Uncovering the genetic variation involved in asthma exacerbations through multiple genomic approaches

Asthma exacerbations are episodes of symptoms worsening that require urgent intervention to prevent a serious outcome. These usually involve unexpected asthma care, hospitalizations and/or oral corticosteroids use, and are influenced by a complex interplay of genetic, environmental, and behavioural factors. Due to the clinical and socio-economic burden of asthma exacerbations, there is a critical need to establish potential biomarkers to guide prevention. This doctoral thesis aimed to identify genetic variants involved in asthma exacerbations through multiple genomic approaches. A literature search for previous genetic associations for asthma exacerbations was conducted in order to detect relevant loci to validate in independent populations with different ancestral backgrounds. Moreover, in order to explore genetic variation on six genomic regions harbouring genes whose combined sputum gene expression had been previously shown to predict asthma exacerbations, a candidate-gene association study of asthma exacerbations was conducted. Additionally, a genome-wide association study of asthma with severe exacerbations in ethnically diverse children and youth and a multi-ancestry meta-analysis of genome-wide association studies of asthma exacerbations revealed three novel genetic loci implicated in asthma exacerbations. Likewise, the exploration of genomic variation by leveraging local ancestry in a context of admixed populations with differential asthma exacerbations rates uncovered two genetic loci for severe asthma exacerbations that may exert ethnic-specific effects. Finally, the functional effects of the genetic variation on DNA methylation and gene expression were investigated using public online data bases and whole-blood data from ethnically diverse populations. Our findings provided insights into the pathogenesis of asthma exacerbations and prioritised potential targets of research.Asthma exacerbations are episodes of symptoms worsening (i.e., dysnea, cough, wheezing or chest tightness) that require urgent intervention to prevent a serious outcome. These usually involve unexpected asthma care, hospitalizations and/or oral corticosteroids use, and are influenced by a complex interplay of genetic, environmental, and behavioural factors. Due to the clinical and socio-economic burden of asthma exacerbations, there is a critical need to establish potential biomarkers to guide prevention. This doctoral thesis aimed to identify genetic variants involved in asthma exacerbations through multiple genomic approaches. A literature search for previous genetic associations for asthma exacerbations was conducted in order to detect relevant loci to validate in independent populations with different ancestral backgrounds. Moreover, in order to explore genetic variation on six genomic regions harbouring genes whose combined sputum gene expression had been previously shown to predict asthma exacerbations, a candidate-gene association study of asthma exacerbations was conducted. Additionally, a genome-wide association study of asthma with severe exacerbations in ethnically diverse children and youth and a multi-ancestry meta-analysis of genome-wide association studies of asthma exacerbations revealed three novel genetic loci implicated in asthma exacerbations. Likewise, the exploration of genomic variation by leveraging local ancestry in a context of admixed populations with differential asthma exacerbations rates uncovered two genetic loci for severe asthma exacerbations that may exert ethnic-specific effects. Finally, the functional effects of the genetic variation on DNA methylation and gene expression were investigated using public online data bases and whole-blood data from ethnically diverse populations. Our findings provided insights into the pathogenesis of asthma exacerbations and prioritised potential targets of research moving forward precision medicine, including the DNASE1L3, LINC01913, PKDCC, EXTL2, PANK1, DPYSL3, and SCGB3A2 genes.This doctoral thesis was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund ¿ERDF A way of making Europe¿ by the European Union (grant SAF2017-83417R), and by the MCIN/AEI/10.13039/501100011033 (grant PID2020-116274RB-I00). My fellowship for the Predoctoral Research Personnel Training Contracts (PRE2018-08383) was funded from the MCIN/AEI/10.13039/501100011033 and by the European Social Fund ¿ESF Investing in your future¿.This doctoral thesis was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 and the European Regional Development Fund “ERDF A way of making Europe” by the European Union (grant SAF2017-83417R), and by the MCIN/AEI/10.13039/501100011033 (grant PID2020-116274RB-I00). My fellowship for the Predoctoral Research Personnel Training Contracts (PRE2018-08383) was funded from the MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”

Determinación experimental de nuevas correlaciones estadísticas para el cálculo del coeficiente de transferencia de calor por convección para placa plana, cilindros y bancos de tubos

Introducción: En este proyecto se llevó a cabo una investigación experimental con el diseño, montaje y puesta en marcha de un banco de pruebas de transferencia de calor por convección.Objetivo: Determinar nuevas correlaciones estadísticas que permitan conocer los coeficientes de transferencia de calor por convección del aire, con mayor exactitud, en aplicaciones con diferentes configuraciones geometrías calefactoras.Metodología: Se estudiaron tres configuraciones geométricas, como lo son placa plana, cilindros y bancos de tubos en función de sus propiedades físicas a través de los números de Reynolds y Prandtl utilizando una interfaz de transmisión de datos mediante controladores Arduino® con los que se midió la temperatura del aire a través del ducto para obtener datos en tiempo real y relacionar el calor cedido del elemento calefactor al fluido y poder realizar el modelamiento matemático en un software estadístico especializado. El estudio se hizo para las tres geometrías mencionadas, una potencia por elemento calefactor y dos velocidades de salida de aire con 10 repeticiones.Resultados: Se obtuvieron tres correlaciones matemáticas con coeficientes de regresión mayores a 0.972, una para cada elemento calefactor, obteniéndose errores de predicción en los coeficientes convectivos de transferencia de calor de 7,50% para la placa plana, 2,85% para la placa cilíndrica y 1,57% para el banco de tubos.Conclusiones: Se observó que en geometrías constituidas por varios elementos individuales se logra un ajuste estadístico mucho más exacto para predecir el comportamiento de los coeficientes de calor por convección debido a que cada unidad alcanza una estabilidad en el perfil de temperatura de la superficie con mayor rapidez, otorgándole a la geometría en general una medición más precisa en los parámetros que rigen la transferencia de calor, como es en el caso de la geometría del banco de tubos.Introduction− This project carried out an experimental research with the design, assembly and commissioning of a convection heat transfer test bench.Objective−To determine new statistical correlations that allow to know the heat transfer coefficients by air convection with greater accuracy in ap-plications with different heating geometry configurations.Methodology−Three geometric configurations, such as flat plate, cylin-ders and tube banks were studied according to their physical properties through Reynolds and Prandtl numbers, using a data transmission inter-face using Arduino® controllers Measured the air temperature through the duct to obtain real-time data and to relate the heat transferred from the heating element to the fluid and to perform mathematical modeling in spe-cialized statistical software. The study was made for the three geometries mentioned, one power per heating element and two air velocities with 10 repetitions.Results− Three mathematical correlations were obtained with regression coefficients greater than 0.972, one for each heating element, obtaining prediction errors in the heat transfer convective coefficients of 7.50% for the flat plate, 2.85% for the plate Cylindrical and 1.57% for the tube bank.Conclusions−It was observed that in geometries constituted by several individual elements, a much more accurate statistical adjustment was ob-tained to predict the behavior of the convection heat coefficients, since each unit reaches a stability in the surface temperature profile with Greater speed, giving the geometry in general, a more precise measurement in the parameters that govern the transfer of heat, as it is in the case of the ge-ometry of the tube ban

Multi-ancestry genome-wide association study of asthma exacerbations

Asthma exacerbations; Single-nucleotide polymorphismExacerbaciones del asma; Polimorfismo de un solo nucleótidoExacerbacions de l'asma; Polimorfisme d'un sol nucleòtidBackground Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10−5) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC allele = 0.89, p = 1.30 × 10−2). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.This work was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033, and the European Regional Development Fund “ERDF A way of making Europe” by the European Union (SAF2017-83417R), by MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00) and by the Allergopharma-EAACI award 2021. This study was also supported by the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. GALA II and SAGE studies were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL141992, and R01HL141845), National Institute of Health and Environmental Health Sciences (R01ES015794 and R21ES24844); the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443, and R56MD013312); the National Institute of General Medical Sciences (NIGMS) (RL5GM118984); the Tobacco-Related Disease Research Program (24RT-0025 and 27IR-0030); and the National Human Genome Research Institute (NHGRI) (U01HG009080) to EGB. The PACMAN study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The Slovenia study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) and from SysPharmPediA grant, co-financed by the Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and were established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. Genotyping of samples from BREATHE, PAGES, and GoSHARE was funded by AC15/00015 and conducted at the Genotyping National Centre (CeGEN) CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019). ALSPAC was supported by the UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol. The Swedish Heart-Lung Foundation, the Swedish Research Council, and Region Stockholm (ALF project and database maintenance) funded the BAMSE study. The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. U-BIOPRED was funded by the Innovative Medicines Initiative (IMI) Joint Undertaking, under grant agreement no. 115010, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and kind contributions from companies in the European Federation of Pharmaceutical Industries and Associations (EFPIA). Genotyping of samples from GEMAS and MEGA studies was funded by the Spanish Ministry of Science and Innovation (SAF2017-87417R) at the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen, PRB3, and was supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The genotyping of GEMAS was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC19/17). The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. ALLIANCE Cohort was funded by grants from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) as part of the German Centre for Lung Research (DZL) funding. The Hartford-Puerto Rico study was funded by the U.S. National Institutes of Health (grant HL07966 to JCC). MP-Y was funded by the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”. MP-Y and JV were supported by CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain (CB/06/06/1088). EH-L was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018-083837). JP-G was supported by a fellowship awarded by Spanish Ministry of Universities (FPU19/02175). AE-O reports funding from the Spanish Ministry of Science, Innovation, and Universities (MICIU) and Universidad de La Laguna (ULL). NH-P was supported by a Medium-Term Research Fellowship by the European Academy of Allergy and Clinical Immunology (EAACI) and a Long-Term Research Fellowship by the European Respiratory Society (ERS) (LTRF202101-00861). UP and MG were supported by the Ministry of Education, Science and Sport of the Republic of Slovenia, grant PERMEABLE (contract number C3330-19-252012). SCSGES results were contributed by authors FTC and YYS. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore); Grant Numbers: N-154-000-038-001, R-154-000-191-112, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, R-154-000-A91-592, R-154-000-A95-592, R-154-000-B99-114, BMRC/01/1/21/18/077, BMRC/04/1/21/19/315, SIgN-06-006, SIgN-08-020, NMRC/1150/2008, and H17/01/a0/008. F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships with grant number: R-141-000-036-281. QY conducted the analysis from Hartford-Puerto Rico and United Kingdom Biobank studies. QY was funded by the U.S. National Institutes of Health (HL138098)

El primer asentamiento europeo estable en las Islas Canarias: San Marcial de Rubicón (Yaiza, Lanzarote) y el comienzo de la circulación monetaria en el archipiélago en los umbrales del siglo XV1

The city of San Marcial de Rubicón was the first European city founded in the Canary Islands, a few years after the conquerors Jean de Bethencourt and Gadifer de La Salle arrived on the island of Lanzarote and began, in 1402, the seigniorial conquest of the Canary archipelago. The aim of this article is to present the unique batch of coins found during the archaeological excavations carried out in San Marcial de Rubicón in 2021, as well as the context in which it was found. The interest of this finding lies in the fact that it is the first documented sample of the beginnings of monetary circulation on the islands. In addition, most of the coins bear a countermark consisting of a Gothic letter B, which almost undoubtedly evokes the initial of the Norman conqueror Jean de Bethencourt. Finally, the appearance of these coins in sealed archaeological contexts may fuel the current debate on the issuance of money by monarchs Henry II and his grandson, Henry III, the very sovereign to whom Bethencourt first paid tribute, according to Le Canarien, the French chronicle of the conquest of the Canary Islands.La ciudad de San Marcial de Rubicón fue la primera ciudad europea fundada en Canarias, unos años después de que los conquistadores Jean de Bethencourt y Gadifer de La Salle arribaran a la isla de Lanzarote y diera comienzo, en 1402, la conquista señorial del archipiélago canario. Este artículo pretende dar a conocer el singular lote monetal hallado durante las excavaciones arqueológicas que se llevaron a cabo en 2021, así como el contexto en el que apareció. Su interés radica en que se trata de la primera muestra documentada de los inicios de la circulación monetaria en las islas. A ello se suma que la mayoría de ellas lleva una contramarca que consiste en una letra B gótica que evoca, casi sin lugar a duda, la inicial del conquistador normando. Por último, la aparición de estas monedas en contextos arqueológicos sellados podrá alimentar el debate abierto hoy en día en torno a las emisiones monetarias de los monarcas Enrique II y de su nieto, Enrique III, precisamente el soberano a quien Bethencourt rindió pleito-homenaje por primera vez, según relata Le Canarien, crónica francesa de la conquista

El primer asentamiento europeo estable en las Islas Canarias: San Marcial de Rubicón (Yaiza, Lanzarote) y el comienzo de la circulación monetaria en el archipiélago en los umbrales del siglo XV1

La ciudad de San Marcial de Rubicón fue la primera ciudad europea fundada en Canarias, unos años después de que los conquistadores Jean de Bethencourt y Gadifer de La Salle arribaran a la isla de Lanzarote y diera comienzo, en 1402, la conquista señorial del archipiélago canario. Este artículo pretende dar a conocer el singular lote monetal hallado durante las excavaciones arqueológicas que se llevaron a cabo en 2021, así como el contexto en el que apareció. Su interés radica en que se trata de la primera muestra documentada de los inicios de la circulación monetaria en las islas. A ello se suma que la mayoría de ellas lleva una contramarca que consiste en una letra B gótica que evoca, casi sin lugar a duda, la inicial del conquistador normando. Por último, la aparición de estas monedas en contextos arqueológicos sellados podrá alimentar el debate abierto hoy en día en torno a las emisiones monetarias de los monarcas Enrique II y de su nieto, Enrique III, precisamente el soberano a quien Bethencourt rindió pleito-homenaje por primera vez, según relata Le Canarien, crónica francesa de la conquista

The Treatment With the SGLT2 Inhibitor Empagliflozin Modifies the Hepatic Metabolome of Male Zucker Diabetic Fatty Rats Towards a Protective Profile

[Abstract] The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial evidenced the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of patients with diabetes and cardiovascular disease. Recent evidences have shown the benefits of the SGLT2 inhibitor empagliflozin on improving liver steatosis and fibrosis in patients with T2DM. Metabolomic studies have been shown to be very useful to improve the understanding of liver pathophysiology during the development and progression of metabolic hepatic diseases, and because the effects of empagliflozin and of other SGLT2 inhibitors on the complete metabolic profile of the liver has never been analysed before, we decided to study the impact on the liver of male Zucker diabetic fatty (ZDF) rats of a treatment for 6 weeks with empagliflozin using an untargeted metabolomics approach, with the purpose to help to clarify the benefits of the use of empagliflozin at hepatic level. We found that empagliflozin is able to change the hepatic lipidome towards a protective profile, through an increase of monounsaturated and polyunsaturated glycerides, phosphatidylcholines, phosphatidylethanolamines, lysophosphatidylinositols and lysophosphatidylcholines. Empagliflozin also induces a decrease in the levels of the markers of inflammation IL-6, chemerin and chemerin receptor in the liver. Our results provide new evidences regarding the molecular pathways through which empagliflozin could exert hepatoprotector beneficial effects in T2DM.This work was supported by Boehringer Ingelheim Pharma GmbH and Co., by the National Institute of Health “Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III” Madrid, Spain (PI15/00681, PI17/00409, PI18/00821, PI20/00902, RETICS Programme RD16/0012/0014 and CIBER de Enfermedades Cardiovasculares (CIBERCV)); European Regional Development Fund (FEDER) and European Union framework MSCA-RISE-H2020 Programme (Project number 734899). AH-A was funded by predoctoral research grants from Xunta de Galicia and FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain); MF-S was funded by the predoctoral research grants “Programa Científico do Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) (Spain) and Xunta de Galicia; and AV-L was funded by the predoctoral research grant from the PFIS Program of the Spanish Ministry of Science and Instituto de Salud Carlos III (Spain

The Mutational Landscape of Acute Myeloid Leukaemia Predicts Responses and Outcomes in Elderly Patients from the PETHEMA-FLUGAZA Phase 3 Clinical Trial

This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer.[Simple Summary] Mutational profiling using a custom 43-gene next-generation sequencing panel revealed that patients with mutated DNMT3A or EZH2, or an increase in TET2 VAF and lower TP53 VAF showed a higher overall response. NRAS and TP53 variants were associated with shorter overall survival (OS), whereas only mutated BCOR was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk and mutated NRAS benefited from azacytidine therapy and patients with mutated TP53 showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML.[Abstract] We sought to predict treatment responses and outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) from our FLUGAZA phase III clinical trial (PETHEMA group) based on mutational status, comparing azacytidine (AZA) with fludarabine plus low-dose cytarabine (FLUGA). Mutational profiling using a custom 43-gene next-generation sequencing panel revealed differences in profiles between older and younger patients, and several prognostic markers that were useful in young patients were ineffective in older patients. We examined the associations between variables and overall responses at the end of the third cycle. Patients with mutated DNMT3A or EZH2 were shown to benefit from azacytidine in the treatment-adjusted subgroup analysis. An analysis of the associations with tumor burden using variant allele frequency (VAF) quantification showed that a higher overall response was associated with an increase in TET2 VAF (odds ratio (OR), 1.014; p = 0.030) and lower TP53 VAF (OR, 0.981; p = 0.003). In the treatment-adjusted multivariate survival analyses, only the NRAS (hazard ratio (HR), 1.9, p = 0.005) and TP53 (HR, 2.6, p = 9.8 × 10−7) variants were associated with shorter overall survival (OS), whereas only mutated BCOR (HR, 3.6, p = 0.0003) was associated with a shorter relapse-free survival (RFS). Subgroup analyses of OS according to biological and genomic characteristics showed that patients with low–intermediate cytogenetic risk (HR, 1.51, p = 0.045) and mutated NRAS (HR, 3.66, p = 0.047) benefited from azacytidine therapy. In the subgroup analyses, patients with mutated TP53 (HR, 4.71, p = 0.009) showed a better RFS in the azacytidine arm. In conclusion, differential mutational profiling might anticipate the outcomes of first-line treatment choices (AZA or FLUGA) in older patients with AML. The study is registered at ClinicalTrials.gov as NCT02319135.This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología–del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369) and the Subdirección General de Investigación Sanitaria (Instituto de Salud Carlos III, Spain) grants PI16/01530, PI16/01661, PI19/01518, and PI19/00730, the CRIS against Cancer foundation, grant 2018/001, and by the Instituto de Investigación Hospital 12 de Octubre (IMAS12) (co-financed by FEDER funds). The study was supported internationally by Cancer Research UK, FCAECC and AIRC under the Accelerator Award Program