Differential expression of TOB/BTG family members in patients with plaque psoriasis: cross-sectional study.

TOB/BTG is a family of antiproliferative proteins that play an important role in the regulation of immune responses, acting as lymphocyte activators and macrophage-mediated cytotoxicity. No previous studies have explored their role in patients with psoriasis. The aim of this study was to characterize the expression of TOB/BTG family and their co-localization in skin from patients with psoriasis. This is an exploratory, observational, and cross-sectional study that included 24 plaque psoriasis patients and 15 controls. Gene expression of TOB/BTG family was determinate by RT-PCR. Protein products of TOB/BTG were evaluated by immunohistochemistry and compared with control skin tissues. Holm-Sidak's multiple comparisons test was performed. TOB/BTG family mRNA levels and protein expression were significantly decreased in psoriatic skin tissue compared to non-inflammatory control skin tissue. Double-positive cell TOB1/2, BTG1,2 and BTG4/CD16 expressions were found in normal control skin tissues through epidermis and dermis (p < 0.001) and lesser percentage in patients with mild, almost absent in moderate-severe plaque psoriasis. This is the first report of the TOB/BTG family gene and protein expression in skin tissues by a CD16 + subpopulation in plaque psoriasis. TOB/BTG family protein might represent a new therapeutic target among immune-mediated inflammatory diseases.

Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth.

Selective and precise activation of signaling transduction cascades is key for cellular reprogramming and tissue regeneration. However, the development of small- or large-molecule agonists for many signaling pathways has remained elusive and is rate limiting to realize the full clinical potential of regenerative medicine. Focusing on the Wnt pathway, here we describe a series of disulfide-constrained peptides (DCPs) that promote Wnt signaling activity by modulating the cell surface levels of ZNRF3, an E3 ubiquitin ligase that controls the abundance of the Wnt receptor complex FZD/LRP at the plasma membrane. Mechanistically, monomeric DCPs induce ZNRF3 ubiquitination, leading to its cell surface clearance, ultimately resulting in FZD stabilization. Furthermore, we engineered multimeric DCPs that induce expansive growth of human intestinal organoids, revealing a dependence between valency and ZNRF3 clearance. Our work highlights a strategy for the development of potent, biologically active Wnt signaling pathway agonists via targeting of ZNRF3.

Monoacylglycerol Lipase Inhibition Prevents Short-Term Mitochondrial Dysfunction and Oxidative Damage in Rat Brain Synaptosomal/Mitochondrial Fractions and Cortical Slices: Role of Cannabinoid Receptors.

Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation.

Factores de riesgo psicosociales que influyen en el comportamiento suicida en las personas privadas de la libertad en Colombia / Psychosocial risk factors that influence suicidal behavior in people deprived of liberty in Colombia

Resumen Objetivo: Identificar los factores de riesgo psicosocial y las características que los componen; que a su vez repercuten en el comportamiento suicida, en los privados de la libertad de Colombia, para mejorar la atención psicológica que se lleva a cabo en los centros penitenciarios. Método: Articulo de revisión documental, de tipo cualitativo, realizado a través de una recolección, revisión y análisis de 55 documentos; de los cuales se seleccionaron 13 artículos que cumplían con los criterios de inclusión y exclusión previamente establecidos. Durante la investigación se tiene en cuenta la elaboración y distinción del documento, de acuerdo a la recolección y organización de la información obtenida a través de bases de datos como Scielo, Scopus, Oxford, Science Direct, Redalyc, Pubmed, entre otros, por lo tanto, se discriminaron las categorías y subcategorías desarrolladas durante la indagación correspondientes al tema a trabajar. Resultados: Se identificaron los factores de riesgo psicosociales fundamentales como: prisionización, vínculo familiar o afectivo, consumo de sustancias psicoactivas, proyecto de vida, problemas psicológicos y tiempo de condena; que presenta la población penitenciaria a nivel mundial, los cuales se tienen en cuenta para reducir las tasas de comportamiento suicida en el ámbito carcelario. Conclusiones: En la revisión documental se logró identificar cuáles son los factores de riesgo que permitan detectar a tiempo el comportamiento suicida en las personas privadas de la libertad, teniendo en cuenta que la población carcelaria a nivel mundial va en aumento y el comportamiento suicida es catalogado como un problema grave de salud pública; se evidenció la falta de existencia de información para la investigación con base a la atención psicosocial que se le brinda a las personas privadas de la libertad alrededor de los factores de riesgos psicosociales que influyen en el comportamiento suicida; por tal razón es importante investigar a profundidad acerca de los factores protectores que pueden prevenir el suicidio en la población.

Abstract Objective: To identify the characteristics that make up the psychosocial risk factors that have an impact on suicidal behavior in Colombian prisoners, in order to improve the psychological care provided in penitentiaries. Method: Documentary review article, of qualitative type, carried out through a collection, review and analysis of 50 documents; of which 13 articles were selected for the elaboration of the results. During the research, the elaboration and distinction of the document is taken into account, according to the collection and organization of information collected through databases such as Scielo, Scopus, Oxford, Science Direct, Redalyc, Pubmed, among others, Therefore, the categories and subcategories developed during the investigation corresponding to the topic to work are discriminated. Results: Key psychosocial risk factors were identified, such as: prison ionization, family or affective bond, use of psychoactive substances, life plan, psychological problems and time of sentence; presented by the prison population worldwide, which are taken into account to reduce suicide rates in prison settings. Conclusions: The documentary review identifies the risk factors and protective factors that allow the timely detection of suicidal behaviour in persons deprived of their liberty, taking into account that some of the risk factors may also be protective factors, such as family ties, the life plan, the process of imprisonment and the time of sentence, and other factors if they are highly relevant because of their risk in suicidal behavior; such as substance use and psychological problems.

Antibody targeting of E3 ubiquitin ligases for receptor degradation.

Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for 'on-demand' degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.

On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence.

The endocannabinoid system (ECS) is composed of endogenous cannabinoids; components involved in their synthesis, transport, and degradation; and an expansive variety of cannabinoid receptors. Hypofunction or deregulation of the ECS is related to pathological conditions. Consequently, endogenous enhancement of endocannabinoid levels and/or regulation of their metabolism represent promising therapeutic approaches. Several major strategies have been suggested for the modulation of the ECS: (1) blocking endocannabinoids degradation, (2) inhibition of endocannabinoid cellular uptake, and (3) pharmacological modulation of cannabinoid receptors as potential therapeutic targets. Here, we focused in this review on degradation/reuptake inhibitors over cannabinoid receptor modulators in order to provide an updated synopsis of contemporary evidence advancing mechanisms of endocannabinoids as pharmacological tools with therapeutic properties for the treatment of several disorders. For this purpose, we revisited the available literature and reported the latest advances regarding the biomedical properties of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in pre-clinical and clinical studies. We also highlighted anandamide and 2-arachidonoylglycerol reuptake inhibitors with promising results in pre-clinical studies using in vitro and animal models as an outlook for future research in clinical trials.

Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.

Subcutaneous Allergen-Specific Immunotherapy Is Safe in Pediatric Patients with Allergic Rhinitis.

INTRODUCTION: Subcutaneous allergen-specific immunotherapy (SCIT) is one of the main cornerstones in the treatment of allergic rhinitis in pediatric patients. It has demonstrated symptoms and quality of life improvement, but it is not exempt from adverse reactions (ADVrs). Nevertheless, there are a few reports that have evaluated their safety. Our objective was to evaluate the ADVr to SCIT in pediatric patients. METHODS: We reviewed 786 clinical records with SCIT from 2005 to 2018, comparing the clinical characteristics of patients with ADVrs with SCIT versus a group of a similar number of patients who completed SCIT (control group, CG). The analysis of ADVrs was according to the World Allergy Organization (WAO) 2010 grading system by frequency analysis, survival curve, and log rank. RESULTS: Of 786 patients, 106 (13.4%) presented ADVrs, and the patients with ADVr had sensitivity and immunotherapy with at least 2 allergens versus CG p < 0.001, containing a combination of standardized and nonstandardized allergens (p = 0.003). The ADVrs were in the buildup phase (p < 0.001). The survival curve showed that 50% had some reaction at 12 weeks of SCIT. The most frequent ADVr was grade 1 in 73/106 patients (68.8%) and grade 2 in 33/106 (31.1%). The log-rank analysis between the grades of the WAO grading system showed a statistically significant difference (p = 0.02). CONCLUSIONS: The SCIT is safe in pediatric patients. The ADVrs are infrequent, grade 1 being the most reported; however, at >12 weeks, the risk of ADVrs that involve 2 organs systems increases.

Amygdala inhibitory neurons as loci for translation in emotional memories.

To survive in a dynamic environment, animals need to identify and appropriately respond to stimuli that signal danger1. Survival also depends on suppressing the threat-response during a stimulus that predicts the absence of threat (safety)2-5. An understanding of the biological substrates of emotional memories during a task in which animals learn to flexibly execute defensive responses to a threat-predictive cue and a safety cue is critical for developing treatments for memory disorders such as post-traumatic stress disorder5. The centrolateral amygdala is an important node in the neuronal circuit that mediates defensive responses6-9, and a key brain area for processing and storing threat memories. Here we applied intersectional chemogenetic strategies to inhibitory neurons in the centrolateral amygdala of mice to block cell-type-specific translation programs that are sensitive to depletion of eukaryotic initiation factor 4E (eIF4E) and phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). We show that de novo translation in somatostatin-expressing inhibitory neurons in the centrolateral amygdala is necessary for the long-term storage of conditioned-threat responses, whereas de novo translation in protein kinase Cδ-expressing inhibitory neurons in the centrolateral amygdala is necessary for the inhibition of a conditioned response to a safety cue. Our results provide insight into the role of de novo protein synthesis in distinct inhibitory neuron populations in the centrolateral amygdala during the consolidation of long-term memories.

Generation of model tissues with dendritic vascular networks via sacrificial laser-sintered carbohydrate templates.

Sacrificial templates for patterning perfusable vascular networks in engineered tissues have been constrained in architectural complexity, owing to the limitations of extrusion-based 3D printing techniques. Here, we show that cell-laden hydrogels can be patterned with algorithmically generated dendritic vessel networks and other complex hierarchical networks by using sacrificial templates made from laser-sintered carbohydrate powders. We quantified and modulated gradients of cell proliferation and cell metabolism emerging in response to fluid convection through these networks and to diffusion of oxygen and metabolites out of them. We also show scalable strategies for the fabrication, perfusion culture and volumetric analysis of large tissue-like constructs with complex and heterogeneous internal vascular architectures. Perfusable dendritic networks in cell-laden hydrogels may help sustain thick and densely cellularized engineered tissues, and assist interrogations of the interplay between mass transport and tissue function.

S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling.

During the growth of lymphatic vessels (lymphangiogenesis), lymphatic endothelial cells (LECs) at the growing front sprout by forming filopodia. Those tip cells are not exposed to circulating lymph, as they are not lumenized. In contrast, LECs that trail the growing front are exposed to shear stress, become quiescent, and remodel into stable vessels. The mechanisms that coordinate the opposed activities of lymphatic sprouting and maturation remain poorly understood. Here, we show that the canonical tip cell marker Delta-like 4 (DLL4) promotes sprouting lymphangiogenesis by enhancing VEGF-C/VEGF receptor 3 (VEGFR3) signaling. However, in lumenized lymphatic vessels, laminar shear stress (LSS) inhibits the expression of DLL4, as well as additional tip cell markers. Paradoxically, LSS also upregulates VEGF-C/VEGFR3 signaling in LECs, but sphingosine 1-phosphate receptor 1 (S1PR1) activity antagonizes LSS-mediated VEGF-C signaling to promote lymphatic vascular quiescence. Correspondingly, S1pr1 loss in LECs induced lymphatic vascular hypersprouting and hyperbranching, which could be rescued by reducing Vegfr3 gene dosage in vivo. In addition, S1PR1 regulates lymphatic vessel maturation by inhibiting RhoA activity to promote membrane localization of the tight junction molecule claudin-5. Our findings suggest a potentially new paradigm in which LSS induces quiescence and promotes the survival of LECs by downregulating DLL4 and enhancing VEGF-C signaling, respectively. S1PR1 dampens LSS/VEGF-C signaling, thereby preventing sprouting from quiescent lymphatic vessels. These results also highlight the distinct roles that S1PR1 and DLL4 play in LECs when compared with their known roles in the blood vasculature.

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling.

RATIONALE: We previously identified somatic activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homologue) gene in the endothelium of the majority of human sporadic brain arteriovenous malformations; a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to arteriovenous malformations, remains unknown. OBJECTIVE: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for arteriovenous malformations. METHODS AND RESULTS: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce brain arteriovenous malformations. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity but instead seem to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent arteriovenous malformations in zebrafish are refractory to inhibition of the downstream effector PI3K but instead require active MEK (mitogen-activated protein kinase kinase 1) signaling. CONCLUSIONS: We demonstrate that active KRAS expression in the endothelium is sufficient for brain arteriovenous malformations, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for arteriovenous malformation patients. Graphical Abstract: A graphical abstract is available for this article.

Utilidad de la plasmaféresis en la pancreatitis aguda por hipertrigliceridemia: a propósito de un caso / The usefulness of plamapheresis in acute pancreatitis due to hypertriglyceridemia: A case report

Resumen Introducción: la pancreatitis aguda es una entidad de alta incidencia e impacto a nivel mundial. Presenta múltiples causas dentro de las cuales las más frecuentes son la obstrucción de la vía biliar, el consumo de alcohol y, en tercer orden, la hipertrigliceridemia. Esta última se entiende como aquellos niveles séricos de triglicéridos >1000 mg/dL. Dicho escenario representa entre el 1 y el 7 % del total de los casos. Metodología: presentamos un caso de pancreatitis aguda secundaria a hipertrigliceridemia severa, manejada con plasmaféresis. Se realiza una revisión de la literatura sobre las condiciones, indicaciones y ventajas de esta estrategia terapéutica. Conclusiones: en casos escogidos, la plasmaféresis es una estrategia de manejo segura y efectiva en el tratamiento de pacientes con pancreatitis aguda secundaria a hipertrigliceridemia severa.

Abstract Introduction: Globally, acute pancreatitis has a high incidence and a large. Among its numerous causes, the most frequent are obstructions of the bile duct, alcohol consumption and hypertriglyceridemia (triglyceride serum levels higher than 1000 mg/dL). Hypertriglyceridemia accounts for 1% to 7% of the total cases. Methodology: We present a case of acute pancreatitis secondary to severe hypertriglyceridemia which was managed with plasmapheresis. We include a review of the literature on the conditions, indications and advantages of this therapeutic strategy. Conclusions: In selected cases, plasmapheresis is a safe and effective management strategy for patients with acute pancreatitis secondary to severe hypertriglyceridemia.

Functional role of PGAM5 multimeric assemblies and their polymerization into filaments.

PGAM5 is a mitochondrial protein phosphatase whose genetic ablation in mice results in mitochondria-related disorders, including neurodegeneration. Functions of PGAM5 include regulation of mitophagy, cell death, metabolism and aging. However, mechanisms regulating PGAM5 activation and signaling are poorly understood. Using electron cryo-microscopy, we show that PGAM5 forms dodecamers in solution. We also present a crystal structure of PGAM5 that reveals the determinants of dodecamer formation. Furthermore, we observe PGAM5 dodecamer assembly into filaments both in vitro and in cells. We find that PGAM5 oligomerization into a dodecamer is not only essential for catalytic activation, but this form also plays a structural role on mitochondrial membranes, which is independent of phosphatase activity. Together, these findings suggest that modulation of the oligomerization of PGAM5 may be a regulatory switch of potential therapeutic interest.

Histone H3 binding to the PHD1 domain of histone demethylase KDM5A enables active site remodeling.

Histone demethylase KDM5A removes methyl marks from lysine 4 of histone H3 and is often overexpressed in cancer. The in vitro demethylase activity of KDM5A is allosterically enhanced by binding of its product, unmodified H3 peptides, to its PHD1 reader domain. However, the molecular basis of this allosteric enhancement is unclear. Here we show that saturation of the PHD1 domain by the H3 N-terminal tail peptides stabilizes binding of the substrate to the catalytic domain and improves the catalytic efficiency of demethylation. When present in saturating concentrations, differently modified H3 N-terminal tail peptides have a similar effect on demethylation. However, they vary greatly in their affinity towards the PHD1 domain, suggesting that H3 modifications can tune KDM5A activity. Furthermore, hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) experiments reveal conformational changes in the allosterically enhanced state. Our findings may enable future development of anti-cancer therapies targeting regions involved in allosteric regulation.

Evaluation of Antioxidant Capacity, Protective Effect on Human Erythrocytes and Phenolic Compound Identification in Two Varieties of Plum Fruit (Spondias spp.) by UPLC-MS.

Plum edible part was used to obtained extracts by during a 4 h maceration process using three different solvents (ethanol, methanol and water) for the determination of total phenols and flavonoids, antioxidant capacity by (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hemolysis inhibition in human blood assays. Subsequently, phenolic compounds were identified using ultra-performance liquid chromatography (UPLC-MS). The results indicated that the ethanolic extract of plum fruit being a good source of phenolic (12⁻18 mg GAE/g FW) and flavonoids (2.3⁻2.5 mg QE/g FW) content in both varieties of plum. Also, the fruits proved a good source of antioxidants as measured by DPPH and ABTS; likewise, plum aqueous extracts showed the highest protective effect on human erythrocytes with 74.34 and 64.62% for yellow and red plum, respectively. A total of 23 bioactive compounds were identified by UPLC-MS, including gallic acid, rutin, resorcinol, chlorogenic acid, catechin, and ellagic acid, and the antioxidant capacity can be attributed to these species. The edible part of plum contains compounds of biological interest, suggesting that this fruit has antioxidant potential that can be exploited for various technologies.

MS4A2-rs573790 Is Associated With Aspirin-Exacerbated Respiratory Disease: Replicative Study Using a Candidate Gene Strategy.

Aspirin exacerbated respiratory disease (AERD) is a set of diseases of the unified airway, and its physiopathology is related to disruption of the metabolism of arachidonic acid (AA). Genetic association studies in AERD had explored single nucleotide polymorphism (SNPs) in several genes related to many mechanisms (AA metabolism, inflammation, drug metabolism, etc.) but most lack validation stages in second populations. Our aim is to evaluated whether contribution to susceptibility of SNPs reported in other populations are associated with AERD in Mexican Mestizo patients. We developed a replicative study in two stages. In the first, 381 SNPs selected by fine mapping of associated genes, (previously reported in the literature), were integrated into a microarray and tested in three groups (AERD, asthma and healthy controls -HC-) using the GoldenGate array. Results associated to risk based on genetic models [comparing: AERD vs. HC (comparison 1, C1), AERD vs. asthma (C2), and asthma vs. HC (C3)] were validated in the second stage in other population groups using qPCR. In the first stage, we identified 11 SNPs associated with risk in C1.The top SNPs were ACE-rs4309C (p = 0.0001) and MS4A2-rs573790C (p = 0.0002). In C2, we detected 14 SNPs, including ACE-rs4309C (p = 0.0001). In C3, we found MS4A2-rs573790C (p = 0.001). Using genetic models, C1 MS4A2-rs57370 CC (p = 0.001), and ACE-rs4309 CC (p = 0.002) had associations. In C2 ACE-rs4309 CC (p = 0.0001) and C3 MS4A2-rs573790 CC (p = 0.001) were also associate with risk. In the second stage, only MS4A2-rs573790 CC had significance in C1 and C3 (p = 0.008 and p = 0.03). We concluded that rs573790 in the MS4A2 gene is the only SNP that supports an association with AERD in Mexican Mestizo patients in both stages of the study.