chronic hepatitis C virus, 7 non-alcoholic steatohepatitis, 2 primary biliary cirrhosis, and 1 autoimmune hepatitis) and 51 age- and sex-matched control subjects chosen from among healthy blood donors were included in the study. Isoelectric focusing for identifying alpha-1 antitrypsin phenotypes was performed in all patients and control subjects, whereas the histopathological examination was done only in patients. Alpha-1 antitrypsin-deficient variant was absent in patients and controls. The mean serum alpha-1 antitrypsin level was significantly lower in patients (157.4 ± 33 mg/dl) than controls (134.8 ± 30 mg/dl) (p<0.00). Histological activity index and fibrosis grade in the liver were not related to the serum alpha-1 antitrypsin level (p: 0.276 and 0.902, respectively). Additionally, the serum alpha-1 antitrypsin levels among normal variants of alpha-1 antitrypsin did not differ according to the underlying liver diseases (p: 0.928). This prospective case-control study could not define any additional effect of alpha-1 antitrypsin deficiency on liver histopathology in chronic hepatitis patients.

Identification of Compound Heterozygous Mutation in a Korean Patient with Alpha 1-antitrypsin Deficiency

Alpha 1-antitrypsin (AAT) deficiency is a genetic disorder that primarily affects the lungs and liver. While AAT deficiency is one of the most common genetic disorders in the Caucasian population, it is extremely rare in Asians. Here, we report the case of a 36-year-old Korean woman with AAT deficiency who visited the emergency department of our hospital for the treatment of progressive dyspnea that had begun 10 years ago. She had never smoked. Chest computed tomography revealed panlobular emphysema in both lungs, which suggested AAT deficiency. The serum AAT level was 33 mg/dL (reference interval: 90-200 mg/dL). Four exons of the SERPINA1 gene, which is responsible for AAT deficiency, and their flanking regions were analyzed by PCR-direct sequencing. The patient was found to have 1 missense mutation (c.230C>T, p.Ser77Phe; Siiyama) and 1 frameshift mutation (c.1158dupC, p.Glu387ArgfsX14; QOclayton). This is the first Korean case of AAT deficiency confirmed by genetic analysis and the second case of a compound heterozygote of Siiyama and QOclayton, the first case of which was reported from Japan.

Respiratory function in patients with pemphigus vulgaris - a small clinical study

Pemphigus vulgaris belongs to a group of rare, autoimmune, blistering disorders, requiring intensive immunosuppressive therapy. Lung infections are common in patients with pemphigus vulgaris. To evaluate pulmonary function in patients with pemphigus vulgaris, in order to detect possible factors that might predispose PV patients to lung damage. Ten patients first diagnosed with severe pemphigus vulgaris and 10 healthy individuals,were included in the study. Pulmonary function testing, blood gas analysis and quantification of α1-antitrypsin serum levels were performed. Mild reduction of CO diffusing capacity was recorded, compared to the mean predicted normal value. DLCOSB (single-breath carbon monoxide diffusing capacity test) values did not significantly differ between patients with pemphigus vulgaris and healthy controls, while differences regarding DLCO/VA (VA: Alveolar Volume) were statistically significant. Alpha 1-antitrypsin serum levels were decreased (<2.0g/L) in 60% (6/10) of patients with pemphigus vulgaris and were found normal in none of the healthy controls. A mild reduction of pulmonary diffusing capacity was observed in patients with pemphigus vulgaris.

The ubiquitin ligase Hrd1 promotes degradation of the Z variant alpha 1-antitrypsin and increases its solubility

Alpha 1-antitrypsin (AAT) deficiency is an autosomal recessive disorder that is characterized by the retention of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant decrease in the serum levels of AAT. Previous studies have demonstrated that the ubiquitin-proteasome pathway is involved in the degradation of the Z variant of AAT (ATZ). However, the detailed mechanisms of ATZ degradation are not fully understood. We investigated whether the ER membrane-embedded ubiquitin ligase (E3) Hrd1 promotes the removal of ATZ through ER-associated degradation (ERAD). Our results indicate that Hrd1 decreases intracellular levels of ATZ, especially the detergent-insoluble fraction, in cells transfected with a plasmid-encoding ATZ. The degradation of ATZ was also found to be dependent on the functional E3 activity of Hrd1. In addition, we demonstrated that Hrd1 increases the solubility of ATZ. Cycloheximide (CHX) chase and proteasome inhibition experiments showed that the ubiquitin-proteasome pathway is involved in Hrd1-mediated ATZ degradation. Furthermore, we found that Hrd1 helped to maintain normal morphology of ATZ expressing cells. These data indicate that Hrd1 enhances the removal of ATZ through ERAD and attenuates intracellular ATZ accumulation and toxicity, which implies a potential value for Hrd1 in the treatment of AAT deficiency diseases.

Influence of alpha-1 antitrypsin heterozygosity on treatment efficacy of HCV combination therapy

The role of heterozygosity for alpha-1 antitrypsin (A1AT) alleles in patients with chronic hepatitis C virus (HCV) is unclear. There is limited evidence to suggest that there is an increased prevalence of heterozygous A1AT carriers in HCV, but it is unclear how this affects treatment success. To investigate the (i) prevalence of A1AT heterozygosity among two HCV cohorts and (ii) its effect on treatment outcome. We performed a retrospective cohort study using two different cohorts. Cohort 1 consisted of 678 German HCV patients, 507 of them were treated for HCV with standard therapy. Cohort 2 consisted of 370 Dutch HCV patients of which 252 were part of a clinical trial (treatment with amantadine or placebo, in combination with pegylated interferon alpha-2b and ribavirin) whereas 37 HCV patients received standard therapy. We analyzed A1AT status using direct sequencing of the A1AT gene (cohort 1) or isoelectric focusing of serum (cohort 2). In addition, we measured A1AT serum levels (cohort 2). In total, we included 1048 HCV patients; 986 (94%) were wildtype [protease inhibitor (Pi) MM], whereas 61 (6%) were heterozygous for a mutant A1AT allele (41 Pi MS, 20 Pi MZ). Mean A1AT serum levels (370 patients) were lower in A1AT heterozygous patients (1.68 vs. 1.36 g/l), (P<0.05) compared with wildtypes. Sustained viral response (SVR) after treatment was equal between the wildtypes and heterozygotes (54 vs. 56%). We found a heterozygosity rate of 0.06, in line with healthy controls in other studies. Serum A1AT levels from A1AT heterozygous HCV patients are significantly lower compared with wildtype patients, although they do not discriminate on an individual level. Finally, SVR in A1AT wildtypes was not different from SVR in A1AT heterozygotes.

α1-Antitrypsin Deficiency with Bronchiectasis in Two Sisters

Two sisters with alpha 1-antitrypsin deficiency and bronchiectasis are reported. The 53-year-old older sister (propositus) had pneumonia 3 times during her forties. She developed dyspnea on exertion in February, 1988, and a few months later she was seen at our hospital. Her serum alpha 1-antitrypsin level was 11 mg/dl. Vascular markings on chest X-ray were mildly decreased. Bronchography showed generalized cystic bronchiectasis. The younger sister was seen at our hospital at the age of 50. She had been in good health until one year previously when she had developed pneumonia, and thereafter she had suffered from productive cough and dyspnea on exertion. Her alpha 1-antitrypsin level was 22 mg/dl. Chest X-ray showed ring-like shadows and tram lines. Chest CT scans of both sisters revealed cystic changes, dilatation of bronchi, and the connection of these lesions diffusely. The alpha 1-antitrypsin phenotype of these sisters was found to be PiSiiyama (homozygote). Family study revealed that alpha 1-antitrypsin levels of 7 members were intermediate and no members had symptoms. We consider that bronchiectasis may have been related to alpha 1-antitrypsin deficiency in these sisters.

Effect of a high saturated fatty acids load on serum concentrations of C-reactive protein, alpha1-antitrypsin, fibrinogen and alpha1-acid glycoprotein in obese women

Obesity is associated with increased inflammation. Creactive protein (CRP) and inflammation-sensitive plasma protein (ISPs) are inflammatory markers. Proinflammatory process may be influenced by high saturated fatty acid intake. The aim of the present study was to evaluate the role of saturated fatty acids load on postprandial circulating levels of PCR and ISPs (alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen) in obese women. A total of 15 obese women (age = 31,7 +/- 4,5 years, BMI = 37,9 +/- 7,3 kg/m(2)) and 15 lean controls women (age = 30,6 +/- 4,6 years, BMI = 20,6 +/- 2,6 kg/m(2)) were recruited for this study. After and overnight fast subjects ate the fat load consisted of 75 g of fat (100% saturated fatty acid, 0% cholesterol), 5 g of carbohydrates, and 6 g of protein per m2 body surface area. Postprandial serum levels of CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen were measured. Anthropometry and blood biochemical parameters were measured in both groups. The obese women had fasting serum PCR levels higher (p = 0,013) and fibrinogen (p = 0,04) than those of control women. Serum CRP and fibrinogen levels was positively related to body mass index (BMI) in obese group. There weren't differences in fasting serum alpha1- antitrypsin levels (p = 0,40), and alpha1-acid glucoprotein (p = 0,28) levels in obese group in comparison to lean control group. Serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen did not change postprandially (p = > 0,05 difference to fasting levels). A high-saturated fatty acids load is not associated with serum CRP, alpha1-antitrypsin, alpha1-acid glucoprotein, and fibrinogen levels increase. Serum alpha1-antitripsin and alpha1-acid glucoprotein levels are not increased in obese women. Serum PCR and fibrinogen levels are increased in obese women, and are positively related to BMI.

Low Serum Alpha-Antitrypsin Associated with Anti-PR-3 ANCA in Autistic Children with GI Disease.

To assess the possible relationship between serum alpha-1 antitrypsin (AAT) levels and anti-neutrophil cytoplasmic antibodies (ANCA) in autistic children with severe GI disease and to test the hypothesis that there is an association between low serum AAT levels, the presence of ANCA and inflammatory GI disease seen in some autistic children. Serum from 40 autistic children with chronic digestive disease (many with ileo-colonic lymphoid nodular hyperplasia (LNH) and inflammation of the colorectum, small bowel and/or stomach), and 41 controls (21 age matched autistic children with no GI disease and 20 age matched children without autism or GI disease) were tested using ELISAs designed to quantitate ANCA (anti-PR3), AAT and PR3 levels. We found that a significant number of autistic children with chronic digestive disease had anti-PR3 ANCA, high serum PR3 and high severity of disease when compared to controls. This same group of autistic children had low serum levels of AAT compared to controls, which also correlated with the presence of anti-PR3 ANCA, high serum PR3, as well as the severity of intestinal disease, particularly LNH and severe erythema. These results suggest a relationship between low AAT levels, ANCA and severity of GI disease seen in a subpopulation of ASD individuals. We suggest that low AAT levels may result in high levels of PR3, which may, in turn be associated with the presence of ANCA.

Comparison of Gliclazide Treatment with Diet Therapy on Acute Phase Protein Levels in Patients with Type 2 Diabetes

Aims: It is known that there is a relationship between diabetic complications and chronic inflammation characterized by alterations in circulating acute phase proteins. It has been emphasized that inflammation contributes to diabetic complications and that gliclazide -an antidiabetic sulfonylurea - decreases the development of such complications. In this study, we aimed to investigate whether gliclazide or diet treatment has an effect on serum levels of acute phase reactants, markers of inflammation. Materials and Methods: Fifty-six newly diagnosed patients with type 2 diabetes and 30 clinically healthy subjects were evaluated prospectively. Twenty-six patients were treated with proper diet and daily gliclazide (80 mg/daily) and 30 patients were randomized to only diet therapy for 6 months. After the 6-month therapy, blood was taken from patients and controls and acute phase protein levels were determined. Results: Serum alpha-1 acid glycoprotein, alpha-2 macroglobulin, alpha-1 antitrypsin, and albumin levels did not differ between the gliclazide and control groups. In the diet group, mean serum alpha-1 acid glycoprotein, alpha-2 macroglobulin, and alpha-1 antitrypsin were significantly higher and mean albumin level was significantly lower than the other groups. Glucose, hemoglobin A1C and haptoglobulin levels were significantly higher, whereas transferrin and prealbumin levels were significantly lower in both diet therapy and gliclazide therapy when compared with the control group. Mean C-reactive protein level did not differ between the groups. Conclusions: Levels of acute phase proteins significantly differ in type 2 diabetes when compared with healthy subjects. Gliclazide may provide better control on acute phase proteins.

Low Serum Alpha-1 Antitrypsin (AAT) in Family Members of Individuals with Autism Correlates with PiMZ Genotype

Deficiency of Alpha-1-antitrypsin (AAT) can be a genetic condition that increases the risk of developing liver, lung and possibly gastrointestinal disease. Since many autistic children also have gastrointestinal disorders, this study was designed to measure serum concentration of AAT and establish AAT genotypes in autistic children, age and gender matched non-autistic siblings, parents and controls. We used an indirect ELISA with monoclonal IgG to AAT to measure AAT serum concentrations in 71 members from 16 families of individuals with autism and 18 controls (no family history of autism). We used a duplex polymerase chain reaction to detect M, S and Z alleles for alpha-1 antitrypsin expression in 52 members of 12 of the above families. A significantly high number of autistic family members had lower than normal serum levels of AAT when compared to controls. Autistic children with regressive onset had significantly lower levels of AAT compared to controls, and a significant number of autistic children with low serum AAT also had hyperbilirubinemia, gastrointestinal disease and respiratory problems. We also found that a significantly high number of these individuals had the PiMZ genotype and correspondingly low levels of serum alpha-1 antitrypsin. Knowing that low levels of alpha-1 antitrypsin may be inherited, and that low levels of AAT may be associated with GI disease in autistic children, genotyping autistic children may help identify individuals susceptible to developing digestive problems.

Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency Caitriona McLean*, Catherine M Greene*, Noel G McElvaneyRespiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; *Each of these authors contributed equally to this workAbstract: Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to

Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.

THE RELATIONSHIP BETWEEN ALPHA-1 ANTITRYPSIN LEVELS AND LESS COMMON NON-MM PHENOTYPES IN SOUTHEASTERN KENTUCKY

PURPOSE: Non-MM phenotype's serum concentration of alpha-1 antitrypsin (AAT) were reported to be lower than the levels in MM phenotype subjects. This study is to determine the correlation between serum AAT levels and phenotype in less commonly reported phenotypes.

Deficiência de alfa-1 antitripsina: diagnóstico e tratamento

Alpha-1 antitrypsin deficiency is a recently identified genetic disease that occurs almost as frequently as cystic fibrosis. It is caused by various mutations in the SERPINA1 gene, and has numerous clinical implications. Alpha-1 antitrypsin is mainly produced in the liver and acts as an antiprotease. Its principal function is to inactivate neutrophil elastase, preventing tissue damage. The mutation most commonly associated with the clinical disease is the Z allele, which causes polymerization and accumulation within hepatocytes. The accumulation of and the consequent reduction in the serum levels of alpha-1 antitrypsin cause, respectively, liver and lung disease, the latter occurring mainly as early emphysema, predominantly in the lung bases. Diagnosis involves detection of low serum levels of alpha-1 antitrypsin as well as phenotypic confirmation. In addition to the standard treatment of chronic obstructive pulmonary disease, specific therapy consisting of infusion of purified alpha-1 antitrypsin is currently available. The clinical efficacy of this therapy, which appears to be safe, has yet to be definitively established, and its cost-effectiveness is also a controversial issue that is rarely addressed. Despite its importance, in Brazil, there are no epidemiological data on the prevalence of the disease or the frequency of occurrence of deficiency alleles. Underdiagnosis has also been a significant limitation to the study of the disease as well as to appropriate treatment of patients. It is hoped that the creation of the Alpha One International Registry will resolve these and other important issues.

Spontaneous Pneumothorax in Flight as First Manifestation of Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency is a genetic condition that increases the risk of a variety of conditions including pulmonary emphysema and chronic liver disease. We report on a 33-yr-old male fighter pilot with early-onset pulmonary emphysema with bullae who developed spontaneous pneumothorax during in-flight combat training. A CT scan of his chest after removal of the chest tube showed multiple variably sized bullae and pulmonary cysts scattered throughout both lungs. Serum levels of alpha-1 antitrypsin were markedly decreased. Genetic analyses showed a PI ZZ genotype. Alpha-1 antitrypsin deficiency often goes undiagnosed by flight surgeons, which is a risk to flight safety.

Alpha-1 antitrypsin Null mutations and severity of emphysema

Alpha-1 antitrypsin (AAT) deficiency is an autosomal-codominant disorder, caused by mutations in the SERPINA1 gene on chromosome 14. Individuals affected by the most common mutations, SZ and ZZ, have serum AAT concentrations of 25% and 15% of normal levels, and present a higher risk of emphysema. Mutations causing total absence of serum AAT (Null mutations) were suggested to be associated with very early onset emphysema but their clinical phenotype is poorly known. Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ. We genotyped all known Dutch subjects (n=12) with absent serum AAT, and compared their lung function values (FEV1 and KCO) with those of individuals with ZZ and SZ genotype, matched for age and smoking history. All subjects with absent serum AAT presented homozygous Null mutations. In three subjects, a new mutation in exon 2 of the SERPINA1 gene was found. Subjects with Null mutations showed significantly lower lung function values than SZ and ZZ individuals (p=0.000 and 0.001 for FEV1 and KCO, respectively). In all groups, there was a positive correlation between serum AAT and lung function values (p=0.025 and 0.014 for FEV1 and KCO, respectively). Serum levels of AAT are correlated with the severity of pulmonary phenotype. Subjects with Null mutations should be considered a subgroup at particularly high risk of emphysema within AAT deficiency (AATD). Early detection of carriers of this genotype would be important for preventive and therapeutic interventions.