RESUMEN
Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.
Asunto(s)
Asma , Estudio de Asociación del Genoma Completo , Inmunoglobulina G , Polimorfismo de Nucleótido Simple , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/genética , Adulto , Femenino , Masculino , Asma/genética , Asma/inmunología , Asma/sangre , Niño , Adolescente , Receptores de IgG/genética , Persona de Mediana Edad , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/sangre , Alelos , Adulto Joven , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/sangre , Cromosomas Humanos Par 17/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA/inmunología , Proteínas de la MembranaRESUMEN
OBJECTIVE: To investigate the correlation between serum Rac1 enzyme (Rac1) level with asthma control, airway inflammatory response and lung function in asthmatic children. METHODS: A retrospective analysis was performed on 79 children with asthma who were diagnosed and treated in our hospital from June 2020 to January 2023. According to the severity of the disease, the children were divided into mild group (25 cases), moderate group (30 cases) and severe group (24 cases). 36 healthy children who underwent physical examination at the same period in our hospital were selected as the control group. The state of an illness, control level, serum mRNA Rac1, inflammatory factors, and lung function of the children in two groups were compared between the control group and the observation group. RESULTS: The Rac1 mRNA levels, forced vital capacity (FVC), forced expiratory volume in one second/FVC (FEV1/FVC), peak expiratory flow (PEF), and maximum mid-expiratory flow (MMEF) in the observation group were significantly lower than these in the control group (P < 0.05). The tumor necrosis factor-alpha (TNF-α), interleukin-5 (IL-5), IL-6, and IL-33 in the observation group were markedly higher than these in the control group (P < 0.05). As the state of an illness worsened, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually reduced (P < 0.05), while the levels of TNF-α, IL-5, IL-6, and IL-33 increased (P < 0.05). As the degree of disease control improved, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually elevated (P < 0.05), and the levels of TNF- α, IL-5, IL-6, and IL-33 showed the opposite trend (P < 0.05). Rac1 was negatively related to the levels of TNF-α, IL-5, IL-6 and IL-33 (P < 0.05), and positively to the levels of FVC, FEV1/FVC, PEF and MMEF (P < 0.001). Rac1 mRNA levels, FVC, FEV1/FVC, PEF and MMEF were protective factors, while TNF-α, IL-5, IL-6 and IL-33 were risk factors for the prognosis of children with asthma (P < 0.05). CONCLUSION: Children with asthma have obviously lower serum Rac1 mRNA levels, higher inflammatory factor levels and lower lung function. Serum Rac1 mRNA level may be associated with better asthma control, lower airway inflammatory response, better lung function and lower disease severity. It has important reference value for the evaluation of the state of an illness, efficacy and prognosis of children with bronchial asthma.
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Asma , Proteína de Unión al GTP rac1 , Humanos , Asma/fisiopatología , Asma/genética , Asma/sangre , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rac1/genética , Femenino , Masculino , Niño , Estudios Retrospectivos , Capacidad Vital , Volumen Espiratorio Forzado , Pulmón/fisiopatología , Pruebas de Función Respiratoria , Factor de Necrosis Tumoral alfa/sangre , Estudios de Casos y Controles , Interleucina-33/sangre , Interleucina-33/genética , Preescolar , Interleucina-6/sangre , Adolescente , Índice de Severidad de la Enfermedad , Interleucina-5/sangre , ARN Mensajero/metabolismoRESUMEN
The aim is to investigate the evidence for shared genetic architecture between each of asthma, allergic rhinitis and eczema with gastro-esophageal reflux disease (GERD). Structural equation models (SEM) and polygenic risk score (PRS) analyses are applied to three Swedish twin cohorts (n = 46,582) and reveal a modest genetic correlation between GERD and asthma of 0.18 and bidirectional PRS and phenotypic associations ranging between OR 1.09-1.14 and no correlations for eczema and allergic rhinitis. Linkage disequilibrium score regression is applied to summary statistics of recently published GERD and asthma/allergic disease genome wide association studies and reveals a genetic correlation of 0.48 for asthma and GERD, and Genomic SEM supports a single latent factor. A gene-/gene-set analysis using MAGMA reveals six pleiotropic genes (two at 12q13.2) associated with asthma and GERD. This study provides evidence that there is a common genetic architecture unique to asthma and GERD that may explain comorbidity and requires further investigation.
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Asma , Reflujo Gastroesofágico , Estudio de Asociación del Genoma Completo , Humanos , Reflujo Gastroesofágico/genética , Asma/genética , Femenino , Masculino , Predisposición Genética a la Enfermedad , Suecia/epidemiología , Adulto , Persona de Mediana Edad , Herencia Multifactorial , Hipersensibilidad/genética , Desequilibrio de LigamientoRESUMEN
Background: High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. Method: To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. Results: IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP. Conclusion: IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.
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Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-6 , Humanos , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Estudio de Asociación del Genoma Completo , COVID-19/genética , Teorema de Bayes , SARS-CoV-2/fisiología , Asma/genética , Asma/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Interleucina-6/genética , Interleucina-6/antagonistas & inhibidoresRESUMEN
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 60 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood and lung tissue. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD.
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Asma , Displasia Broncopulmonar , Eosinofilia , Fenotipo , Polimorfismo de Nucleótido Simple , Humanos , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patología , Masculino , Femenino , Eosinofilia/genética , Niño , Asma/genética , Proteína 1 Similar al Receptor de Interleucina-1/genética , Predisposición Genética a la Enfermedad , Recién Nacido , Estudio de Asociación del Genoma Completo , Preescolar , Metilación de ADN , LactanteRESUMEN
The mechanisms underlying severe allergic asthma are complex and unknown, meaning it is a challenge to provide the most appropriate treatment. This study aimed to identify novel biomarkers for stratifying allergic asthmatic patients according to severity, and to uncover the biological mechanisms that lead to the development of the severe uncontrolled phenotype. By using miRNA PCR panels, we analyzed the expression of 752 miRNAs in serum samples from control subjects (n = 15) and mild (n = 11) and severe uncontrolled (n = 10) allergic asthmatic patients. We identified 40 differentially expressed miRNAs between severe uncontrolled and mild allergic asthmatic patients. Functional enrichment analysis revealed signatures related to inflammation, angiogenesis, lipid metabolism and mRNA regulation. A random forest classifier trained with DE miRNAs achieved a high accuracy of 97% for severe uncontrolled patient stratification. Validation of the identified biomarkers was performed on a subset of allergic asthmatic patients from the CAMP cohort at Brigham and Women's Hospital, Harvard Medical School. Four of these miRNAs (hsa-miR-99b-5p, hsa-miR-451a, hsa-miR-326 and hsa-miR-505-3p) were validated, pointing towards their potential as biomarkers for stratifying allergic asthmatic patients by severity and providing insights into severe uncontrolled asthma molecular pathways.
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Asma , Biomarcadores , Inflamación , Metabolismo de los Lípidos , MicroARNs , Índice de Severidad de la Enfermedad , Humanos , Asma/genética , Asma/sangre , Asma/metabolismo , MicroARNs/genética , MicroARNs/sangre , Femenino , Masculino , Metabolismo de los Lípidos/genética , Adulto , Biomarcadores/sangre , Inflamación/genética , Inflamación/sangre , Inflamación/metabolismo , Persona de Mediana Edad , Perfilación de la Expresión Génica , Regulación de la Expresión GénicaRESUMEN
Missing regulatory effects of asthma genetic risks might be hidden within specific cell states. In this issue of Cell Genomics, Djeddi et al.1 uncover how airway epithelial cells, when activated by rhinovirus, influence genetic susceptibility to childhood-onset asthma, and this preview emphasizes the need to address these missing regulatory effects across diverse cell states.
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Asma , Rhinovirus , Humanos , Asma/virología , Asma/genética , Asma/epidemiología , Asma/etiología , Rhinovirus/genética , Niño , Predisposición Genética a la Enfermedad , Células Epiteliales/virología , Células Epiteliales/patología , Edad de InicioRESUMEN
Respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and coronavirus pneumonia, present a major global health challenge. Current diagnostic and therapeutic options for these diseases are limited, necessitating the urgent development of novel biomarkers and therapeutic strategies. In recent years, microRNAs (miRNAs) within extracellular vesicles (EVs) have received considerable attention due to their crucial role in intercellular communication and disease progression. EVs are membrane-bound structures released by cells into the extracellular environment, encapsulating a variety of biomolecules such as DNA, RNA, lipids, and proteins. Specifically, miRNAs within EVs, known as EV-miRNAs, facilitate intercellular communication by regulating gene expression. The expression levels of these miRNAs can reflect distinct disease states and significantly influence immune cell function, chronic airway inflammation, airway remodeling, cell proliferation, angiogenesis, epithelial-mesenchymal transition, and other pathological processes. Consequently, EV-miRNAs have a profound impact on the onset, progression, and therapeutic responses of respiratory diseases, with great potential for disease management. Synthesizing the current understanding of EV-miRNAs in respiratory diseases such as COPD, asthma, lung cancer, and novel coronavirus pneumonia, this review aims to explore the potential of EV-miRNAs as biomarkers and therapeutic targets and examine their prospects in the diagnosis and treatment of these respiratory diseases.
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Biomarcadores , COVID-19 , Vesículas Extracelulares , MicroARNs , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , MicroARNs/genética , MicroARNs/metabolismo , COVID-19/genética , Asma/genética , Asma/metabolismo , Asma/terapia , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/terapia , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Animales , SARS-CoV-2RESUMEN
BACKGROUND: Asthma, a prevalent chronic inflammatory disorder, is shaped by a multifaceted interplay between genetic susceptibilities and environmental exposures. Despite strides in deciphering its pathophysiological landscape, the intricate molecular underpinnings of asthma remain elusive. The focus has increasingly shifted toward the metabolic aberrations accompanying asthma, particularly within the domain of pyrimidine metabolism (PyM)-a critical pathway in nucleotide synthesis and degradation. While the therapeutic relevance of PyM has been recognized across various diseases, its specific contributions to asthma pathology are yet underexplored. This study employs sophisticated bioinformatics approaches to delineate and confirm the involvement of PyM genes (PyMGs) in asthma, aiming to bridge this significant gap in knowledge. METHODS: Employing cutting-edge bioinformatics techniques, this research aimed to elucidate the role of PyMGs in asthma. We conducted a detailed examination of 31 PyMGs to assess their differential expression. Through Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), we explored the biological functions and pathways linked to these genes. We utilized Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) to pinpoint critical hub genes and to ascertain the diagnostic accuracy of eight PyMGs in distinguishing asthma, complemented by an extensive correlation study with the clinical features of the disease. Validation of the gene expressions was performed using datasets GSE76262 and GSE147878. RESULTS: Our analyses revealed that eleven PyMGs-DHODH, UMPS, NME7, NME1, POLR2B, POLR3B, POLR1C, POLE, ENPP3, RRM2B, TK2-are significantly associated with asthma. These genes play crucial roles in essential biological processes such as RNA splicing, anatomical structure maintenance, and metabolic processes involving purine compounds. CONCLUSIONS: This investigation identifies eleven PyMGs at the core of asthma's pathogenesis, establishing them as potential biomarkers for this disease. Our findings enhance the understanding of asthma's molecular mechanisms and open new avenues for improving diagnostics, monitoring, and progression evaluation. By providing new insights into non-cancerous pathologies, our work introduces a novel perspective and sets the stage for further studies in this field.
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Asma , Biomarcadores , Biología Computacional , Aprendizaje Automático , Pirimidinas , Asma/genética , Asma/metabolismo , Asma/diagnóstico , Humanos , Biología Computacional/métodos , Biomarcadores/metabolismo , FemeninoRESUMEN
Atopic diseases, including atopic dermatitis (AD) and allergic asthma (AA), are characterized by complex immune responses involving various T cells subsets and their cytokine profiles. It is assumed that single nucleotide polymorphisms (SNPs) in the Vitamin D receptor (VDR) gene and the Vitamin D-binding protein (GC) gene are related to the action of Vitamin D and, consequently, play a role in regulating the immune response. However, there is not enough data to unequivocally support the hypothesis about the relationship between T cells profile and VDR or GC SNPs. Two hundred sixty-six subjects (aged > 18 years) were involved in the study: 100 patients with mild or moderate AD, 85 patients with mild or moderate AA, and 81 healthy individuals. Blood cell counts were determined by standard methods. Flow cytometric analysis was used to evaluate CD4+ T-helper (Th) cell subtypes: Th2, Th1, Th17, and T regulatory (Treg) cells in peripheral blood. Measurements of cytokines, total immunoglobulin E (IgE), and Vitamin D levels in serum were evaluated by ELISA. Significantly higher levels of Th1, Th2, and Th17 cells, along with lower levels of Tregs, were found in patients with atopic diseases compared to healthy individuals. Additionally, higher serum levels of interleukin (IL) 5, IL-17A, and transforming growth factor-ß1 (TGF-ß1), as well as lower levels of IL-10, were observed in patients with atopic diseases than in control. The study established associations between VDR SNPs and immune profiles: the AA genotype of rs731236 was associated with increased Th2 and Th17 cells and a higher Th1/Th2 ratio; the GG genotype of rs731236 was linked to decreased serum IL-10 and TGF-ß1 levels; and the TT genotype of rs11168293 was associated with increased IL-10 levels. Additionally, the GG genotype of GC gene SNP rs4588 was associated with reduced Th2 and Th17 lymphocytes, while the TT genotype of rs4588 was linked to decreased IL-10 levels. Furthermore, the CC genotype of rs7041 was associated with higher levels of Th2, Th17, IL-10, and IL-35, as well as reduced levels of TGF-ß1, while the GG genotype of rs3733359 was associated with reduced IL-10 levels. In conclusion, our study demonstrates that the Vitamin D receptor gene single nucleotide polymorphisms rs731236 and rs11168293, along with polymorphisms in the Vitamin D-binding protein gene (rs4588, rs7041, rs3733359), are significantly associated with variations in T cell profiles in atopy. These variations may play a crucial role in promoting inflammation and provide insight into the genetic factors contributing to the pathogenesis of atopy.
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Asma , Dermatitis Atópica , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol , Proteína de Unión a Vitamina D , Humanos , Receptores de Calcitriol/genética , Proteína de Unión a Vitamina D/genética , Masculino , Femenino , Adulto , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Dermatitis Atópica/sangre , Asma/genética , Asma/inmunología , Asma/sangre , Persona de Mediana Edad , Vitamina D/sangre , Citocinas/sangre , Citocinas/genética , Citocinas/metabolismo , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/sangre , GenotipoRESUMEN
Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.
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Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Polimorfismo de Nucleótido Simple/genética , Masculino , Femenino , Adulto , Asma/genética , Estudios de Casos y Controles , Subunidad beta del Receptor de Interleucina-10/genética , Receptores de IgE/genética , Persona de Mediana Edad , Adolescente , Hipersensibilidad/genética , NiñoRESUMEN
Research on dietary fatty acids (FAs) and lung health has reported skeptical findings. This study aims to examine the causal relationship between circulating FAs and Chronic Obstructive Pulmonary Disease (COPD) onset and exacerbation, using a two-sample Mendelian Randomization (MR) analysis. Strong and independent genetic variants of FAs were obtained from the UK Biobank of European ancestry. The exposure traits included saturated FA (SFA), poly- and mono-unsaturated FA (PUFA and MUFA), omega-3 and omega-6 PUFA, docosahexaenoic acid (DHA), and linoleic acid (LA), all expressed as total FA (TFA) percentages. Summary statistics for COPD outcomes were obtained from the FinnGen consortium including COPD, COPD hospitalization, COPD/asthma-related infections, COPD-related respiratory insufficiency, and COPD/asthma/interstitial lung disease (ILD)-related pneumonia. The inverse-variance weighted (IVW) was the primary MR approach. MR-Egger regression and MR-PRESSO were utilized to evaluate heterogeneity and pleiotropy. MR-PRESSO tests suggested no obvious horizontal pleiotropy. MR results by the IVW approach indicated that the genetically high SFA/TFA levels were associated with an increased risk of COPD/asthma/ILD-related pneumonia (OR: 1.275, 95%CI: 1.103-1.474, p for FDR = 0.002). No significant relationship was observed between other types of FAs and COPD outcomes. Our MR analysis suggests that there is weak evidence that the genetically predicted high SFA/TFA was associated with an increased risk of pneumonia.
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Ácidos Grasos Insaturados , Análisis de la Aleatorización Mendeliana , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Ácidos Grasos Insaturados/sangre , Ácidos Grasos/sangre , Asma/genética , Asma/sangre , Asma/epidemiología , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Ácidos Grasos Omega-3/sangreRESUMEN
PURPOSE: This study aimed to elucidate the causal relationship between Obstructive Sleep Apnea (OSA) and Chronic Respiratory Diseases (CRDs), employing Mendelian Randomization (MR) to overcome limitations inherent in observational studies. METHODS: Utilizing a two-sample MR approach, this study analyzed genetic variants as instrumental variables to investigate the causal link between OSA and various CRDs, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and idiopathic pulmonary fibrosis (IPF). Data were sourced from the FinnGen Consortium (OSA, n = 375,657) and UK Biobank, focusing on genome-wide associations between single-nucleotide polymorphisms (SNPs) and the diseases. Instrumental variables were selected based on strict criteria, and analyses included a random-effects inverse-variance weighted method supplemented by several sensitivity analyses. RESULTS: The study suggests a protective effect of OSA against COPD (OR = 0.819, 95% CI 0.722-0.929, P-value = 0.002), which becomes non-significant after adjusting for BMI, indicating a potential mediating role of BMI in the OSA-COPD nexus. No significant causal links were found between OSA and other CRDs (asthma, IPF, bronchiectasis) or between COPD, asthma, and OSA. CONCLUSIONS: Our findings reveal a BMI-mediated protective effect of OSA on COPD, with no causal connections identified between OSA and other CRDs. These results emphasize the complex relationship between OSA, BMI, and COPD, guiding future clinical strategies and research directions, particularly in light of the study's genetic analysis limitations.
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Asma , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/genética , Apnea Obstructiva del Sueño/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Asma/genética , Asma/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Bronquiectasia/genética , Bronquiectasia/epidemiología , Estudio de Asociación del Genoma Completo , Índice de Masa Corporal , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/epidemiología , Anciano , Enfermedad CrónicaRESUMEN
The most promising treatment options for severe uncontrolled asthma (SUA) have emerged in recent years with the development of monoclonal antibodies for blocking selective targets responsible for the underlying inflammation, such as mepolizumab and benralizumab. However, there is variability in treatment response that is not fully controlled. The variability of the response to mepolizumab and benralizumab could be influenced by single-nucleotide polymorphisms (SNPs), and it would be useful to detect these and use them as predictive biomarkers of response. We conducted a retrospective observational cohort study of 72 Caucasian patients recruited from a tertiary hospital with severe uncontrolled eosinophilic asthma treated with mepolizumab and benralizumab. Polymorphisms in the IL5 (rs4143832, rs17690122), RAD50 (rs11739623, rs4705959), IL1RL1 (rs1420101, rs17026974, rs1921622), GATA2 (rs4857855), IKZF2 (rs12619285), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs569108), and ZNF415 (rs1054485) genes were analyzed by real-time polymerase chain reaction (PCR) using Taqman probes. The response was analyzed after 12 months of treatment. In patients under mepolizumab treatment, a treatment response defined as a reduction in exacerbations was associated with ZNF415 rs1054485-T (p = 0.042; OR = 5.33; 95% CI = 1.06-30.02), treatment response defined as a reduction in oral corticosteroids use was associated with the number of exacerbations in the previous year (p = 0.029; OR = 3.89; 95% CI = 1.24-14.92), and treatment response defined as improvement in lung function was associated with the age at the beginning of biological therapy (p = 0.002; OR = 1.10; 95% CI = 1.04-1.18), FCER1B rs569108-AA (p < 0.001; OR = 171.06; 95% CI = 12.94-6264.11), and FCER1A rs2427837-A (p = 0.021; OR = 8.61; 95% CI = 1.71-76.62). On the other hand, in patients under benralizumab treatment, treatment response, defined as a reduction in exacerbations, was associated with ZNF415 rs1054485-T (p = 0.073; OR = 1.3 × 108; 95% CI = 1.8 × 10-19-NA), FCER1B rs569108-AA (p = 0.050; OR = 11.51; 95% CI = 1.19-269.78), allergies (p = 0.045; OR = 4.02; 95% CI = 1.05-16.74), and sex (p = 0.028; OR = 4.78; 95% CI = 1.22-20.63); and treatment response defined as improvement in lung function was associated with polyposis (p = 0.027; OR = 9.16; 95% CI = 1.58-91.4), IKZF2 rs12619285-AA (p = 0.019; OR = 9.1; 95% CI = 1.7-75.78), IL5 rs4143832-T (p = 0.017; OR = 11.1; 95% CI = 1.9-112.17), and FCER1B rs1441586-C (p = 0.045; OR = 7.81; 95% CI = 1.16-73.45). The results of this study show the potential influence of the studied polymorphisms on the response to mepolizumab and benralizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.
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Antiasmáticos , Anticuerpos Monoclonales Humanizados , Asma , Polimorfismo de Nucleótido Simple , Humanos , Asma/tratamiento farmacológico , Asma/genética , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Antiasmáticos/uso terapéutico , Adulto , Estudios Retrospectivos , Biomarcadores , Resultado del Tratamiento , AncianoRESUMEN
OBJECTIVE: The objective of this study is to elucidate the causal association between asthma and alopecia areata (AA) through the application of Mendelian randomization (MR) analysis, leveraging summary data from genome-wide association studies (GWAS). Additionally, it explores potential mediating factors. MATERIALS AND METHODS: Mendelian randomization (MR) analysis was employed to investigate the causal relationship between asthma and AA using genetic instrumental variables (IVs) for asthma, 91 circulating inflammatory proteins, and AA extracted from large-scale GWAS. The primary analytical approach utilized the inverse-variance weighted (IVW) method, supplemented by weighted median and MR-Egger methods to assess robustness. Tests for heterogeneity and pleiotropy were conducted to ensure result reliability. Furthermore, the study examined the mediating role of circulating inflammatory proteins in the asthma-AA relationship. RESULTS: The findings revealed an increased risk of AA among asthma patients (odds ratio (OR) = 14.070; 95% confidence interval (CI) = 1.410-140.435; P = 0.024). Interleukin-33 (IL-33) emerged as a significant mediator in the asthma-AA relationship, explaining 13.1% of the mediation effect. Bidirectional Mendelian randomization analyses did not establish a causal effect of AA on asthma occurrence. CONCLUSION: This study, utilizing Mendelian Randomization, elucidates the causal link between asthma and AA, highlighting the mediating role of IL-33. These findings underscore the importance of considering AA risk in asthma management and offer insights for potential therapeutic strategies targeting IL-33. Future research should explore additional biomarkers and mediating mechanisms between asthma and AA to enhance treatment approaches and patient quality of life.
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Alopecia Areata , Asma , Estudio de Asociación del Genoma Completo , Interleucina-33 , Análisis de la Aleatorización Mendeliana , Humanos , Alopecia Areata/genética , Asma/genética , Asma/epidemiología , Asma/sangre , Interleucina-33/genética , Interleucina-33/sangre , Análisis de Mediación , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Past observational studies have documented an association between rheumatoid arthritis (RA) and chronic respiratory diseases. Undertaking the approach of Mendelian randomization (MR) analysis, this research aims to delve deeper into the probability of a causal connection between RA and chronic respiratory diseases. Collated genome-wide association study data covering RA with 4199 cases against 208,254 controls, asthma comprising 8216 cases versus 201,592 controls, and chronic obstructive pulmonary disease (COPD) detailing 3315 cases in contrast to 201,592 controls were derived from the repository of the Japanese Biobank. A selection of 10 RA-related, 8 asthma-related, and 4 COPD-related single nucleotide polymorphisms notable for their statistical significance (Pâ <â 5â ×â 10-8) were identified as instrumental variables. The primary analytical technique was the inverse variance-weighted (IVW) method, alongside the MR-Egger protocol, weighted median, and weighted mode to reinforce the validity and solidity of the principal results. For scrutinizing possible implications of horizontal pleiotropy, we harnessed the MR-Egger intercept examination and the Mendelian Randomization Pleiotropy REsidual Sum and Outlier test. Employing the inverse variance-weighted technique, we established a positive correlation between genetic predispositions for RA and actual occurrences of asthma (odds ratios [OR]â =â 1.14; 95% confidence intervals [CI]: 1.04-1.24; Pâ =â .003). This correlation remained strong when testing the results utilizing various methods, including the MR-Egger method (ORâ =â 1.32; 95% CI: 1.09-1.60; Pâ =â .023), the weighted median (ORâ =â 1.16; 95% CI: 1.06-1.26; Pâ <â .001), and the weighted mode (ORâ =â 1.21; 95% CI: 1.11-1.32; Pâ =â .002). Furthermore, our findings from the inverse variance-weighted method also demonstrated a positive association between genetically predicted RA and COPD (ORâ =â 1.12; 95% CI: 1.02-1.29; Pâ =â .021). However, no such link was discerned in supplementary analyses. In a shifted perspective-the reverse MR analysis-no correlation was identified between genetically predicted instances of asthma (IVW, Pâ =â .717) or COPD (IVW, Pâ =â .177) and RA. The findings confirm a causal correlation between genetically predicted RA and an elevated risk of either asthma or COPD. In contrast, our results offer no support to the presumed causal relationship between genetic susceptibility to either asthma or COPD and the subsequent development of RA.
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Artritis Reumatoide , Asma , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Artritis Reumatoide/genética , Artritis Reumatoide/epidemiología , Asma/genética , Asma/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Japón/epidemiología , Predisposición Genética a la Enfermedad , Femenino , Masculino , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
INTRODUCTION: MDM2 is known as the primary negative regulator of p53, and MDM2 promotes lung cancer fibrosis and lung injury through p53-dependent and p53-independent pathways. However, the mechanism by which MDM2 influences the pathogenesis of asthma is unknown. In this study, we investigated the function of MDM2 in lung epithelial cells in type 2 lung inflammation. METHODS: We used type II alveolar epithelial cell-specific heterozygous knockout of Mdm2 mice to validate its function. Then papain-induced asthma model was established, and changes in inflammation were observed by measuring immunohistochemistry and flow cytometry analysis. RESULTS: In this study, we knockdown the mouse Mdm2 gene in type 2 alveolar epithelial cells. We demonstrated that heterozygous Mdm2 gene-deleted mice were highly susceptible to protease allergen papain-induced pulmonary inflammation characterized by increased ILC2 numbers, IL-5 and IL-13 cytokine levels, and lung pathology. A mechanistic study showed that following the decreased expression of Mdm2 in lung epithelial cells and A549 cell line, p53 was overactivated, and the expression of its downstream genes p21, Puma, and Noxa was elevated, which resulted in apoptosis. After Mdm2 knockdown, the mRNA expression of inflammation-related gene IL-25, HMGB1, and TNF-α were increased, which further amplified the downstream ILC2 response and lung inflammation. CONCLUSION: These results indicate that Mdm2 maintains the homeostasis of lung epithelial cells by targeting P53 and regulates the function of lung epithelial cells under type 2 lung inflammation.
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Asma , Homeostasis , Ratones Noqueados , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor , Animales , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ratones , Humanos , Asma/inmunología , Asma/metabolismo , Asma/inducido químicamente , Asma/genética , Células A549 , Modelos Animales de Enfermedad , Apoptosis , Células Epiteliales/metabolismo , Células Epiteliales Alveolares/metabolismo , Papaína , Ratones Endogámicos C57BL , Neumonía/inmunología , Neumonía/metabolismoRESUMEN
Asthma is a complex disease caused by genetic and environmental factors. Studies show that wheezing during rhinovirus infection correlates with childhood asthma development. Over 150 non-coding risk variants for asthma have been identified, many affecting gene regulation in T cells, but the effects of most risk variants remain unknown. We hypothesized that airway epithelial cells could also mediate genetic susceptibility to asthma given they are the first line of defense against respiratory viruses and allergens. We integrated genetic data with transcriptomics of airway epithelial cells subject to different stimuli. We demonstrate that rhinovirus infection significantly upregulates childhood-onset asthma-associated genes, particularly in non-ciliated cells. This enrichment is also observed with influenza infection but not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or cytokine activation. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.
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Asma , Células Epiteliales , Predisposición Genética a la Enfermedad , Infecciones por Picornaviridae , Rhinovirus , Humanos , Asma/genética , Asma/virología , Asma/inmunología , Células Epiteliales/virología , Células Epiteliales/metabolismo , Infecciones por Picornaviridae/genética , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/virología , Niño , Factores de Riesgo , SARS-CoV-2 , Gripe Humana/genética , Gripe Humana/inmunología , Gripe Humana/virología , COVID-19/genética , COVID-19/virología , COVID-19/inmunologíaRESUMEN
Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity-associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small-molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO-regulated transcriptome-wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue-specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL-4/IL-13-treated epithelial cells and house dust mite (HDM)-induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF-α signaling via NF-κB and epithelial-mesenchymal transition-related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23-induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM-induced mice, potentially through diverse cellular processes and epithelial-mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Asma , Inflamación , Animales , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Ratones , Asma/metabolismo , Asma/genética , Inflamación/metabolismo , Humanos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Células Epiteliales/metabolismo , Ratones Endogámicos BALB C , Femenino , Hipersensibilidad/metabolismo , Hipersensibilidad/tratamiento farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
Objective: To explore the causal relationship between asthma, allergic rhinitis (AR), and chronic sinusitis (CRS), using two sample Mendelian randomization (MR) analysis, thereby providing foundational evidences for the pathogenesis and treatment of CRS. Methods: The genetic variations in AR and asthma were used as instrumental variables, with genetic data from the Integrated Epidemiology Unit (IEU) Open database. A total of 14 283 asthma and 18 934 AR cases were included, with 98 300 and 64 595 corresponding normal control cases, respectively. For CRS, there were 3 236 CRSwNP and 8 524 CRSsNP, respectively, with 167 849 and 167 849 corresponding normal control cases, respectively. The genetic data were analyzed using the inverse variance weighting method (IVW), MR Egger method, weighted median method, and Cochran's Q-test. Results: The IVW analysis showed that asthma increased the risk of both CRSwNP (OR=482.8, 95%CI: 57.18-4 077.78, P<0.001) and CRSsNP (OR=25.73, 95%CI: 9.79-67.56, P<0.001); AR significantly increased the risk of CRSsNP (OR=5.40, 95%CI: 1.68-17.26, P=0.004), but not CRSwNP (OR=7.38, 95%CI: 0.80-67.73, P=0.077). Conversely, neither CRSwNP nor CRSsNP increased the risk of asthma or AR. Conclusion: According to Mendelian genetic laws, asthma is a risk factor for CRSwNP and CRSsNP, while AR is a risk factor for CRSsNP.