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BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling. ispartof: GASTROENTEROLOGY vol:159 issue:2 pages:534-+ ispartof: location:United States status: published

α1-Antitrypsin (AAT) encoded by the SERPINA1 gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP-homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most up-regulated genes in livers of PiZ mice that express ATZ and in human livers of patients homozygous for the Z allele. Compared with controls, juvenile PiZ/Chop-/- mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-Seq analysis. Livers of PiZ/Chop-/- mice also showed reduced SERPINA1 mRNA levels. By chromatin immunoprecipitations and luciferase reporter-based transfection assays, CHOP was found to up-regulate SERPINA1 cooperating with c-JUN, which was previously shown to up-regulate SERPINA1, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN up-regulate SERPINA1 transcription and play an important role in hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

Background and aims Alpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases. Methods We have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures. Results Transcriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4). Conclusions Liver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

Background: Invasive ductal carcinoma (IDC) is the most common type of metastatic breast cancer. Due to the lack of valuable molecular biomarkers, the diagnosis and prognosis of IDC remain a challenge. A large number of studies have confirmed that coagulation is positively correlated with angiogenesis-related factors in metastatic breast cancer. Therefore, the purpose of this study was to construct a COAGULATION-related genes signature for IDC using the bioinformatics approaches.Methods: The 50 hallmark gene sets were obtained from the molecular signature database (MsigDB) to conduct Gene Set Variation Analysis (GSVA). Gene Set Enrichment Analysis (GSEA) was applied to analyze the enrichment of HALLMARK_COAGULATION. The COAGULATION-related genes were extracted from the gene set. Then, Limma Package was used to identify the differentially expressed COAGULATION-related genes (DECGs) between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) samples in GSE26340 data set. A total of 740 IDC samples from The Cancer Genome Atlas (TCGA) database were divided into a training set and a validation set (7:3). The univariate and multivariate Cox regression analyses were performed to construct a risk signature, which divided the IDC samples into the high- and low-risk groups. The overall survival (OS) curve and receiver operating characteristic (ROC) curve were drawn in both training set and validation set. Finally, a nomogram was constructed to predict the 1-, 2-, 3-, 4-, and 5-year survival rates of IDC patients. Quantitative real-time fluorescence PCR (qRT-PCR) was performed to verify the expression levels of the prognostic genes.Results: The “HALLMARK_COAGULATION” was significantly activated in IDC. There was a significant difference in the clinicopathological parameters between the DCIS and IDC patients. Twenty-four DECGs were identified, of which five genes (SERPINA1, CAPN2, HMGCS2, MMP7, and PLAT) were screened to construct the prognostic model. The high-risk group showed a significantly lower survival rate than the low-risk group both in the training set and validation set (p=3.5943e-06 and p=0.014243). The risk score was demonstrated to be an independent predictor of IDC prognosis. A nomogram including risk score, pathological_stage, and pathological_N provided a quantitative method to predict the survival probability of 1-, 2-, 3-, 4-, and 5-year in IDC patients. The results of decision curve analysis (DCA) further demonstrated that the nomogram had a high potential for clinical utility.Conclusion: This study established a COAGULATION-related gene signature and showed its prognostic value in IDC through a comprehensive bioinformatics analysis, which may provide a potential new prognostic mean for patients with IDC.

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo., This research was funded by COMPETE 2020 of PT2020 through the European Regional Development Fund (ERDF), “NETDIAMOND—New Targets in DIAstolic heart failure: from coMOrbidities to persoNalizeD medicine” project financed by the European Structural and Investment Funds (ESIF), through the Programa Operacional Regional (POCI-01-0145-FEDER-016385) and HEALTHUNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological, and infectious diseases, NORTE- 01-0145-FEDER-000039. FB was supported by FCT—Fundação para a Ciência e Tecnologia/MEC— Ministério da Educação e Ciência with a PhD fellowship (SFRH/BD/123674/2016).

Research in European and Asian populations has reported associations between single nucleotide polymorphisms (SNPs) in CYP17A1 and SERPINA6/A1 and circulating glucocorticoid concentrations, and some key cardiometabolic risk factors. This study aimed to investigate these associations in black South African adults, who are disproportionally affected by the metabolic syndrome and its related cardiometabolic risk factors. The dataset included black South African adults (n = 4,431; 56.7% women) from the AWI-Gen study, genotyped on the H3A genotyping array and imputed using the African reference panel at the Sanger imputation service. From the imputed data, 31 CYP17A1 SNPs and 550 SERPINA6/A1 SNPs were extracted. The metabolic syndrome and its components were defined using the 2009 harmonized guidelines. Serum glucocorticoid concentrations were measured in a subset of 304 men and 573 women, using a liquid chromatography-mass spectrometry method. Genetic associations were detected using PLINK. Bonferroni correction was used to control for multiple testing. A SNP at SERPINA6/A1, rs17090691 (effect allele G), was associated with higher diastolic blood pressure (BP) in all adults combined (p = 9.47 × 10−6). Sex-stratified analyses demonstrated an association between rs1051052 (effect allele G), another SERPINA6/A1 SNP, and higher high-density lipoprotein (HDL) cholesterol concentrations in women (p = 1.23 × 10−5). No association was observed between these variants and glucocorticoids or between any of the CYP17A1 SNPs and metabolic outcomes after adjusting for multiple testing. Furthermore, there were no associations between any of the SNPs tested and the metabolic syndrome. This study reports novel genetic associations between two SNPs at SERPINA6/A1 and key cardiometabolic risk factors in black South Africans. Future replication and functional studies in larger populations are required to confirm the role of the identified SNPs in the metabolic syndrome and assess if these associations are mediated by circulating glucocorticoids.

Autophagy has an important role in regulating tumor cell survival. However, the roles of autophagy-related genes (ARGs) during colon adenocarcinoma (COAD) progression and their prognostic value have remained elusive. The present study aimed to identify the correlation between ARGs and the progression of COAD, as well as the prognostic significance of ARGs. The transcriptome profiles and the corresponding clinicopathological information of patients with COAD were downloaded from The Cancer Genome Atlas and Genotype-Tissue Expression databases. A list of ARGs was obtained from the Human Autophagy Database and bioinformatics analysis was performed to investigate the functions of these ARGs. Statistical analyses of these genes were performed to identify independent prognostic markers. The selected prognostic markers were then validated in 15 patients with COAD via immunohistochemistry. Differentially expressed ARGs between normal and tumor tissues were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the differentially expressed ARGs were mainly enriched in toxoplasmosis and pathways in cancer. The ATG4B, DAPK1 and SERPINA1 genes were determined to be associated with COAD progression. In addition, a risk signature was proposed that may serve as an independent prognostic marker. In conclusion, ATG4B, DAPK1 and SERPINA1 are crucial participants in tumorigenesis of COAD. The present study may promote the development of novel treatment strategies for COAD.

Background There is an association between persistent preschool wheezing phenotypes and school-age asthma. These wheezing/asthma phenotypes likely represent clinical entities having specific genetic risk factors. The SERPINA1 gene encodes α 1 -antitrypsin (AAT), and mutations in the gene are important in the pathophysiology of pulmonary diseases. We hypothesized that there might be an association between SERPINA1 gene polymorphisms and the risk of developing wheezing/school age asthma. Objective To examine 10 single nucleotide polymorphisms (SNPs) of SERPINA1 (rs6647, rs11832, rs17580, rs709932, rs1243160, rs2854254, rs8004738, rs17751769, rs28929470, and rs28929474) and relate them to childhood wheezing phenotypes and doctor-diagnosed asthma in the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Methods Wheeze data, reports of physician-diagnosed asthma and data on the SERPINA1 gene SNPs, were available for 7964 children. Binary logistic regression was used to assess the associations between allele prevalence and wheezing and asthma phenotypes. P values were adjusted to account for multiple hypotheses using the Benjamini-Hochberg false discovery rate. Results Only within a subgroup of children with asthma who had no prior diagnosis of preschool wheeze was there a trend for association between rs28929474 (Glu342Lys, Pi*Z causing AAT deficiency; P = .0058, adjusted P = .058). No SNP was associated with wheezing and asthma in those with preschool wheeze. Conclusion Analyzed SNPs in SERPINA1 are not associated with wheezing/asthma phenotypes. Only rs28929474, the most common pathologic SNP (Pi*Z) in the SERPINA1 gene, might be associated with a risk of developing school-age asthma without exhibiting preschool wheeze.

Background Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the ‘Z’ and ‘S’ variants – single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V. However, SERPINA1 is highly polymorphic, with numerous potentially clinically relevant variants reported. Novel variants continue to be discovered, and without reports of pathogenicity, it can be difficult for clinicians to determine the best course of treatment. Methods We assessed the utility of next-generation sequencing (NGS) and predictive computational analysis to guide the diagnosis of patients suspected of having AATD. Blood samples on serum separator cards were submitted to the DNA1 Advanced Screening Program (Biocerna LLC, Fulton, Maryland, USA) by physicians whose patients were suspected of having AATD. Laboratory analyses included quantification of serum AAT levels, qualitative analysis by isoelectric focusing, and targeted genotyping and NGS of the SERPINA1 gene. Molecular modeling software UCSF Chimera (University College of San Francisco, CA) was used to visualize the positions of amino acid changes as a result of rare/novel SNVs. Predictive software was used to assess the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain). Results Samples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were probably deleterious, and two were possibly deleterious. For the majority of probably/possibly deleterious SNVs (I50N, P289S, M385T, M221T, D341V, V210E, P369H, V333M and A142D), the mechanism is probably via disruption of the packed hydrophobic core of AAT. Several deleterious variants occurred in combination with more common deficiency alleles, resulting in very low AAT levels. Conclusions NGS and computational modeling are useful tools that can facilitate earlier, more precise diagnosis, and consideration for AAT therapy in AATD. Electronic supplementary material The online version of this article (10.1186/s12881-019-0852-5) contains supplementary material, which is available to authorized users.

Alpha-1 antitrypsin deficiency (AATD) arises from mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT) that lead to AAT retention in the endoplasmic reticulum of hepatocytes, causing proteotoxic liver injury and loss-of-function lung disease. The homozygous Pi∗Z mutation (Pi∗ZZ genotype) is responsible for the majority of severe AATD cases and can precipitate both paediatric and adult liver diseases, while the heterozygous Pi∗Z mutation (Pi∗MZ genotype) is an established genetic modifier of liver disease. We review genotype-related hepatic phenotypes/disease predispositions. We also describe the mechanisms and factors promoting the development of liver disease, as well as approaches to evaluate the extent of liver fibrosis. Finally, we discuss emerging diagnostic and therapeutic approaches for the clinical management of this often neglected disorder.

Background Diagnostic biomarkers for detecting chronic obstructive pulmonary disease (COPD) in acute coronary syndrome (ACS) patients are not available. SERPINA1, coding for the most potent circulating anti-inflammatory protein in the lung, has been found to be differentially methylated in blood cells from COPD patients. This study aimed to investigate the methylation profile of SERPINA1 in blood cells from ACS patients, with (COPD+) or without COPD (COPD−). Methods Blood samples were from 115 ACS patients, including 30 COPD+ and 85 COPD− according to lung function phenotype, obtained with spirometry. DNA treated with sodium bisulfite was PCR-amplified at SERPINA1 promoter region. Methylation analysis was carried out by sequencing the PCR products. Lymphocytes count in ACS patients was recorded at hospital admission and discharge. Results SERPINA1 was hypermethylated in 24/30 (80%) COPD+ and 48/85 (56.5%) COPD− (p SERPINA1 hypermethylated (1.98 × 103 ± 0.6 cell/µl) than in COPD− carrying SERPINA1 hypomethylated (1.7 × 103 ± 0.48 cell/µl) (p Conclusions SERPINA1 is hypermethylated in blood cells from COPD+ patients. COPD− carrying SERPINA1 hypermethylated and high lymphocytes count may be at risk of COPD development. Therefore, SERPINA1 hypermethylation may represent a potential biomarker for predicting COPD development in ACS patients.

Alpha 1 Antitrypsin Deficiency (AATD) is a rare condition primarily associated with lung complications and liver disease. As disease symptoms are similar to those in other respiratory conditions, patients generally experience long delays before receiving an accurate diagnosis and treatment. AATD results from mutations in the SERPINA1 gene that encodes Alpha 1 Antitrypsin (AAT). Over 500 single-nucleotide variants have been reported in mutation databases; however, there is increasing interest in the clinical significance of rare and novel SERPINA1 variants. In this case series of four patients from a single US center, next-generation sequencing (NGS) was used to guide AATD diagnosis. Four distinct rare variants of SERPINA1 (P289S; I50N; E204K; H262Y) were identified, three of which were found in patients with advanced chronic obstructive pulmonary disease (COPD)/emphysema. Computational modeling predicted these mutations to have potentially deleterious effects, a finding supported by AAT levels that were comparable with those seen in individuals heterozygous for the most common deficiency allele (PI*MZ). The remaining mutation (E204K) was found in a patient with a cerebral aneurysm; potential links between SERPINA1 variants and neurological conditions, such as cerebral aneurysm and arterial dissections, have been previously reported in individuals with heterozygous AATD phenotypes (PI*MS and PI*MZ). Novel and rare variants, often not detected by basic AATD diagnostic tests, have the potential to contribute to the development of COPD and emphysema. Detection of these variants can be enhanced by NGS, and modeling techniques can help determine if variants are pathogenic, thereby enabling a quicker, more accurate AATD diagnosis.

Cristina Martinez-González,1 Ignacio Blanco,2 Isidro Diego,3 Patricia Bueno,4 Marc Miravitlles5 1Pulmonology Department, University Central Hospital of Asturias, Universidad de Oviedo, Instituto de Investigación del Principado de Asturias (ISPA), Oviedo, Spain; 2Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT), Spanish Society of Pneumology and Thoracic Surgery (SEPAR), Barcelona, Spain; 3Materials and Energy Department, School of Mining Engineering, Oviedo University, Oviedo, Spain; 4Internal Medicine Department, County Hospital of Jarrio, Jarrio, Spain; 5Pneumology Department, Hospital Universitari Vall d’Hebron/Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, SpainCorrespondence: Marc MiravitllesPneumology Department, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, Barcelona, 08035, SpainEmail marcm@separ.esBackground: 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.Keywords: SERPINA1, α 1-antitrypsin, PiMZ genotype, genetic epidemiology, COPD, tobacco smoking, inverse distance weighted interpolation, IDW, geographic information system, GIS

Infection rates, severity, and fatalities due to COVID‐19, the pandemic mediated by SARS‐CoV‐2, vary greatly between countries. With few exceptions, these are lower in East and Southeast Asian and Sub‐Saharan African countries compared with other regions. Epidemiological differences may reflect differences in border closures, lockdowns, and social distancing measures taken by each county, and by cultural differences, such as common use of face masks in East and Southeast Asian countries. The plasma serine protease inhibitor alpha‐1 antitrypsin was suggested to protect from COVID‐19 by inhibiting TMPRSS2, a cell surface serine protease essential for the SARS‐CoV‐2 cell entry. Here, we present evidence that population differences in alpha‐1 antitrypsin deficiency allele frequencies may partially explain national differences in the COVID‐19 epidemiology. Our study compared reported national estimates for the major alpha‐1 antitrypsin deficiency alleles PiZ and PiS (SERPINA1 rs28929474 and rs17580, respectively) with the Johns Hopkins University Coronavirus Resource Center dataset. We found a significant positive correlation (R = .54, P = 1.98e−6) between the combined frequencies of the alpha‐1 antitrypsin PiZ and PiS deficiency alleles in 67 countries and their reported COVID‐19 mortality rates. Our observations suggest that alpha‐1 antitrypsin deficiency alleles may contribute to national differences in COVID‐19 infection, severity, and mortality rates. Population‐wide screening for carriers of alpha‐1 antitrypsin deficiency alleles should be considered for prioritizing individuals for stricter social distancing measures and for receiving a SARS‐CoV‐2 vaccine once it becomes available.

Background: Alpha-1 antitrypsin deficiency (AATD) is an under-diagnosed hereditary disorder characterized by reduced serum levels of alpha-1 antitrypsin (AAT) and increased risk to develop lung and liver diseases at an early age. AAT is encoded by the highly polymorphic SERPINA1 gene. The most common deficiency alleles are named S and Z, but more than 100 rare variants lead to low levels of the protein. To identify pathological allelic variants, different from S and Z, the sequencing of the gene coding regions is required. Objectives Since sequencing is expensive and time-consuming, we decided to evaluate the accuracy of A1AT Genotyping Test (Progenika, Grifols), a new diagnostic genotyping kit which allows to identify 14 deficiency variants of the SERPINA1 gene (including S and Z) based on Luminex technology. Methods: A total of 418 consecutive samples, with AATD suspicion, were analyzed both by applying the diagnostic algorithm currently in use, and by applying the Progenika assay based on Luminex 200. Results: The Progenika assay gave these results: 101 samples (24,2%) were positive for at least one of the 14 deficiency variants, 316 (75,6%) were negative for all the variants analysed. The identified mutations showed a 100% correlation with the results obtained with our diagnostic algorithm. Seventeen samples (4%) resulted negative for the assay but sequencing identified other rare pathological variants. Conclusions The A1AT Genotyping Test assay resulted to be highly reliable and robust; it allows shorter diagnostic times of response. In certain cases it has been necessary to sequence the SERPINA1 gene to identify other rare mutations not included in the kit.

Purpose of ReviewThe aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments.Recent FindingsTherapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule-aggregation.SummaryA1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity.

Non-small-cell lung carcinomas (NSCLC) is the most common type of lung cancer and it has a poor prognosis, because overall survival after 5 years is 20-25% for all stages. Thus, it is extremely important to increase the survival rate in the early stages NSCLC by focusing on novel screening tests of cancer identifying specific biomarkers expression associated with a more accurate tumor staging and patient prognosis. In this study, we focused our attention on quantitative proteomics of three heavily glycosylated serum proteins: AMBP,α2 macroglobulin, and SERPINA1. In particular, we analyzed serum samples from 20 NSCLC lung adenocarcinoma cancer patients in early and advanced stages, and 10 healthy donors to obtain a relative quantification through the MRM analysis of these proteins that have shown to be markers of cancer development and progression. AMBP, α2 macroglobulin, and SERPINA1 were chosen because all of them possess endopeptidase inhibitor activity and play key roles in cancer. We observe a variation in the expression of these proteins linked to the stage of the disease. Therefore, we believe that proteins like α2 macroglobulin, αmicroglobulin/bikunin, and SERPINA1 could be useful biomarkers for early detection of lung cancer and in monitoring its evolution.

International audience; PURPOSE OF REVIEW: Cystic fibrosis (CF; OMIM 219700) is caused by variations in the cystic fibrosis transmembrane conductance regulator gene. CF-related liver disease (CFLD) affects approximately one-third of patients with CF, but the severity of CFLD is highly variable. This review provides the latest knowledge in the pathophysiology and CF genetic modifier research in CFLD.RECENT FINDINGS: So far, the only modifier gene validated in CFLD is SERPINA1 (α-1-antitrypsin) Z allele. Recent studies support the view that cholangiopathy arising in CF is the result of an ill-adapted innate immune response to endotoxins coming from the intestine and triggering a pro-inflammatory response.SUMMARY: The pathophysiology of liver disease remains uncertain and so far, no therapy has proven effective to prevent the progression of CFLD. A better understanding of the pathophysiology and the effect of environmental and non-cystic fibrosis transmembrane conductance regulator genetic influences in the context of CFLD development would help improve management and develop new drug therapies.

The presence of the homozygous &lsquo, Pi*Z&rsquo, variant of alpha-1 antitrypsin (AAT) (&lsquo, Pi*ZZ&rsquo, genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM &ge, 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene, which encodes the alpha-1 antitrypsin (AAT) protein. Currently, over 200 SERPINA1 variants have been identified, many of which cause the quantitative and/or qualitative changes in AAT responsible for AATD-associated lung and liver disease. The types of these pathogenic mutations are varied, often resulting in misfolding, or truncating of the AAT amino acid sequence, and improvements in sequencing technology are helping to identify known and novel genetic variants. However, due to the diversity and novelty of rare variants, the clinical significance of many is largely unknown. There is, therefore, a lack of guidance on how patients should be monitored and treated when the clinical significance of their variant combination is unclear or variable. Nevertheless, it is important that physicians understand the advantages and disadvantages of the different testing methodologies available to diagnose AATD. Owing to the autosomal inheritance of the genetic mutations responsible for AATD, genetic testing should be offered not only to patients at increased AATD risk (e.g. patients with chronic obstructive pulmonary disease), but also to relatives of those with an abnormal result. Genetic counseling may help patients and family members understand the possible outcomes of testing and the implications for the family. While stress/anxiety can arise from genetic diagnosis or confirmation of carrier status, there can be positive consequences to genetic testing, including improved lifestyle choices, directed medical care, and empowered family planning. As genetic testing technology grows and becomes more popular, testing without physician referral is becoming more prevalent, irrespective of the availability of genetic counseling. Therefore, the Alpha-1 Foundation offers genetic counseling, as well as other support and educational material, for patients with AATD, as well as their families and physicians, to help improve the understanding of potential benefits and consequences of genetic testing.

Genetic screening is an advanced tool for reducing recessive disease burden. Nowadays, it is still unclear as to the number of genes or their variants that are necessary for effective screening. This paper describes the development of a carrier screening custom panel for cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss consisting of 116 variants in the CFTR, PAH, SERPINA1, and GJB2 genes. The approach is based on the cheapest and fastest method, on using a small number of genes, and on the estimation of the effectiveness of carriers&rsquo, detection. The custom panel was tested on a population-based cohort that included 1244 participants. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The frequency of heterozygotes in the Russian population was 16.87% or 1:6 (CI95%: 14.76&ndash, 19.00% by Clopper-Pearson exact method): in CFTR&mdash, 2.81% (1:36), PAH&mdash, 2.33% (1:43), SERPINA1&mdash, 4.90% (1:20), and GJB2&mdash, 6.83% (1:15). The data on allele frequencies were obtained for the first time on a Russian population. The panel allows us to identify the vast majority of carriers of recessive diseases in the population. It is an effective approach to carrier screening for common recessive diseases.

Background The aim of this study is to identify genetic loci associated with post-bronchodilator FEV1/FVC and FEV1, and develop a multi-gene predictive model for lung function in COPD. Methods Genome-wide association study (GWAS) of post-bronchodilator FEV1/FVC and FEV1 was performed in 1645 non-Hispanic White European descent smokers. Results A functional rare variant in SERPINA1 (rs28929474: Glu342Lys) was significantly associated with post-bronchodilator FEV1/FVC (p = 1.2 × 10− 8) and FEV1 (p = 2.1 × 10− 9). In addition, this variant was associated with COPD (OR = 2.3; p = 7.8 × 10− 4) and severity (OR = 4.1; p = 0.0036). Heterozygous subjects (CT genotype) had significantly lower lung function and higher percentage of COPD and more severe COPD than subjects with the CC genotype. 8.6% of the variance of post-bronchodilator FEV1/FVC can be explained by SNPs in 10 genes with age, sex, and pack-years of cigarette smoking (P

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. METHODS: In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. RESULTS: 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. CONCLUSIONS: 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes. This work was supported by SEPAR 201/2013 and ISCIII PI17/01250 grants and European Regional Development Funds. Sí

Of all breast cancer patients, about 70% are ER+ and 10% are ER+/HER2+. The ER+/HER2+ patients have a worse outcome compared to ER+/HER2- patients. Currently there is a lack of effective prognosis biomarkers for the prediction of outcome in ER+/HER2+ patients. Genome-wide differences in ER binding between the endocrine-responsive and endocrine-resistant cells were discovered using ChIP-seq, and combined with gene expression microarray data to identify direct ER target genes. These genes were correlated to survival outcome using publicly available breast cancer patient cohorts. We found the expression of the gene SERPINA1 to have a significant predictive value for the overall survival (OS) of ER+ patients in the TCGA cohort, and validated this finding in the Curtis cohort. SERPINA1 also has a significant predictive value for the OS of ER+/HER2+ patients in the TCGA cohort, with validation in the Bild cohort. The expression of SERPINA1 can be suppressed by fulvestrant and HER2 siRNA. Our results indicate that ER is constitutively activated, resulting in an E2-independent ER binding to the SERPINA1 gene and upregulation of SERPINA1 expression. Importantly, results of survival correlation suggests that high expression of SERPINA1 could be predictive for a better clinical outcome of ER+ and ER+/HER2+ patients.

// Chae Hwa Kwon 1,* , Hye Ji Park 1,* , Jin Hwa Choi 1 , Ja Rang Lee 1 , Hye Kyung Kim 1 , Hong-jae Jo 2 , Hyun Sung Kim 2 , Nahmgun Oh 2 , Geun Am Song 3 and Do Youn Park 1 1 Department of Pathology, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Seo-Gu, Busan, Korea 2 Department of Surgery, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Seo-Gu, Busan, Korea 3 Department of Internal Medicine, Pusan National University Hospital and Pusan National University School of Medicine, and BioMedical Research Institute, Pusan National University Hospital, Seo-Gu, Busan, Korea * These authors have contributed equally to this work Correspondence to: Do Youn Park, email: // Keywords : colorectal cancer, snail, serpinA1, prognosis, fibronectin Received : December 16, 2014 Accepted : April 10, 2015 Published : April 29, 2015 Abstract The role of Snail and serpin peptidase inhibitor clade A member 1 (serpinA1) in tumorigenesis has been previously identified. However, the exact role and mechanism of these proteins in progression of colorectal cancer (CRC) are controversial. In this study, we investigated the role of Snail and serpinA1 in colorectal cancer (CRC) and examined the mechanisms through which these proteins mediate CRC progression. Immunohistochemical analysis of 528 samples from patients with CRC showed that elevated expression of Snail or serpinA1 was correlated with advanced stage, lymph node metastasis, and poor prognosis. Moreover, we detected a correlation between Snail and serpinA1 expression. Functional studies performed using the CRC cell lines DLD-1 and SW-480 showed that overexpression of Snail or serpinA1 significantly increased CRC cell invasion and migration. Conversely, knockdown of Snail or serpinA1 expression suppressed CRC cell invasion and migration. ChIP analysis revealed that Snail regulated serpinA1 by binding to its promoter. In addition, fibronectin mediated Snail and serpinA1 signaling was involved in CRC cell invasion and migration. Taken together, our data showed that Snail and serpinA1 promoted CRC progression through fibronectin. These findings suggested that Snail and serpinA1 were novel prognostic biomarkers and candidate therapeutic targets in CRC.

Ignacio Blanco,1 Patricia Bueno,2 Isidro Diego,3 Sergio Pérez-Holanda,4 Beatriz Lara,5 Francisco Casas-Maldonado,6 Cristina Esquinas,7 Marc Miravitlles7,8 1Alpha1-Antitrypsin Deficiency Spanish Registry (REDAAT), Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain; 2Internal Medicine Department, County Hospital of Jarrio, Principality of Asturias, Spain; 3Materials and Energy Department, School of Mining Engineering, Oviedo University, Principality of Asturias, Spain; 4Surgical Department, University Central Hospital of Asturias, Oviedo, Spain; 5Respiratory Medicine Department, Coventry and Warwickshire University Hospital, Coventry, UK; 6Pneumology Department, University Hospital San Cecilio, Granada, Spain; 7Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 8CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain Abstract: The alpha-1 antitrypsin (AAT) haplotype Pi*S, when inherited along with the Pi*Z haplotype to form a Pi*SZ genotype, can be associated with pulmonary emphysema in regular smokers, and less frequently with liver disease, panniculitis, and systemic vasculitis in a small percentage of people, but this connection is less well established. Since the detection of cases can allow the application of preventive measures in patients and relatives with this congenital disorder, the objective of this study was to update the prevalence of the SZ genotype to achieve accurate estimates of the number of Pi*SZ subjects worldwide, based on studies performed according to the following criteria: 1) samples representative of the general population, 2) AAT phenotyping characterized by adequate methods, and 3) selection of studies with reliable results assessed with a coefficient of variation calculated from the sample size and 95% confidence intervals. Studies fulfilling these criteria were used to develop tables and maps with an inverse distance-weighted (IDW) interpolation method, to provide numerical and geographical information of the Pi*SZ distribution worldwide. A total of 262 cohorts from 71 countries were included in the analysis. With the data provided by these cohorts, a total of 1,490,816 Pi*SZ were estimated: 708,792 in Europe; 582,984 in America and Caribbean; 85,925 in Africa; 77,940 in Asia; and 35,176 in Australia and New Zealand. Remarkably, the IDW interpolation maps predicted the Pi*SZ prevalence throughout the entire world even in areas lacking real data. These results may be useful to plan strategies for future research, diagnosis, and management of affected individuals. Keywords: SERPINA1, alpha-1 antitrypsin deficiency, protease inhibitor, genetic epidemiology, SZ genotype, inverse distance-weighted interpolation, geographic information system

Background. AAT deficiency is not a rare disease, but one of the most common congenital disorders increasing susceptibility of deficiency individuals to both lung and liver disease as well as other several adverse health effects. Therefore, information on accurate estimates of the magnitude of alpha-1 antitrypsin deficiency in any given country is critical for the development of screening programs for detection, diagnosis, and treatment of those individuals and/or families at risk. Method. Genetic epidemiological studies for alpha-1 antitrypsin deficiency made by others have been used to determine the percentages and estimates of the numbers in each of the five phenotypic classes (PI MS, PI MZ, PI SS, PI SZ, and PI ZZ) of the most common deficiency alleles: PI S and PI Z in each of 69 countries worldwide and also when grouped into 13 major geographic regions. Results. Our studies have demonstrated striking differences between these estimates when comparisons were made in numeric tables, maps and figures. Conclusions. Our studies demonstrated striking differences in the prevalences of both the PIS and PIZ alleles among these 69 countries and the numbers at risk for AAT Deficiency in a given country in specific geographic regions. Data on the prevalence of the two major deficiency alleles as well as the numbers in those phenotypic classes known to be at risk for AAT Deficiency is considered critical for the identification of individuals at risk for adverse health effects associated with AAT Deficiency as well as the treatment and management of those individuals identified in a given country.

A young Caucasian female with severe bronchial asthma and Alpha1-antitrypsin (AAT) deficiency, MZ phenotype, experienced a quick and severe limitation of her physical capacity, which negatively affected her psychological state and social life, though she was under a strong antiasthmatic treatment. Given her declining health status and the significant chronic corticoid administration- related side-effects (including high reduction of muscle mass and bone density), a clinical trial with commercial intravenous AAT was proposed by the patient’s doctors, and accepted by the Spanish Ministry of Health, although it this therapy was not approved for MZ phenotypes yet. This new therapy quickly stopped lung function decline rate, dramatically reduced the number of hospital admissions of the patient, suppressed the oral administration of prednisone, reversed the corticosteroid-related health adverse effects, significantly improving her quality of life. Thus, although AAT replacement therapy is not approved nor indicated for the treatment of bronchial asthma in MZ patients, its favourable effects observed in this isolated case support the hypothesis that bronchial asthma could be due to pathogenic mechanisms related to a protease- antiprotease imbalance, what which could open new perspectives for future research on the field.

Background. AAT deficiency is not a rare disease, but one of the most common congenital disorders increasing susceptibility of individuals with this deficiency to both lung and liver disease as well as other several adverse health effects. Studies to develop accurate estimates of the magnitude of this genetic disorder in any given country is critical for the development of screening programs for detection, diagnosis, and treatment of those individuals and/or families at risk. In the present study, estimates of the prevalence of the two major deficiency alleles PI S and PI Z were estimated for 25 countries in the Caribbean and North, Central, and South America to supplement our previous studies on 69 countries worldwide. Method. Using data on the prevalence of the two most common deficiency alleles PI S and PIZ in the mother countries that provided the majority of immigrants to these 25 countries, as well as genetic epidemiological studies on various genetic subgroups indigenous to the Caribbean and North, Central and South America it was possible to develop new formulas to estimate the numbers in each of five phenotypic classes, namely PI MS, PI MZ, PI SS, PI SZ and PI ZZ for each country. Results. When these 25 countries were grouped into six different geographic regions, the present study demonstrated striking differences when comparisons were made in numeric tables, maps and figures. Highly significant numbers of individuals at risk for AAT Deficiency were found in both the European, Mestizo and Mulatto populations for most of the 25 countries studied in the Caribbean and North, Central and South America. Conclusions. Our studies demonstrated striking differences in the prevalence of both the PIS and PIZ alleles among these 25 countries in the Caribbean and North, Central and South America and significant numbers of individuals at risk for adverse health effects associated with AAT Deficiency in a given country. When these data are added to the results from our earlier studies on 69 countries, we now have data on AAT Deficiency in 94 of the 193 countries worldwide listed in the CIA FactBook.

Summary Background 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. Hypothesis Absence of AAT in Null mutations results in more severe emphysema as compared to ZZ and SZ. Methods We genotyped all known Dutch subjects ( n =12) with absent serum AAT, and compared their lung function values (FEV 1 and K CO ) with those of individuals with ZZ and SZ genotype, matched for age and smoking history. Results 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 FEV 1 and K CO , respectively). In all groups, there was a positive correlation between serum AAT and lung function values ( p =0.025 and 0.014 for FEV 1 and K CO , respectively). Conclusions 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.

BACKGROUND: SERPINA1 is the gene for alpha-1 antitrypsin (AAT), an acute phase protein with anti-protease and immunoregulatory activities. Mutations in SERPINA1 gene cause AAT deficiency and predispose individuals to early-onset emphysema and liver diseases. Expression of the SERPINA1 gene is regulated by different promoters and alternative splicing events among non-coding exons 1A, 1B and 1C. METHODS: We have developed three quantitative PCR (QT-PCR) assays (1A, 1B and 1C). These assays were applied for the analysis of SERPINA1 alternative transcripts in: (1) 16 human tissues and (2) peripheral blood leukocytes from 33 subjects with AAT mutations and 7 controls. RESULTS: Tissue-specific expression was found for the SERPINA1 transcripts. The 1A transcripts were mainly expressed in leukocytes and lung tissue while those detected with the 1B assay were highly restricted to leukocytes. Only 1B transcripts significantly correlated with serum AAT levels. The 1C transcripts were specifically found in lung, liver, kidney and pancreas. Furthermore, the expression of transcripts was related to AAT genotypes. While deficient variants of AAT had no pronounced effect on the transcript expression, null alleles were associated with significant reduction of different transcripts. CONCLUSIONS: The possibility to discriminate between SERPINA1 alternative splicing products will help us to understand better the regulation of SERPINA1 gene and its association with SERPINA1 mutations-related diseases. We thank collaborators from the REDAAT (Spanish Registry of Alpha-1 Antitrypsin deficiency patients) and all members of the Human Genetics Area of the ISCIII for their support. Special thanks to Prof. Halpin for reviewing the manuscript. This work has been partially funded by the Instituto de Salud Carlos III Grants TPY1250/12, TPY1269/15 and PI14CIII/00070 (BMD). Sí

Serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1 (SERPINA1) deficiency is one of the main genetic causes related to liver disease in children. In SERPINA1 deficiency the most frequent SERPINA1 alleles found are the PI*S and PI*Z alleles. We used the polymerase chain reaction and the amplification created restriction site (ACRS) technique to investigate the prevalence of the PI*S and PI*Z alleles in a group of Brazilian children (n = 200) with liver disease and established the general frequency of the PI*S allele in our population. We found a significant association of the PI*Z allele and liver disease, but no such relationship was found for the PI*S allele. Our results show that SERPINA1 deficiency due to the PI*Z allele, even when heterozygous, is a frequent cause of liver disease in our group of Brazilian children but that the PI*S allele does not confer an increased risk of hepatic disorders in our group of Brazilian children.

The prevalence of PI*Z and PI*S alleles of SERPINA1 gene related to alpha-1-antitrypsin deficiency has previously been estimated to be lower in Finland than in the other countries of Northern Europe. The prevalence of PI*M (Malton) has not been studied in Finland before. We determined alpha-1-antitrypsin PI*Z and PI*S and PI*M (Malton) genotypes from a representative population sample. The number of subjects was 6,354 in the PI*S and PI*M (Malton) genotyping. PI*Z genotyping was performed in a subsample of 2,482 subjects. The allele frequencies were PI*Z 19.7/1,000 and PI*S 10.2/1,000. No PI*M (Malton) was found. The number of carriers of PI*Z and PI*S is significantly higher than previously estimated. The prevalences are in line with the findings in the neighboring countries.Keywords: alpha-1-antitrypsin deficiency; Europe; Finland; genetic epidemiology; PI*Z; PI*S; PI*M (Malton); prevalence; SERPINA1(Published: 24 September 2015)Citation: European Clinical Respiratory Journal 2015, 2: 28829 - http://dx.doi.org/10.3402/ecrj.v2.28829