The SERPINA1 gene is highly polymorphic, with more than 100 variants described in databases. SERPINA1 encodes the alpha-1 antitrypsin (AAT) protein, and severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. In Spanish patients with AAT deficiency, we identified seven new variants of the SERPINA1 gene involving amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala), and PiValencia (Lys328Glu). We examined the characteristics of these variants and the putative association with the disease. Mutant proteins were overexpressed in HEK293T cells, and AAT expression, polymerization, degradation, and secretion, as well as antielastase activity, were analyzed by periodic acid-Schiff staining, Western blotting, pulse-chase, and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C, and T249A variants formed intracellular polymers and did not secrete AAT protein. Both the E151K and K328E variants secreted AAT protein and did not form polymers, although K328E showed intracellular retention and reduced antielastase activity. We conclude that deficient variants may be more frequent than previously thought and that their discovery is possible only by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and management of individuals with AAT deficiency.
alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin/metabolism , Adult , Aged , Female , Gene Frequency , HEK293 Cells , Humans , Male , Middle Aged , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Mutation, Missense , Protein Stability , Proteolysis , alpha 1-Antitrypsin/chemistry
Antecedentes y objetivo: El síndrome de apnea-hipopnea durante el sueño (SAHS) es un factor de riesgo de arteriosclerosis. Nuestro objetivo fue evaluar la arteriosclerosis subclínica en los pacientes con SAHS y el efecto del tratamiento con continuous positive airway pressure (CPAP, «presión positiva continua de la vía aérea superior») sobre el grosor íntima-media carotídeo (GIMc). Pacientes y método: Se incluyeron 125 pacientes con sospecha de SAHS. Después de la polisomnografía, 107 pacientes fueron diagnosticados de SAHS; 58 cumplían criterios de tratamiento con CPAP. El GIMc se midió mediante ecografía a nivel basal y a los 2 años de seguimiento en 50 pacientes con SAHS en tratamiento con CPAP y 35 SAHS sin criterio de CPAP. Resultados: Los valores del GIMc fueron superiores en los pacientes con SAHS respecto a los que no tenían SAHS (665 ± 120 frente a 581 ± 78 μm, p = 0,005), sin asociarse con su nivel de gravedad. La presencia de placas de ateroma fue más prevalente en los SAHS que en los no SAHS (48 frente a 2%, p = 0,004). En los pacientes con SAHS, la media del GIMc permaneció estable durante el seguimiento en el grupo sin CPAP, y en el grupo tratado con CPAP disminuyó significativamente (679 ± 122 frente a 631 ± 117 μm, p < 0,0001). Conclusiones: Los pacientes con SAHS presentan un mayor grado de arteriosclerosis subclínica y no se asocia con su gravedad. La ecografía carotídea en el SAHS es un marcador fiable de arteriosclerosis. El tratamiento con CPAP en el SAHS disminuye el GIMc y el riesgo cardiovascular (AU)
Background and objective: Obstructive sleep apnoea (OSA) is associated with an increased risk of cardiovascular disease. Our objective was to evaluate subclinical atherosclerosis in OSA patients and the effect of continuous positive airway pressure (CPAP) treatment on carotid intima-media thickness (cIMT). Patients and method: We included 125 patients with suspected OSA. After polysomnography, 107 patients were diagnosed with OSA; 58 of these met the criteria for CPAP treatment. cIMT was measured by ultrasonography at baseline in all patients and after 2 years of follow up in 50 patients on CPAP and 35 without CPAP treatment. ResultsThe average cIMT was significantly thicker in OSA than in non-OSA patients (665 ± 120 vs. 581 ± 78 μm, P = .005) and did not differ according to OSA severity. Atheromatous carotid plaque was more prevalent in OSA than non-OSA patients (48 vs. 2%, P = .004). Among OSA patients, the mean cIMT remained stable over time in the group without CPAP, whereas cIMT decreased markedly in the CPAP group (679 ± 122 vs. 631 ± 117 μm, P < .0001). Conclusions: Increased cIMT was associated with presence of OSA, but not with its severity. Carotid ultrasound in OSA is a reliable marker of atherosclerosis. CPAP treatment with CPAP in OSA reduces cIMT and cardiovascular risk (AU)
Humans , Male , Female , Adult , Middle Aged , Arteriosclerosis/complications , Arteriosclerosis/diagnosis , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/diagnosis , Risk Factors , Positive-Pressure Respiration/instrumentation , Continuous Positive Airway Pressure/methods , Continuous Positive Airway Pressure/trends , Continuous Positive Airway Pressure , Polysomnography/instrumentation , Polysomnography/methods , Polysomnography
BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with an increased risk of cardiovascular disease. Our objective was to evaluate subclinical atherosclerosis in OSA patients and the effect of continuous positive airway pressure (CPAP) treatment on carotid intima-media thickness (cIMT). PATIENTS AND METHOD: We included 125 patients with suspected OSA. After polysomnography, 107 patients were diagnosed with OSA; 58 of these met the criteria for CPAP treatment. cIMT was measured by ultrasonography at baseline in all patients and after 2 years of follow up in 50 patients on CPAP and 35 without CPAP treatment. RESULTS: The average cIMT was significantly thicker in OSA than in non-OSA patients (665±120 vs. 581±78µm, P=.005) and did not differ according to OSA severity. Atheromatous carotid plaque was more prevalent in OSA than non-OSA patients (48 vs. 2%, P=.004). Among OSA patients, the mean cIMT remained stable over time in the group without CPAP, whereas cIMT decreased markedly in the CPAP group (679±122 vs. 631±117µm, P<.0001). CONCLUSIONS: Increased cIMT was associated with presence of OSA, but not with its severity. Carotid ultrasound in OSA is a reliable marker of atherosclerosis. CPAP treatment with CPAP in OSA reduces cIMT and cardiovascular risk.
Atherosclerosis/prevention & control , Continuous Positive Airway Pressure , Sleep Apnea, Obstructive/therapy , Adolescent , Adult , Aged , Atherosclerosis/diagnostic imaging , Atherosclerosis/etiology , Carotid Intima-Media Thickness , Case-Control Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Sleep Apnea, Obstructive/complications , Treatment Outcome , Young Adult
OBJECTIVE: To evaluate circulating adipocyte and epidermal fatty acid-binding protein (FABP4 and FABP5) concentrations in patients with obstructive sleep apnea (OSA), as well as the effects of continuous positive airway pressure (CPAP) treatment. METHODS: Our cross-sectional study included 125 patients. After polysomnography, 58 participants met the criteria for CPAP treatment and were included in a closed cohort study of 8 weeks of CPAP treatment. General anthropometric and biochemical data and circulating FABP4 and FABP5 levels were determined in all patients at baseline and after CPAP treatment in those receiving this therapy. RESULTS: Circulating FABP4 but not FABP5 levels were higher in patients with OSA (P = 0.003). FABP4 but not FABP5 values were associated with parameters of OSA severity independently of age, gender, adiposity and insulin resistance (P < 0.05). FABP4 but not FABP5 concentrations were determinants of OSA presence (OR: 1.11, P = 0.010) and severity (OR: 1.06, P = 0.020). After CPAP treatment, FABP4 levels decreased in the more severe patients (P = 0.019), while FABP5 levels increased in all patients (P < 0.001). CONCLUSIONS: FABP4 is directly associated with obstructive sleep apnea severity and did not change with continuous positive airway pressure treatment, while FABP5 was not associated with obstructive sleep apnea severity and increased with continuous positive airway pressure treatment. FABP4 and FABP5 have different associations with obstructive sleep apnea. FABP4 but not FABP5 could be considered a marker of metabolic alterations in obstructive sleep apnea patients.
Fatty Acid-Binding Proteins/blood , Sleep Apnea, Obstructive/blood , Adult , Continuous Positive Airway Pressure , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Polysomnography , Severity of Illness Index , Sleep Apnea, Obstructive/therapy
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Female , Aged , Humans , Respiratory Insufficiency/etiology , Arteriovenous Malformations/complications , Arteriovenous Fistula/complications , Pulmonary Circulation , Hypertension, Pulmonary/complications
