Alpha-1 antitrypsin deficiency and pregnancy complications and birth outcomes: A population-based cohort study in Denmark.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is related to developing lung and liver disease, but no large-scale studies examine its association with birth outcomes. OBJECTIVE: We investigated the risk of pregnancy complications and adverse birth outcomes in mothers and children with AATD. METHODS: Using a large cohort data of Danish mothers and children with AATD from 1973 to 2013 (n = 2,027,229), with 559 cases (305 mothers and 254 children). We conducted Poisson regression to examine associations between alpha-1 antitrypsin deficiency, adverse birth outcomes, and pregnancy complications in mothers and children. RESULTS: AATD was related to term low birth weight [<2500g; Risk Ratio(RR) = 2.04, 95% confidence interval (CI): 1.50-2.79], lowest quartile of abdominal circumference at birth in children of non-smoking mothers (RR = 1.55, 95% CI: 1.14-2.11), delivery via Cesarean-section (RR = 1.59, 95% CI: 1.05-2.40), preterm birth (RR = 1.54, 95% CI: 1.19-2.00) and preeclampsia (RR = 2.64, 95% CI: 1.76-3.94). CONCLUSIONS: This emphasizes the need for mothers with AATD to be monitored closely during pregnancy to reduce the risk of adverse birth outcomes. Routine screening for alpha-1 antitrypsin in pregnancy may be considered among mothers with a pulmonary and liver disease history.

Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD.

Aim: Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Methods: Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Results: Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). Conclusion: In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.

An Alpha-1 Antitrypsin Deficiency Screening Study in Patients with Chronic Obstructive Pulmonary Disease, Bronchiectasis, or Asthma in Turkey.

Purpose: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition characterized by decreased serum alpha-1 antitrypsin (AAT) levels. We aim to identify AATD in patients with chronic obstructive pulmonary disease (COPD), bronchiectasis, or asthma and to report the frequency of AAT variants in Turkey. Patients and Methods: This non-interventional, multicenter, prospective study was conducted between October 2021 and June 2022. Adult patients with COPD, bronchiectasis, asthma, liver symptoms, or family members with AATD were included. Demographic and clinical characteristics, pulmonary diagnosis, respiratory symptoms, and AAT serum levels were assessed. Whole blood samples were collected as dried blood spots, and the most common AATD mutations were simultaneously tested by allele-specific genotyping. Results: A total of 1088 patients, mainly diagnosed with COPD (92.7%) and shortness of breath (78.7%), were assessed. Fifty-one (5%) were found to have AATD mutations. Fifteen (29.4%) patients had Pi*S or Pi*Z mutations, whereas 36 (70.6%) patients carried rare alleles Pi*M malton (n=18, 35.3% of mutations), Pi*I (n=8, 16%), Pi*P lowell (n=7, 14%), Pi*M heerlen (n=2, 4%), and Pi*S iiyama (n=1, 2%). The most common heterozygous combinations were Pi*M/Z (n=12, 24%), and Pi*M/M malton (n=11, 22%). Ten patients with severe AATD due to two deficiency alleles were identified, two with the Pi*Z/Z genotype, four with the genotype Pi*M malton/M malton, three with Pi*Z/M malton, and one with Pi*Z/M heerlen. Conclusion: Our results identified AATD mutations as a genetic-based contributor to lung disease in patients with COPD or bronchiectasis and assessed their frequency in a population of Turkish patients.

Initial alpha-1 antitrypsin screening in Turkish patients with chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 antitrypsin (AAT) deficiency is associated with several types of pathology, and the reported effects of mutations in the ATT-encoding gene vary worldwide. No Turkish study has yet appeared. We thus explored the AAT status of Turkish patients with chronic obstructive pulmonary disease (COPD). METHODS: This prospective cross-sectional study included outpatients and inpatients treated from June 2021 to June 2022. Serum AAT levels were checked, and dry blood samples were subjected to genetic analysis. RESULTS: : Genetic mutations were found in 21 (3.52%) of 596 patients with prior and new COPD diagnoses treated in our pneumonology outpatient department. The mean serum AAT level was 114.80 mg/dL (minimum 19, maximum 209; standard deviation 27.86 mg/dL). The most frequent mutation was M/Plowell (23.8%, n = 5), followed by M/S (23.8%, n = 5), M/I (19%, n = 4), M/Malton (14.3%, n = 3), Z/Z (9.5%, n = 2), M/Z (4.8%, n = 1), and Kayseri/Kayseri (4.8%, n = 1). Thoracic computed tomography revealed that 85.7% (n = 18) of all patients had emphysema, 28.5% (n = 6) had bronchiectasis, and 28.5% (n = 6) had mass lesions. Of the emphysema patients, 55% (n = 10) had only upper lobe emphysema, and 83.3% (n = 15) had emphysema in additional areas, but statistical significance was lacking (p > 0.05). DISCUSSION: In patients with emphysema and normal serum AAT levels, genetic analyses may reveal relevant heterozygous mutations, which are commonly ignored. Most clinicians focus on lower lobe emphysema. Evaluations of such patients might reveal AAT mutations that are presently overlooked because they are not considered to influence COPD status.

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO.

BACKGROUND: Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. RESULTS: Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. CONCLUSIONS: The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.

Testing Patterns and Disparities for Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency is an under-recognized genetic cause of chronic lung and liver disease; it remains unclear what the testing frequency and disparities are for alpha-1 antitrypsin deficiency. METHODS: This is a retrospective cohort study of people with newly diagnosed chronic obstructive pulmonary disease and liver disease identified at the University of Florida between January 1, 2012 and December 31, 2021. We performed incidence and prevalence analysis for alpha-1 antitrypsin (AAT) testing and point-biserial correlation analysis for tobacco use and AAT testing. We evaluated characteristics with AAT testing using adjusted multivariable logistic regression. RESULTS: Among 75,810 subjects with newly diagnosed chronic obstructive pulmonary disease and liver disease between 2012 and 2021, 4248 (5.6%) were tested for AAT deficiency. All subjects had an AAT level performed, while 1654 (39%) had phenotype testing. Annual incidence of testing increased for subjects with newly diagnosed chronic obstructive pulmonary disease or liver disease from 2.8% and 5.4%, respectively, in 2012 to 4.1% and 11.3%, respectively, in 2021. Adjusted multivariable regression analysis showed factors favoring AAT testing were White race, and concomitant chronic obstructive pulmonary disease and liver disease. Increasing age, non-White race, current tobacco use, and being a male with chronic obstructive pulmonary disease had lower odds of AAT testing. CONCLUSION: Although slowly improving, testing for AAT deficiency continues to have a low uptake in the clinical setting despite guidelines recommending broader testing. Individuals of White race and those with concomitant chronic obstructive pulmonary disease and liver disease are more likely to be tested, while older subjects, individuals of non-White race, current tobacco use, and men with chronic obstructive pulmonary disease are less favored to be tested.

Increased Prevalence of Alpha-1-Antitrypsin Deficiency in Patients with Biliary Tract Cancer and Its Associated Clinicopathological Features.

Alpha-1 antitrypsin deficiency (A1ATD) is underdiagnosed and associated with liver diseases. Here, we genotyped 130 patients with biliary tract cancer (BTC) scheduled for liver resection and found A1ATD in 10.8% of the patients. A1ATD was found in all BTC subtypes, and patients had similar clinical features as non-A1ATD BTC, not permitting their identification using clinical routine liver tests. In intrahepatic cholangiocarcinoma (iCCA), the abundance of A1AT protein was increased in the tumor and appeared to be influenced by the genomic alterations. On the one hand, BTC with A1ATD had lower perineural invasion at histopathology and displayed a longer survival, suggesting that a deficiency in this protein is associated with a less aggressive phenotype. On the other hand, iCCA with high A1AT expression had more advanced tumor staging and enriched pathways for complement system and extracellular matrix interactions, indicating that A1AT protein might contribute to a more aggressive phenotype. With increased awareness, screening, and basic studies, A1ATD could represent one more layer of stratification for future targeted therapies in BTC.

Prevalence of genetic mutations in alpha-1 antitrypsin deficiency (aatd) in patients with chronic obstructive pulmonary disease in Colombia.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder associated mainly with pulmonary emphysema and Chronic Obstructive Pulmonary Disease (COPD). All individuals with COPD regardless of age or ethnicity should be tested for AATD, but in Colombia its prevalence in unknown. MAIN OBJECTIVE: To determine the prevalence of the genetic mutations, present in AATD in adult patients with COPD in Colombia, using a genotyping test on cells from the oral mucosa. METHODS: This was a multicentre, observational, cross-sectional study which included adult patients attending seven COPD care centres in Colombia. Demographic data, medical history, including history of exposure to smoking and biomass smoke, most recent spirometry, pharmacological and non-pharmacological treatment received, serum AAT levels, and mutations detected by the genotyping test were recorded for all the recruited patients. For the comparison of variables between the groups with and without mutation, we used the X2 test for the qualitative variables and the Student's t-test or Mann-Whitney U test according to their distribution. MAIN FINDINGS: We collected a sample of 1,107 patients, the median age was 73.8 years (87.6-79.9). Mutations were documented in 144 patients (13.01%), the majority had the M/S mutation (78.50%), followed by M/Z (9.72%). One patient had a ZZ mutation and two patients had null alleles. In total, 23 patients had mutations associated with serum AAT deficiency (levels below 60 mg/dl). CONCLUSIONS: Genetic mutations were documented in 13.01% of patients with COPD in Colombia and 2.07% were AATD-related, showing that there is a significant number of underdiagnosed patients.

The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency: results from the Austrian Alpha-1 Lung Registry.

BACKGROUND: Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder that can manifest as lung disease. A delay between onset of symptoms and diagnosis of AATD is common and associated with worse clinical status and more advanced disease stage but the influence on survival is unclear. OBJECTIVE: We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients. METHODS: We analysed 268 AATD patients from the prospective multi-centre Austrian Alpha-1 Lung (AAL) Registry, employing descriptive statistics, Chi-square-test as well as univariable (Kaplan-Meier plots, log-rank test) and multivariable survival analysis (Cox regression). RESULTS: The predominant phenotype was Pi*ZZ (82.1%). At diagnosis, 90.2% had an AAT level below 0.6 g/L. At inclusion, 28.2% had never smoked, 68.0% had quit smoking and 3.8% continued to smoke. Lung disease was diagnosed in 98.5%, thereof most patients were diagnosed with emphysema (63.8%) and/or chronic obstructive pulmonary disease (44.0%). Median diagnostic delay was 5.3 years (inter-quartile range [IQR] 2.2-11.5 years). In multivariable analysis (n = 229), a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.61; 95% CI 1.09-2.38; p = 0.016) and TS (HR 1.43; 95% CI 1.08-1.89; p = 0.011), independent from age, smoking status, body mass index (BMI), forced expiratory volume in one second (FEV1) and long-term oxygen treatment. Furthermore, BMI, age and active smoking were significantly associated with worse OS as well as BMI, active smoking and FEV1 were with worse TS. CONCLUSIONS: A delayed diagnosis was associated with significantly worse OS and TS. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Occupational and environmental exposures in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

INTRODUCTION: Sarcoidosis is a granulomatous disorder thought to be caused by exposures in genetically susceptible individuals. This study investigated whether specific exposures were associated with different sarcoidosis phenotypes. METHODS: Extensive demographic, occupational and environmental exposure data was analyzed from subjects enrolled in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. RESULTS: In patients with sarcoidosis, radiation exposure was significantly associated with an increased risk of cardiac sarcoidosis versus non-cardiac sarcoidosis. No exposures were significantly associated with pulmonary only disease versus extrapulmonary disease with or without pulmonary involvement, Scadding Stage II/III/IV versus Scadding Stage 0/I, acute or remitting disease versus non-acute or non-remitting disease, nor chronic versus non-chronic disease. Although not reaching statistically significance after adjustment for multiple comparisons, there were a number of exposures associated with specific disease phenotypes, including exposures where relationships to sarcoidosis have previously been described such as rural exposures and pesticide exposures. CONCLUSIONS: Radiation exposure may be a risk factor for cardiac sarcoidosis. Other exposures may also be associated with specific phenotypes and should be further explored. The study was limited by small groups of exposed subjects for individual exposures and multiple comparisons. The development of novel and innovative exposure assessment tools is needed.

Distribution of the Clinical Manifestations of Alpha 1 Antitrypsin Deficiency in Respiratory Outpatients from an Area of Northern Italy.

BACKGROUND: Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that affects Caucasians of the European population due to the presence of a deficient allele of the SERPINA1 gene. A frequency of about 1/5,000 individuals has been estimated in Italy. OBJECTIVES: The aim of the study was to evaluate the distribution of the clinical manifestations of severe and intermediate genetic AATD in the geographic area around Parma in Northern Italy. METHOD: 238 subjects were submitted to molecular analysis of the SERPINA1 gene, and data on anthropometric variables, smoking habits, number of packs per year, AAT serum concentration, and clinical manifestations were recorded and presented as mean ± SD or median values (1st quartile; 3rd quartile). RESULTS: The results show a distribution of genetic AATD of 4.1% of the screened population in the area encompassing the city of Parma. PI*MS and PI*MZ were the most common genotypes at 40.9% and 28.2% of the population with genetic AATD, and asthma and emphysema were the most represented clinical manifestations. CONCLUSION: Our study allowed to increase the knowledge of the distribution of genetic AATD in Northern Italy providing information regarding frequencies of genotypes and clinical manifestations of the disorder.

Disease progression in patients with PI*ZZ alpha-1 antitrypsin deficiency.

BACKGROUND AND OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is an uncommon but underdiagnosed cause of cirrhosis and lacks medical treatment options. It is important to recognize risk factors that contribute to disease progression and liver transplantation. We aimed to assess if age, sex, or smoking status was associated with liver or lung disease progression. METHODS: Forty-three patients with ZZ-AATD cirrhosis were consecutively sampled from an Institutional Review Board-approved registry of 240 patients with AATD of any genotype seen as outpatients in the Cleveland Clinic between 1999 and 2019. To determine the association between risk factors and lung or liver disease progression, linear mixed-effects models with fixed effects for linear time, risk factor, and time-by-risk factor interaction, and the random intercepts for intra-patient correlation were used. RESULTS: Based on the mixed-effects model analysis, there was a significant association between liver disease progression and smoking history, and no association with age or sex. There was no association between lung disease progression and age, sex, or smoking history. However, smoking history was significantly associated with lower forced expiratory volume values. CONCLUSION: This study found that in a cohort of patients with PI*ZZ genotype AATD (ZZ-AATD) and cirrhosis, smoking history was associated with liver disease progression, whereas age and sex were not.

[Alpha 1-antitrypsin deficiency]. / Le déficit en alpha 1-antitrypsine.

INTRODUCTION: Pulmonary emphysema and liver disease are the clinical expressions of alpha 1-antitrypsin deficiency, an autosomal recessive genetic disease. STATE OF THE ART: Alpha 1-antitrypsin deficiency is usually associated with the homozygous Z variant of the SERPINA1 gene. Its clinical expression always consists in a substantial reduction of alpha 1-antitrypsin serum concentration and its variants are analyzed by isoelectric focalization or molecular techniques. Assessed by CO transfer alteration and CT scan, risk of pulmonary emphysema is increased by tobacco consumption. Assessed by transient elastography and liver ultrasound, risk of liver disease is increased by alcohol consumption or obesity. Treatment of COPD-associated alpha 1-antitrypsin deficiency does not differ from that of other forms of COPD. In patients presenting with severe deficiency, augmentation therapy with plasma-derived alpha 1-antitrypsin reduces the progression of emphysema, as shown in terms of CT-based lung density metrics. Patients with alpha 1-antitrypsin deficiency with a ZZ genotype should refrain from alcohol or tobacco consumption, and watch their weight; so should their close relatives. PERSPECTIVES: Modulation of alpha 1-antitrypsin liver production offers an interesting new therapeutic perspective. CONCLUSION: Homozygous (Z) variants of the SERPINA1 gene confer an increased risk of pulmonary emphysema and liver disease, particularly among smokers, drinkers and obese persons.

Cancer risk in severe alpha-1-antitrypsin deficiency.

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, is a risk factor for pulmonary emphysema and liver disease, but its effect on cancer risk is unknown. Our aim was to evaluate the risk and the risk factors for incident cancer in PiZZ individuals compared with the general population with known smoking habits. METHODS: A longitudinal study of PiZZ individuals (n=1595) from the Swedish National AATD Register, and controls (n=5999) from Swedish population-based cohorts. Data on cancer and mortality were obtained by cross-linkage with national registers. Individuals who had undergone lung transplantation (n=10) and those with a cancer diagnosis within 5 years prior to inclusion (n=63) were excluded. The risk factors for developing cancer were analysed using proportional hazards and Fine-Gray regression models, adjusting for age, sex, smoking habits and the presence of liver disease. RESULTS: The median follow-up time was 17 years (interquartile range 11 years) for the whole study population. The incidence rates of hepatic and non-hepatic cancer per 1000 person-years were 1.6 (95% CI 1.1-2.3) and 8.5 (95% CI 7.2-10.0), respectively, for the PiZZ individuals, and 0.1 (95% CI 0.04-0.2) and 6.6 (95% CI 6.0-7.1), respectively, for the controls. The adjusted hazard ratios for hepatic and for non-hepatic cancer were 23.4 (95% CI 9.9-55.4) and 1.3 (95% CI 1.1-1.5), respectively, in the PiZZ individuals compared with the controls. CONCLUSION: These results suggest that individuals with severe AATD may have an increased risk of developing both hepatic and non-hepatic cancer, compared with the general population.

Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study.

BACKGROUND: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. OBJECTIVES: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. PATIENTS/METHODS: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. RESULTS: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0-10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE. CONCLUSIONS: The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population-based Swedish study.

Labelling Alpha-1 antitrypsin deficiency in the medical record - A call to action.

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic cause of chronic obstructive pulmonary disease (COPD) with over 100 allelic variants described. The normal allele is termed "M"; whereas, the "Z" and "S" alleles are the most common abnormal alleles. The ZZ combination accounts for 95% of cases with severe disease. We described the characteristics of patients given the label of AATD in the medical record. Our analysis found there is significant heterogeneity with regards to labelling subjects with AATD in the medical record, and this was true irrespective of the subjects age, gender, PFT measurements, tobacco pack years, or if the physician was a pulmonologist. In summary, this study highlights the need for continued investigation of the role of other mutations developing disease and options for more specific labelling of subjects with non-severe AATD and severe AATD to provide additional clarity for the patient and healthcare providers.

Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Underrecognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. RESEARCH QUESTION: The study addressed three questions: (1) Does a DTC testing service identify previously undetected individuals with AATD? (2) What was the interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and (3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? STUDY DESIGN AND METHODS: In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. RESULTS: Among 195,014 study participants, the allele frequency for the PI∗S and PI∗Z AATD variants was 21.6% (6.5% for PI∗Z and 15.1% for PI∗S); 0.63% were PI∗ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with health care providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI∗ZZ individuals shared their DTC result with an HCP. The OR for PI∗ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 (95% CI = 1.4-2.2) compared with those without a Z allele and for reduced alcohol consumption this was 4.0 (95% CI = 2.6-5.9). INTERPRETATION: In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

Estimated Prevalence and Number of PiMZ Genotypes of Alpha-1 Antitrypsin in Seventy-Four Countries Worldwide.

BACKGROUND: The α-1 antitrypsin (AAT) protease inhibitor PiMZ is a moderately deficient genotype, until recently considered of little or negligible risk. However, a growing number of studies show that MZ carriers have an increased risk of developing lung and liver diseases, if exposed to smoking or other airborne or industrial pollutants, and hepatotoxic substances. METHODS: We used the epidemiological studies performed to determine the frequencies of PiM and PiZ worldwide, based on the following criteria: 1) samples representative of the general population; 2) AAT phenotyping or genotyping characterized by adequate methods, including isoelectric focusing and polymerase chain reaction; and 3) studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals, to measure the precision of the results in terms of dispersion of the data around the mean. RESULTS: The present review reveals an impressive number of MZs of more than 35 million in 74 countries of the world with available data. Seventy-five percent of them are people of Caucasian European heritage, mostly living in Europe, America, Australia and New Zealand. Twenty percent of the remaining MZs live in Asia, with the highest concentrations in the Middle East, Eastern¸ Southern, and South-eastern regions of the Asian continent. The remaining five percent are Africans residing in Western and Eastern Africa. CONCLUSION: Considering the high rate of smoking, the outdoor and the indoor air pollution from solid fuels used in cooking and heating, and the exposure to industrial dusts and chemicals in many of these countries, these figures are very worrying, and hence the importance of adequately assessing MZ subjects, recommending them rigorous preventive measures based on the adoption of healthy lifestyles, including avoidance of smoking and alcohol.