Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

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.

Fungal Pathogens Associated with Aerial Symptoms of Avocado (Persea americana Mill.) in Tenerife (Canary Islands, Spain) Focused on Species of the Family Botryosphaeriaceae.

Fungi of the family Botryosphaeriaceae are considered responsible for various symptoms in avocado such as dieback, external necrosis of branches and inflorescences, cankers on branches and trunks, or stem-end rot of fruits. In recent years, these problems are becoming more frequent in avocado orchards in the Canary Islands (Spain). This work includes the characterization of fungal species involved in these diseases, which were isolated from avocado crops in Tenerife Island between 2018 and 2022. A total of 158 vegetal samples were collected, from which 297 fungal isolates were culture-isolated. Fifty-two of them were selected according to their morphological features as representative isolates of Botryosphaeriaceae, and their molecular characterization was carried out, sequencing the ITS1-2 region as well as the ß-tubulin and the elongation factor 1-alpha genes. Five species of Botryosphaeriaceae were isolated, including Neofusicoccum australe, N. cryptoaustrale/stellenboschiana, N. luteum, N. parvum, and Lasiodiplodia brasiliensis. This is the first time that L. brasiliensis has been associated with avocado dieback and that N. cryptoaustrale/stellenboschiana has been cited in avocado causing symptoms of dieback and stem-end rot. However, it was not possible to assign our isolates unequivocally to N. cryptoaustrale or N. stellenboschiana even additionally using the rpb2 marker for their molecular characterization. Botryosphaeriaceae family seem to be involved in avocado dieback, in the premature fall of fruits during their development in the field and in post-harvest damage in Tenerife, but further studies are needed to clarify the fungal pathogens associated with symptoms in relation to phenological plant growth stages or less frequently observed.

Molecular characterization of PI * S hangzhou , a SERPINA1 allele from continental China encoding a defective alpha-1-antitrypsin.

Alpha-1-antitrypsin deficiency (AATD) is a heritable condition that predisposes to respiratory and hepatic complications. Screenings in East Asia human populations for the AATD alleles most commonly found among Caucasians have yielded poor outcomes. Serum alpha-1-antitrypsin (AAT) levels, AAT phenotypes, and sequences of SERPINA1 gene were examined in a Chinese child with a moderate deficit of serum AAT, who had suffered several episodes of liver disease, as well as in his first-order relatives. Results allowed the identification of PI * S hangzhou , a novel SERPINA1 defective allele, which has been characterized by a L276R substitution, found in a SERPINA1-M3 genetic background. Moreover, potential effects of PI * S hangzhou mutation over the AAT structure were studied by 3D homology modeling. The presence of an arginine residue at position 276 could destabilize the tertiary structure of AAT, since it occurs at a highly conserved hydrophobic cavity in the protein surface, and very close to two positively-charged lysine residues. Attending to the frequency of R276 variant reported in databases for individuals of East Asian ancestry, the PI * S hangzhou allele may explain the global prevalence of the PiS phenotype observed in China.