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Advances in genetic screening technologies have considerably accelerated the discovery of rare alpha-1-antitrypsin (AAT) variants. Expression in cellular models is an effective approach to evaluate the pathogenic potential of these new AAT variants, whose clinical significance would otherwise remain uncertain. Here we provide a detailed description of established methods for in vitro characterization of AAT coding variants expressed in HEK293T/17 cells. The protocols include determination of secretion efficiency, the tendency to form polymeric chains and  the anti-elastase inhibitory activity., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Sequencing of DNA is normally the final procedure carried out to determine the actual pathogenic variants when the techniques used for genotyping are unable to provide complete identification of both AAT alleles. Gene sequencing of complete SERPINA1 gene by using the Sanger method or next-generation sequencing (NGS) is crucial to enable correct diagnosis in patients with alpha1-antitrypsin deficiency caused by uncommon AAT variants.This protocol explains how to correctly sequence SERPINA1 gene both with Sanger method and NGS., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Alpha-1 antitrypsin deficiency patients (AATD) have lower risk of myocardial infarction, a cardiovascular disease that is related to increased remnant cholesterol levels, but not to low-density lipoprotein (LDL) levels. However, when AAT is knocked out in mice (AAT-KO), inflammatory-related, cholesterol metabolism-related, and lipid metabolism-related gene expression in mouse liver was increased, and these data support previous evidence from clinic patients and from a small clinical trial that AAT is in negative feedback regulation with LDL. Herein is a brief summary to examine the roles of AAT in these overlapping pathways., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Lung disease in alpha-1-antitrypsin deficiency (AATD) mainly results from insufficient control of the serine proteases neutrophil elastase (NE) and proteinase-3 due to reduced plasma levels of alpha-1-antitrypsin (AAT) variants. Mutations in the specificity-determining reactive center loop (RCL) of AAT would be predicted to minimally affect protein folding and secretion by hepatocytes but can impair anti-protease activity or alter the target protease. These properly secreted but dysfunctional 'type-2' variants would not be identified by common diagnostic protocols that are predicated on a reduction in circulating AAT. This has potential clinical relevance: in addition to the dysfunctional Pittsburgh and Iners variants reported previously, several uncharacterized RCL variants are present in genome variation databases. To prospectively evaluate the impact of RCL variations on secretion and anti-protease activity, here we performed a systematic screening of amino acid substitutions occurring at the AAT-NE interface. Twenty-three AAT variants that can result from single nucleotide polymorphisms in this region, including 11 present in sequence variation databases, were expressed in a mammalian cell model. All demonstrated unaltered protein folding and secretion. However, when their ability to form stable complexes with NE was evaluated by western blot, enzymatic assays, and a novel ELISA developed to quantify AAT-NE complexes, substrate-like and NE-binding deficient dysfunctional variants were identified. This emphasizes the ability of the RCL to accommodate inactivating substitutions without impacting the integrity of the native molecule and demonstrates that this class of molecule violates a generally accepted paradigm that equates circulating levels with functional protection of lung tissue., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background & Aims: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*S rs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13 (rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to test these associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. Methods: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stages I-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelic discrimination assays. Adjusted p value of ≤ 0.016 was considered significant. Results: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium. SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkage disequilibrium with rs72613567; r²=0.96) also showed no overall association with liver disease, but the GG-genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associated with higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). Conclusions: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis, while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis of different aetiology. [ABSTRACT FROM AUTHOR]

The Sarcolab pilot study of 2 crewmembers, investigated before and after a 6-mo International Space Station mission, has demonstrated the substantial muscle wasting and weakness, along with disruption of muscle's oxidative metabolism. The present work aimed at evaluating the pro/anti-inflammatory status in the same 2 crewmembers (A, B). Blood circulating (c-)microRNAs (miRs), c-proteasome, c-mitochondrial DNA, and cytokines were assessed by real-time quantitative PCR or ELISA tests. Time series analysis was performed (i.e., before flight and after landing) at 1 and 15 d of recovery (R+1 and R+15, respectively). C-biomarkers were compared with an age-matched control population and with 2-dimensional proteomic analysis of the 2 crewmembers' muscle biopsies. Striking differences were observed between the 2 crewmembers at R+1, in terms of inflamma-miRs (c-miRs-21-5p, -126-3p, and -146a-5p), muscle specific (myo)-miR-206, c-proteasome, and IL-6/leptin, thus making the 2 astronauts dissimilar to each other. Final recovery levels of c-proteasome, c-inflamma-miRs, and c-myo-miR-206 were not reverted to the baseline values in crewmember A. In both crewmembers, myo-miR-206 changed significantly after recovery. Muscle biopsy of astronaut A showed an impressive 80% increase of a-1-antitrypsin, a target of miR-126-3p. These results point to a strong stress response induced by spaceflight involving muscle tissue and the proinflammatory setting, where inflamma-miRs and myo-miR-206 mediate the systemic recovery phase after landing. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTR) results from aggregation and extracellular disposition of misfolded TTR mutants. Growing evidence suggests the importance of hepatic chaperones for the modulation of pathogenesis. We took advantage of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from ATTR patients (ATTR-HLCs) to compare chaperone gene expression to that in HLCs from healthy individuals (H-HLCs). From the set of genes analyzed, chaperones that are predominantly located extracellularly were differently expressed. Expression of the chaperones showed a high correlation with TTR in both ATTR-HLCs and H-HLCs. In contrast, after TTR knockdown, the correlation was mainly affected in ATTR-HLCs suggesting that differences in TTR expression triggers aberrant chaperone expression. Serpin family A member 1 (SERPINA1) was the only extracellular chaperone that was markedly upregulated after TTR knockdown in ATTR-HLCs. Co-immunoprecipitation revealed that SERPINA1 physically interacts with TTR. In vitro assays indicated that SERPINA1 can interfere with TTR aggregation. Taken together, our results suggest that extracellular chaperones play a crucial role in ATTR pathogenesis, in particular SERPINA1, which may affect amyloid formation. [ABSTRACT FROM AUTHOR]

Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function.

Papillary thyroid carcinoma (PTC) is the most prevalent malignancy within the endocrine system, exhibiting a rapid growth rate in recent years. Serpin peptidase inhibitor clade A member 1 (SERPINA1) has been previously proposed as a diagnostic biomarker; however, it's potential molecular relevance and biological function in PTC remains largely unexplored. Our study utilized multi-omics bioinformatic data from several public databases, supplemented with transcriptional profiles using our local cohort comprising 79 paired PTC samples. Using multi-omics profiling of a PTC cohort, we have identified SERPINA1 as a potential oncogene involved in PTC progression. Our clinical analysis revealed a significant association between SERPINA1 expression and mutations in BRAF V600E and RAS. Furthermore, SERPINA1 level was correlated with clinicopathological factors in patients with PTC and with a worse prognosis in early-stage patients. Functionally, we found a strong correlation between SERPINA1 expression and increased infiltration of dendritic cells and regulatory T-cells, suggesting an elevated level of immune infiltration. Moreover, SERPINA1 knockdown reduced the proliferative and migrational ability of PTC cells in vitro. Our study highlights the high expression of SERPINA1 in PTC and its potential role in shaping the immune microenvironment, thereby promoting disease progression. These findings suggest that SERPINA1 could serve as a promising therapeutic target for intervention in PTC. • SERPINA1 was identified as a significant upregulated gene in BRAF-driven PTCs. • SERPINA1 expression was associated with BRAF V600E, RAS , TERT , and RET status. • SERPINA1 expression may herald an advanced malignancy of the PTC. • Significant correlations were identified between SERPINA1 level and immune infiltration and drug resistance in PTC. • SERPINA1 affects proliferative and migrational ability of PTC cells in vitro. [ABSTRACT FROM AUTHOR]

Protease inhibitor S (PiS) and protease inhibitor Z (PiZ) variants in the SERPINA1 gene are the main genetics factors associated with COPD; however, investigations about other polymorphisms are scanty. The aim of this study was to evaluate two missense single nucleotide polymorphisms (SNPs) (rs709932 and rs1303) in the SERPINA1 gene in Mexican mestizo patients with chronic obstructive pulmonary disease (COPD) related to tobacco smoking and biomass-burning exposure. 1700 subjects were genotyped and divided into four groups: COPD related to tobacco smoking (COPD-S, n = 297), COPD related to biomass-burning exposure (COPD-BB, n = 178), smokers without COPD (SWOC, n = 674), and biomass-burning exposed subjects (BBES, n = 551) by real-time PCR. Moreover, the patients’ groups were divided according to their exacerbations’ frequency. We carried out a haplotype analysis. We did not find differences in allele and genotype frequencies between groups in unadjusted and adjusted analyses, neither with these SNPs and lung function decline. Exacerbations’ frequency is not associated with these SNPs. However, we found a haplotype with major alleles (CT) associated with reduced risk for COPD (p < 0.05). Our analysis reveals that SNPs different from PiS and PiZ (rs709932 and rs1303) in the SERPINA1 gene are not associated with COPD and lung function decline in a Mexican mestizo population. However, a haplotype shaped by both major alleles (CT haplotype) is associated with reduced risk for COPD.

Aim: This study aimed to identify molecular markers associated with papillary thyroid cancer (PTC) and investigate the therapeutic potential of targeted nanoscale drugs. Materials & methods: We analyzed the effects of circICA1 and miR-486-3p on B-CPAP cells' proliferation, apoptosis, migration and invasion. The regulation of the miR-486-3p /SERPINA1 axis was explored using quantitative real-time reverse transcription PCR and western blot analyses for metastasis. In vivo , we evaluated the effects of hyperbranched polyamidoamine-RGD peptide/si- circICA1 on PTC growth and metastasis. Results: Enhanced miR-486-3p expression inhibits B-CPAP cells' proliferation and invasion. si- circICA1 delivered via hyperbranched polyamidoamine-RGD peptide nanoparticles shows potential for treating metastasis in PTC. Conclusion: This study identifies key molecular mechanisms underlying PTC invasiveness and suggests a promising therapeutic strategy for PTC using targeted nanoscale drugs.

Purpose Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood. Variation in genes SERPINA6 encoding for CBG, SERPINA2 and SERPINA1 (serpin family A member 6, 2, and 1) have been shown to influence morning plasma cortisol and CBG in adults. However, association of this genetic variation with diurnal and stress-induced salivary cortisol remain unknown. This study aims to investigate the effect of genetic variation in SERPINA6 / 2 / 1 loci on diurnal and stress-induced salivary cortisol in children. Methods We studied 186, 8-year-old children with genome-wide genotyping. We generated weighted polygenic risk score (PRS) based on 6 genome-wide significant SNPs (rs11621961, rs11629171, rs7161521, rs2749527, rs3762132, rs4900229) derived from the CORNET meta-analyses. Salivary cortisol was measured across one day and in response to the Trier Social Stress Test for Children (TSST-C). Results Mixed models, adjusted for covariates, showed that the PRS x sampling time interactions associated with diurnal ( P <  0.001) and stress-induced ( P  = 0.009) salivary cortisol. In the high PRS group (dichotomized at median) the diurnal salivary cortisol pattern decreased less from awakening to bedtime than in the low PRS group (standardized estimates of sampling time −0.64 vs. −0.73, P < 0.0001 for both estimates). In response to stress, salivary cortisol increased in the high PRS group while it remained unchanged in the low PRS group (standardized estimates of sampling time 0.12, P  = 0.015 vs. −0.06, P  = 0.16). These results were mainly driven by minor alleles of rs7161521 ( SERPINA6 ) and rs4900229 ( SERPINA1 ). Conclusions Genetic variation in SERPINA6/2/1 loci may underpin higher hypothalamic-pituitary-adrenocortical axis activity in children. [ABSTRACT FROM AUTHOR]

The clinical and molecular characteristics of three patients with previously unreported SERPINA1 mutations associated with severe alpha-1 antitrypsin deficiency (AATD) are described. The pathophysiology of the chronic obstructive pulmonary disease (COPD) present in these patients was characterized through clinical, biochemical, and genetic examinations. Case 1: A 73-year-old male with bilateral centri-to panlobular emphysema and multiple increasing ventrobasal bullae and incomplete fissures, COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade III B), progressive dyspnea on exertion (DOE), AAT level of 0.1–0.2 g/L. Genetic testing revealed a unique SERPINA1 mutation: Pi*Z/c.1072C > T. This allele was designated PiQ0 Heidelberg II. Case 2: A 47-year-old male with severely heterogenous centri-to panlobular emphysema concentrated in the lower lobes, COPD GOLD IV D with progressive DOE, AAT <0.1 g/L. He also had a unique Pi*Z/c.10del mutation in SERPINA1. This allele was named PiQ0 Heidelberg III. Case 3: A 58-year-old female with basally accentuated panlobular emphysema, GOLD II B COPD, progressive DOE. AAT 0.1 g/L. Genetic analysis revealed Pi*Z/c.-5+1G > A and c.-472G > A mutations in SERPINA1. This variant allele was named PiQ0 Heidelberg IV. Each of these patients had a unique and previously unreported SERPINA1 mutation. In two cases, AATD and a history of smoking led to severe lung disease. In the third case, timely diagnosis, and institution of AAT replacement stabilized lung function. Wider screening of COPD patients for AATD could lead to faster diagnosis and earlier treatment of AATD patients with AATD which could slow or prevent progression of their disease. • Three patients with COPD were found to have unique variants of SERPINA1 resulting in severe alpha-1 antitrypsin deficiency. • A patient with less severe disease at diagnosis was treated with AAT augmentation and achieved stable pulmonary function. • More research is warranted to assess whether earlier diagnosis of and therapy for AAT deficiency can improve outcomes. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin (AAT) is an inhibitor of neutrophil elastase and a member of the serine proteinase inhibitor (serpin) superfamily, and little is known about its activity in sickle cell disease (SCD). We hypothesize that AAT may undergo changes in SCD because of the high oxidative stress and inflammation associated with the disease. We have found high AAT levels in SCD patients compared to controls, while mutant genotypes of SERPINA1 gene had decreased AAT levels, in both groups. AAT showed negative correlation with red blood cells, hemoglobin (Hb), hematocrit, high-density lipoprotein cholesterol, urea, creatinine, and albumin and was positively correlated with mean corpuscular Hb concentration, white blood cells, neutrophils, Hb S, bilirubin, lactate dehydrogenase, ferritin, and C-reactive protein. Patients with higher levels of AAT had more infection episodes (OR = 1.71, CI: 1.05–2.65, p = 0.02), gallstones (OR = 1.75, CI: 1.03–2.97, p = 0.02), and had more blood transfusions (OR = 2.35, CI: 1.51–3.65, p = 0.0001). Our data on AAT association with laboratory indices of hemolysis and inflammation suggest that it may be positively associated with SCD severity; the negative correlations with renal parameters suggest a cytoprotective mechanism in SCD patients. In summary, AAT may need to be included in studies related to SCD and in the discussion of further therapeutic strategies.

The presence of the homozygous ‘Pi*Z’ variant of alpha-1 antitrypsin (AAT) (‘Pi*ZZ’ 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 ≥ 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.

Chronic obstructive pulmonary disease (COPD) affects over 65 million individuals worldwide, where α-1-antitrypsin deficiency is a major genetic cause of the disease. The α-1-antitrypsin gene, SERPINA1, expresses an exceptional number of mRNA isoforms generated entirely by alternative splicing in the 5'-untranslated region (5'-UTR). Although all SERPINA1 mRNAs encode exactly the same protein, expression levels of the individual mRNAs vary substantially in different human tissues. We hypothesize that these transcripts behave unequally due to a posttranscriptional regulatory program governed by their distinct 5'-UTRs and that this regulation ultimately determines α-1-antitrypsin expression. Using whole-transcript selective 2'-hydroxyl acylation by primer extension (SHAPE) chemical probing, we show that splicing yields distinct local 5'-UTR secondary structures in SERPINA1 transcripts. Splicing in the 5'-UTR also changes the inclusion of long upstream ORFs (uORFs). We demonstrate that disrupting the uORFs results in markedly increased translation efficiencies in luciferase reporter assays. These uORF-dependent changes suggest that α-1-antitrypsin protein expression levels are controlled at the posttranscriptional level. A leaky-scanningmodel of translation based on Kozak translation initiation sequences alone does not adequately explain our quantitative expression data. However, when we incorporate the experimentally derived RNA structure data, the model accurately predicts translation efficiencies in reporter assays and improves α-1-antitrypsin expression prediction in primary human tissues. Our results reveal that RNA structure governs a complex posttranscriptional regulatory program of α-1-antitrypsin expression. Crucially, these findings describe a mechanism by which genetic alterations in noncoding gene regions may result in α-1-antitrypsin deficiency. [ABSTRACT FROM AUTHOR]

Alpha-1 antitrypsin (AAT) is an inhibitor of neutrophil elastase and a member of the serine proteinase inhibitor (serpin) superfamily, and little is known about its activity in sickle cell disease (SCD). We hypothesize that AAT may undergo changes in SCD because of the high oxidative stress and inflammation associated with the disease. We have found high AAT levels in SCD patients compared to controls, while mutant genotypes of SERPINA1 gene had decreased AAT levels, in both groups. AAT showed negative correlation with red blood cells, hemoglobin (Hb), hematocrit, high-density lipoprotein cholesterol, urea, creatinine, and albumin and was positively correlated with mean corpuscular Hb concentration, white blood cells, neutrophils, Hb S, bilirubin, lactate dehydrogenase, ferritin, and C-reactive protein. Patients with higher levels of AAT had more infection episodes (OR = 1.71, CI: 1.05–2.65, p = 0.02), gallstones (OR = 1.75, CI: 1.03–2.97, p = 0.02), and had more blood transfusions (OR = 2.35, CI: 1.51–3.65, p = 0.0001). Our data on AAT association with laboratory indices of hemolysis and inflammation suggest that it may be positively associated with SCD severity; the negative correlations with renal parameters suggest a cytoprotective mechanism in SCD patients. In summary, AAT may need to be included in studies related to SCD and in the discussion of further therapeutic strategies. [ABSTRACT FROM AUTHOR]

We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive 'multi-omic' analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis. [ABSTRACT FROM AUTHOR]

Background & Aims Fifteen to twenty percent of alpha-1 antitrypsin deficiency patients (A1 ATD) have a severe liver outcome (portal hypertension - PHT) during childhood. Since they all share the same ZZ SERPINA1 genotype and that environmental factors such as alcohol cannot be advanced, the presence of modifier genes is now well recognized. SNPs located on the SERPINA1 and MAN1B1 genes have already been tested in very few studies with contradictory or not replicated results. Methods Our genotype-phenotype correlation study, performed on 92 ZZ children, aimed at determining once and for all if SERPINA1 and MAN1B1 polymorphisms may be implied in the onset of PHT. To do so, we also performed for the first time a complete haplotype reconstruction for data analysis. Results The two genetic associations with severe liver disease that had been suspected previously (one SNP for SERPINA1 and another for MAN1B1) were not confirmed in our cohort. Moreover, the haplotype analysis identified only one major genetic background for the SERPINA1 Z-allele, allowing us to exclude the presence of a frequent modifier SNP within. For MAN1B1, four major haplotypes were identified but the prevalence of PHT did not significantly differ between them. Conclusion We conclude that genetic polymorphisms in these two genes probably do not influence the onset of severe liver disease in A1 ATD. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of α1-antitrypsin PI*ZZ genotypes in patients with COPD is only partially known. We aimed to estimate this prevalence worldwide., Method: A systematic review of the literature was conducted for studies investigating the prevalence of COPD and the prevalence of severe alpha-1-antitrypsin deficiency (AATD) PI*ZZ genotype. Results are shown in tables and on a whole world interpolation map., Results: Studies from 48 countries with available data (21 from Europe, 9 from the Americas, 5 from Africa, 11 from Asia and 2 from Australasia) were selected. About 235,000 individuals with PI*ZZ genotypes were accounted: 50% in Europe, 37% in America, 9% in Asia, 3% in Australasia and 1% in Africa. The estimated crude prevalence of COPD in adults older than 40 years was 12.45% in Europe, 13.51% in America, 13.22% in Africa, 11.70% in Asia and 11.86% in Australasia. The highest PI*ZZ weighted average prevalence among COPD subjects (expressed as 1/x [95% confidence intervals]) were found in Northern Europe (395 [252-576]) followed by Western (797 [538-1165]), Southern (944 [600-1475]) and Central Europe (1096 [687-1738]). Outside Europe, high values were found in Australia-New Zealand (1007 [684-1509]), Saudi Arabia (1276 [563-2961]), United States (1298 [1094-1540]), Canada (1482 [1057-2083]) and Thailand (1807 [717-4692]). In the rest of the world, prevalence was significantly lower, especially in vast regions of Asia and Africa where the PI*Z gene is practically non-existent., Conclusions: Severe AATD is associated with a significant number of cases of COPD, especially in Europe, USA, Canada, New Zealand and Australia., (Copyright © 2023 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease. Papillary thyroid carcinoma (PTC) is the most common endocrine cancer. In recent years the rate of coexistence between PTC and HT has increased but the relationship between them remains unclear, meaning it is necessary to find potential biomarkers for PTC coexistence with HT to predict its potential pathways., Method: A co-expression network was constructed using the weighted gene co-expression network analysis (WGCNA) in the R package. The modules of PTC associated with HT (PTC-W) were identified from the GSE138198 dataset. Protein-protein interaction network (PPI) was used to screen the hub genes. Immunohistochemical (IHC) analysis was performed to validate the expression of the hub genes in tissues. Clinical data from The Cancer Genome Atlas (TCGA) datasets were used to analyse the prognosis of the hub genes. Gene set enrichment analysis (GSEA) was used to screen potential pathways of PTC-W., Result: The MEbrown module representing the most significant module, with 958 differentially expressed genes (DEGs), was screened in PTC-W, based on WGCNA analysis. Through PPI, SERPINA1 was identified as a hub gene. Immunostaining validated that SERPINA1 was highly expressed in PTC-W. Moreover, PTC-W expressing SERPINA1 exhibits a better prognosis than PTC without HT (PTC-WO)., Conclusion: Our study demonstrates that SERPINA1 promotes the occurrence of PTC-W, and its prognosis is better than PTC-WO. SERPINA1 promotes a better prognosis for PTC-W, possibly through a tumour inhibition signalling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Xie, Zhou, Li, Ding, Cai, Song, Zhao and Xu.)

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.

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.

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.

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.

Background: Hashimoto's thyroiditis (HT) is a chronic autoimmune disease that poses a risk factor for papillary thyroid carcinoma (PTC). The present study aimed to identify the key genes shared by HT and PTC for advancing the current understanding of their shared pathogenesis and molecular mechanisms., Methods: HT- and PTC-related datasets (GSE138198 and GSE33630, respectively) were retrieved from the Gene Expression Omnibus (GEO) database. Genes significantly related to the PTC phenotype were identified using weighted gene co-expression network analysis (WGCNA). Differentially expressed genes (DEGs) were identified between PTC and healthy samples from GSE33630, and between HT and normal samples from GSE138198. Subsequently, functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Transcription factors and miRNAs regulating the common genes in PTC and HT were forecasted using the Harmonizome and miRWalk databases, respectively, and drugs targeting these genes were investigated using the Drug-Gene Interaction Database (DGIdb). The key genes in both GSE138198 and GSE33630 were further identified via Receiver Operating Characteristic (ROC) analysis. The expression of key genes was verified in external validation set and clinical samples using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC)., Results: In total, 690 and 1945 DEGs were associated with PTC and HT, respectively; of these, 56 were shared and exhibited excellent predictive accuracy in the GSE138198 and GSE33630 cohorts. Notably, four genes, Alcohol Dehydrogenase 1B ( ADH1B ), Active BCR-related ( ABR ), alpha-1 antitrypsin ( SERPINA1 ), and lysophosphatidic acid receptor 5 ( LPAR5 ) were recognized as key genes shared by HT and PTC. Subsequently, EGR1 was identified as a common transcription factor regulating ABR, SERPINA1 , and LPAR5 expression. These findings were confirmed using qRT-PCR and immunohistochemical analysis., Conclusion: Four ( ADH1B, ABR, SERPINA1 , and LPAR5 ) out of 56 common genes exhibited diagnostic potential in HT and PTC. Notably, this study, for the first time, defined the close relationship between ABR and HT/PTC progression. Overall, this study provides a basis for understanding the shared pathogenesis and underlying molecular mechanisms of HT and PTC, which might help improve patient diagnosis and prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yin, Wang, Li, Dong and Peng.)

Introduction and Objectives: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations., Materials and Methods: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates., Results: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007)., Conclusions: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations., Competing Interests: Conflicts of interest Authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the manuscript. No supporting institution may gain or lose financially through this publication. E.M.G. report funding from the Board of Economy, Industry, Trade, and Knowledge of the Canary Islands Government, with a European Social Fund co-financing rate managed by the Canary Islands Agency for Research, Innovation, Society and Information (ACIISI). E.H.L. was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018–083,837). V.P. has received grant support from MSD. V.d.P. was supported by CIBER de Enfermedades Respiratorias, ISCIII, Spain. E.H.L., and M.P.Y. report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by the European Social Fund “ESF Investing in your future” by the European Union. J.P.G reports funding from the Spanish Ministry of Universities. M.P.Y. report grants from the European Regional Development Fund “ERDF A way of making Europe” by the European Union. M.P.Y. reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work and grants from Instituto de Salud Carlos III, Madrid, Spain. M.P.Y. and J.V. report grants from Instituto de Salud Carlos III, Madrid, Spain., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

NAD(P)H: quinone oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3’ untranslated region (UTR) and the coding region (CR) of SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3’UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase (NE), one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as an RNA-binding protein may help to explain its pleiotropic biological effects. [ABSTRACT FROM AUTHOR]

We explored the involvement of genomic copy number variants ( CNVs) in susceptibility to recurrent airway obstruction ( RAO), or heaves-an asthmalike inflammatory disease in horses. Analysis of 16 RAO-susceptible (cases) and six RAO-resistant (control) horses on a custom-made whole-genome 400K equine tiling array identified 245 CNV regions ( CNVRs), 197 previously known and 48 new, distributed on all horse autosomes and the X chromosome. Among the new CNVRs, 30 were exclusively found in RAO cases and were further analyzed by quantitative PCR, including additional cases and controls. Suggestive association ( P = 0.03; corrected P = 0.06) was found between RAO and a loss on chromosome 5 involving NME7, a gene necessary for ciliary functions in lungs and involved in primary ciliary dyskinesia in humans. The CNVR could be a potential marker for RAO susceptibility but needs further study in additional RAO cohorts. Other CNVRs were not associated with RAO, although several involved genes of interest, such as SPI2/ SERPINA1 from the serpin gene family, which are associated with chronic obstructive pulmonary disease and asthma in humans. The SPI2/ SERPINA1 CNVR showed striking variation among horses, but it was not significantly different between RAO cases and controls. The findings provide baseline information on the relationship between CNVs and RAO susceptibility. Discovery of new CNVs and the use of a larger population of RAO-affected and control horses are needed to shed more light on their significance in modulating this complex and heterogeneous disease. [ABSTRACT FROM AUTHOR]