IDIS - Instituto de Investigación Sanitaria de Santiago de Compostela (Galicia)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16966

El Instituto de Investigación Sanitaria de Santiago (IDIS) Se constituyó el 31 de enero de 2008, mediante un convenio de colaboración entre la Consellería de Sanidade, el Servizo Galego de Saúde y la Universidad de Santiago de Compostela. Es un centro de investigación biomédica de marcado carácter traslacional que aprovecha las sinergias del Complejo Hospitalario Universitario de Santiago de Compostela (CHUS) y de la Universidad de Santiago de Compostela (USC) para impulsar, promover y fomentar la investigación de excelencia, el conocimiento científico y tecnológico y su posterior traslación al sector productivo, así como la docencia y la formación y siempre con un objetivo claro: mejorar la salud de la población. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2010, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Novel risk loci for COVID-19 hospitalization among admixed American populations
(eLife Sciences Publications, 2024-10-03) Diz-de Almeida, Silvia; Cruz, Raquel; Luchessi, Andre D; Lorenzo-Salazar, José M; López de Heredia, Miguel; Quintela, Inés; González-Montelongo, Rafaela; Nogueira Silbiger, Vivian; Porras, Marta Sevilla; Tenorio Castaño, Jair Antonio; Nevado, Julián; Aguado, José María; Aguilar, Carlos; Aguilera-Albesa, Sergio; Almadana, Virginia; Almoguera, Berta; Alvarez, Nuria; Andreu-Bernabeu, Álvaro; Arana-Arri, Eunate; Arango, Celso; Arranz, María J; Artiga, Maria-Jesus; Baptista-Rosas, Raúl C; Barreda-Sánchez, María; Belhassen-García, Moncef; Bezerra, Joao F; Bezerra, Marcos A C; Boix-Palop, Lucía; Brion, María; Brugada, Ramón; Bustos, Matilde; Calderón, Enrique J; Carbonell, Cristina; Castano, Luis; Castelao, Jose E; Conde-Vicente, Rosa; Cordero-Lorenzana, M Lourdes; Cortes-Sanchez, Jose L; Corton, Marta; Darnaude, M Teresa; De Martino-Rodríguez, Alba; Del Campo-Pérez, Victor; Diaz de Bustamante, Aranzazu; Domínguez-Garrido, Elena; Eirós, Rocío; Fariñas, María Carmen; Fernandez-Nestosa, María J; Fernández-Robelo, Uxía; Fernandez-Rodriguez, Amanda; Fernández-Villa, Tania; Gago-Dominguez, Manuela; Gil-Fournier, Belén; Gómez-Arrue, Javier; González Álvarez, Beatriz; González Bernaldo de Quirós, Fernan; González-Neira, Anna; González-Peñas, Javier; Gutiérrez-Bautista, Juan F; Herrero, María José; Herrero-Gonzalez, Antonio; Jimenez-Sousa, Maria Angeles; Lattig, María Claudia; Liger Borja, Anabel; Lopez-Rodriguez, Rosario; Mancebo, Esther; Martín-López, Caridad; Martín, Vicente; Martinez-Nieto, Oscar; Martinez-Lopez, Iciar; Martinez-Resendez, Michel F; Martinez-Perez, Angel; Mazzeu, Juliana F; Merayo Macías, Eleuterio; Minguez, Pablo; Moreno Cuerda, Victor; Oliveira, Silviene F; Ortega-Paino, Eva; Pompa-Mera, Ericka N; Parellada, Mara; Paz-Artal, Estela; Santos, Ney PC; Pérez-Matute, Patricia; Perez, Patricia; Pérez-Tomás, M Elena; Perucho, Teresa; Pinsach-Abuin, Mel·lina; Pita, Guillermo; Porras-Hurtado, Gloria L; Pujol, Aurora; Ramiro León, Soraya; Resino, Salvador; Fernandes, Marianne R; Rodríguez-Ruiz, Emilio; Rodríguez-Artalejo, Fernando; Rodriguez-Garcia, José A; Ruiz-Cabello, Francisco; Ruiz-Hornillos, Javier; Ryan, Pablo; Soria, José Manuel; Souto, Juan Carlos; Tamayo, Eduardo; Tamayo-Velasco, Álvaro; Taracido-Fernandez, Juan Carlos; Teper, Alejandro; Torres-Tobar, Lilian; Urioste, Miguel; Valencia-Ramos, Juan; Yáñez, Zuleima; Zarate, Ruth; de Rojas, Itziar; Ruiz, Agustín; Sánchez, Pascual; Real, Luis Miguel; SCOURGE Cohort Group; Guillén-Navarro, Encarna; Ayuso, Carmen; Parra, Esteban; Riancho, José A; Rojas-Martinez, Augusto; Flores, Carlos; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Banco Santander; Fundación La Caixa; Agencia Estatal de Investigación (España); Gobierno de Canarias (España); Fundación Canaria de Investigación Sanitaria; Xunta de Galicia (España); Fundación Amancio Ortega; Estrella de Levante; Colabora Mujer
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( and ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Isolation and Characterization of Milk Exosomes for Use in Advanced Therapies
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-07-08) Medel-Martínez, Ana; Redrado-Osta, Ana; Crespo-Barreda, Alejandra; Sancho-Albero, Maria; Sánchez, Lourdes; Sebastián, Víctor; Pardo, María; De la Vieja, Antonio; Martin-Duque, Pilar; Instituto de Salud Carlos III; Asociación de Padres de Niños Oncológicos de Aragón; Asociación Española Contra el Cáncer; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Fundación Ramón Areces
Exosomes are cell-derived extracellular vesicles (EVs) with diameters between 30 and 120 nm. In recent years, several studies have evaluated the therapeutic potential of exosomes derived from different fluids due to their low immunogenicity and high biocompatibility. However, producing exosomes on a large scale is still challenging. One of the fluids from which they could be isolated in large quantities is milk. Moreover, regeneration is a well-known property of milk. The present work seeks to optimize a method for isolating exosomes from bovine and human milk, comparing different storage conditions and different extraction protocols. We found differences in the yield extraction associated with pre-storage milk conditions and observed some differences according to the processing agent. When we removed milk fat globules and added rennet before freezing, we obtained a cleaner final fraction. In summary, we attempted to optimize a rennet-based new milk-exosome isolation method and concluded that pre-treatment, followed by freezing of samples, yielded the best exosome population.
The proteomic signature of circulating extracellular vesicles following intracerebral hemorrhage: Novel insights into mechanisms underlying recovery
(Elsevier, 2024-10-15) Casado-Fernández, Laura; Laso-García, Fernando; Piniella, Dolores; Gómez-de Frutos, Mari Carmen; Otero-Ortega, Laura; Bravo, Susana-Belén; Fuentes-Gimeno, Blanca; Docando, Felix; Alonso-López, Elisa; Ruiz-Ares, Gerardo; Rodríguez-Pardo, Jorge; Rigual, Ricardo; de Celis-Ruiz, Elena; Hervás, Carlos; Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María; Alonso de Leciñana, Maria; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); RETICS-Enfermedades Vasculares Cerebrales (ICTUS) (INVICTUS-ISCIII) (España); Unión Europea. Comisión Europea. NextGenerationEU; Ministerio de Universidades (España); Plan de Recuperación, Transformación y Resiliencia (España); Autonomous University of Madrid (España); Ministerio de Sanidad (España)
Circulating extracellular vesicles (EVs) can participate in innate repair processes triggered after intracerebral hemorrhage (ICH). We aimed to describe changes in the proteomic profile of circulating EVs between the acute and subacute phases of ICH and to compare the findings depending on outcomes, as an approach to unraveling such repair mechanisms. This was a prospective observational study including patients with non-traumatic supratentorial ICH. Exclusion criteria were previous disability, signs of herniation on baseline computed tomography, or limited life expectancy. EVs were isolated from blood samples at 24 h and 7 days after symptom onset. After 6-months' follow-up, patients were dichotomized into poor and good outcomes, defining good as an improvement of >10 points or > 50 % on the National Institutes of Health Stroke Scale and a modified Rankin Scale of 0-2. The protein cargo was analyzed by quantitative mass spectrometry and compared according to outcomes. Forty-four patients completed follow-up, 16 (35.5 %) having good outcomes. We identified 1321 proteins in EVs, 37 with differential abundance. In patients with good outcomes, proteins related to stress response (DERA, VNN2, TOMM34) and angiogenesis (RHG01) had increased abundance at 7 days. EVs from patients with poor outcomes showed higher levels of acute-phase reactants (CRP, SAA2) at 7 days compared with 24 h. In conclusion, the protein content of circulating EVs in patients with ICH changes over time, the changes varying depending on the clinical outcome, with greater abundance of proteins potentially involved in the repair processes of patients with good outcomes.
Lung Function and Symptoms of Exposure to the Volcanic Eruption in the Canary Islands: First Follow-Up of the ASHES Study
(Elsevier, 2024-08) Candal-Pedreira, Cristina; Díaz-Pérez, David; Velasco, Valle; Casanova, Ciro; Acosta, Orlando; Peces-Barba, Germán; Barreiro, Esther; Castaño, Argelia; Cañas Portilla, Ana Isabel; Cruz Carmona, María Jesús; Diego, Carmen; Garcia-Aymerich, Judith; Martínez, Cristina; Molina-Molina, María; Muñoz, Xavier; Sanchez Iñigo, Francisco Javier; Ruano-Ravina, Alberto; Sociedad Española de Neumología y Cirugía Torácica
Introduction: Exposure to gases and particulate matter released during volcanic eruptions can prove harmful to population health. This paper reports the preliminary results of the ASHES study, aimed at ascertaining the respiratory health effects of the 2021 volcanic eruption in La Palma Island (Spain) on the adult population without previous respiratory disease. Methods: Ambispective cohort study on the healthy adult population. Three exposure groups were considered: Group 1, high exposure; Group 2, moderate exposure; and Group 3, minor or no exposure. We carried out a descriptive analysis of symptoms during and after the eruption, as well as measure lung function after the eruption (through forced spirometry and diffusing capacity of carbon monoxide). Results: The analysis included 474 subjects: 54 in Group 1, 335 in Group 2, and 85 in Group 3. A significant increase in most symptoms was observed for subjects in the groups exposed during the eruption. After the eruption, this increase remained for some symptoms. There seems to be a dose-response relationship, such that the higher the exposure, the higher the odds ratio. A prebronchodilator FEV1/FVC ratio<70% was observed in 13.0% of subjects in Group 1, 8.6% of subjects in Group 2, and 7.1% of subjects in Group 3. Conclusions: This study is the first to report a dose-response relationship between exposure to volcanic eruptions and the presence of symptoms in adults. Furthermore, there is a tendency toward obstructive impairment in individuals with higher exposure.
Impact of Initiating Biologics in Patients With Severe Asthma on Long-Term Oral Corticosteroids or Frequent Rescue Steroids (GLITTER): Data From the International Severe Asthma Registry.
(Elsevier, 2023-09) Chen, Wenjia; Tran, Trung N; Sadatsafavi, Mohsen; Murray, Ruth; Wong, Nigel Chong Boon; Ali, Nasloon; Ariti, Con; Bulathsinhala, Lakmini; Gil, Esther Garcia; FitzGerald, J Mark; Alacqua, Marianna; Al-Ahmad, Mona; Altraja, Alan; Al-Lehebi, Riyad; Bhutani, Mohit; Bjermer, Leif; Bjerrum, Anne-Sofie; Bourdin, Arnaud; von Bülow, Anna; Busby, John; Canonica, Giorgio Walter; Carter, Victoria; Christoff, George C; García-Cosío, Borja; Costello, Richard W; Fonseca, João A; Gibson, Peter G; Yoo, Kwang Ha; Heaney, Liam G; Heffler, Enrico; Hew, Mark; Hilberg, Ole; Hoyte, Flavia; Iwanaga, Takashi; Jackson, David J; Jones, Rupert C; Koh, Mariko Siyue; Kuna, Piotr; Larenas-Linnemann, Désirée; Lehmann, Sverre; Lehtimäki, Lauri; Lyu, Juntao; Mahboub, Bassam; Maspero, Jorge; Menzies-Gow, Andrew N; Newell, Anthony; Sirena, Concetta; Papadopoulos, Nikolaos G; Papaioannou, Andriana I; Perez-de-Llano, Luis; Perng Steve, Diahn-Warng; Peters, Matthew; Pfeffer, Paul E; Porsbjerg, Celeste M; Popov, Todor A; Rhee, Chin Kook; Salvi, Sundeep; Taillé, Camille; Taube, Christian; Torres-Duque, Carlos A; Ulrik, Charlotte Suppli; Ra, Seung Won; Wang, Eileen; Wechsler, Michael E; Price, David B
Background: Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with HOCS alone. Objective: To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS. Methods: This was a propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry. Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCSs for ≥1 year or ≥4 courses of rescue OCSs within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with noninitiators. The impact of biologic initiation on asthma outcomes was assessed using generalized linear models. Results: We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations per year versus noninitiators (0.64 vs 2.06; rate ratio, 0.27 [95% CI, 0.10-0.71]). Biologic initiators were 2.2 times more likely than noninitiators to take a daily long-term OCS dose of less than 5 mg (risk probability, 49.6% vs 22.5%; P = .002) and had a lower risk of asthma-related emergency department visits (relative risk, 0.35 [95% CI, 0.21-0.58]; rate ratio, 0.26 [0.14-0.48]) and hospitalizations (relative risk, 0.31 [95% CI, 0.18-0.52]; rate ratio, 0.25 [0.13-0.48]). Conclusions: In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and health care resource utilization.
Dietary Iron, Anemia Markers, Cognition, and Quality of Life in Older Community-Dwelling Subjects at High Cardiovascular Risk
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-10-19) Donat-Vargas, Carolina; Mico, Víctor; San-Cristobal, Rodrigo; Martínez-González, Miguel Ángel; Salas-Salvado, Jordi; Corella, Dolores; Fitó, Montserrat; Alonso-Gómez, Ángel Maria; Wärnberg, Julia; Vioque, Jesus; Romaguera, Dora; López-Miranda, José; Estruch, Ramon; Damas-Fuentes, Miguel; Lapetra, José; Serra-Majem, Lluis; Bueno-Cavanillas, Aurora; Tur, Josep A; Cinza-Sanjurjo, Sergio; Pintó, Xavier; Delgado-Rodríguez, Miguel; Matía-Martín, Pilar; Vidal, Josep; Causso, Claudia; Ros, Emilio; Toledo, Estefanía; Manzanares, Josep Maria; Ortega-Azorín, Carolina; Castañer, Olga; Peña-Orihuela, Patricia Judith; Zazo, Juan Manuel; Muñoz Bravo, Carlos; Martinez-Urbistondo, Diego; Chaplin, Alice; Casas, Rosa; Cano Ibáñez, Naomi; Tojal-Sierra, Lucas; Gómez-Perez, Ana María; Pascual Roquet-Jalmar, Elena; Mestre, Cristina; Barragán, Rocío; Schröder, Helmut; Garcia-Rios, Antonio; Candela García, Inmaculada; Ruiz-Canela, Miguel; Babio, Nancy; Malcampo, Mireia; Daimiel, Lidia; Martínez, Alfredo
Anemia causes hypo-oxygenation in the brain, which could lead to cognitive disorders. We examined dietary iron intake as well as anemia markers (i.e., hemoglobin, hematocrit, mean corpuscular volume) and diabetes coexistence in relation to neuropsychological function and quality of life. In this study, 6117 community-dwelling adults aged 55-75 years (men) and 60-75 years (women) with overweight/obesity and metabolic syndrome were involved. We performed the Mini-Mental State Examination (MMSE), the Trail Making Test parts A and B (TMT-A/B), Semantic Verbal Fluency of animals (VFT-a), Phonological Verbal Fluency of letter P (VFT-p), Digit Span Test (DST), the Clock Drawing Test (CDT), and the Short Form-36 Health Survey (SF36-HRQL test). Dietary iron intake did not influence neuropsychological function or quality of life. However, anemia and lower levels of anemia markers were associated with worse scores in all neurophysiological and SF36-HRQL tests overall, but were especially clear in the MMSE, TMT-B (cognitive flexibility), and the physical component of the SF36-HRQL test. The relationships between anemia and diminished performance in the TMT-A/B and VFT tasks were notably pronounced and statistically significant solely among participants with diabetes. In brief, anemia and reduced levels of anemia markers were linked to inferior cognitive function, worse scores in different domains of executive function, as well as a poorer physical, but not mental, component of quality of life. It was also suggested that the coexistence of diabetes in anemic patients may exacerbate this negative impact on cognition. Nevertheless, dietary iron intake showed no correlation with any of the outcomes. To make conclusive recommendations for clinical practice, our findings need to be thoroughly tested through methodologically rigorous studies that minimize the risk of reverse causality.
Dietary intake of polychlorinated dibenzo-p-dioxins and furans, adiposity and obesity status
(Elsevier, 2023-06-15) Khoury, Nadine; Martínez, María Ángeles; Paz-Graniel, Indira; Martínez-González, Miguel Ángel; Corella, Dolores; Castañer, Olga; Martínez, J Alfredo; Alonso-Gómez, Ángel M; Wärnberg, Julia; Vioque, Jesus; Romaguera, Dora; López-Miranda, José; Estruch, Ramon; Tinahones, Francisco J; Lapetra, José; Serra-Majem, Lluis; Bueno-Cavanillas, Aurora; Tur, Josep A; Sanjurjo, Sergio Cinza; Pintó, Xavier; Gaforio, José Juan; Matía-Martín, Pilar; Vidal, Josep; Vazquez, Clotilde; Daimiel, Lidia; Ros, Emilio; Sayon-Orea, Carmen; Sorli, Jose V.; Pérez-Vega, Karla-Alejandra; Garcia-Rios, Antonio; Bellvert, Nuria Gómez; Gómez-Gracia, Enrique; Zulet, MA; Chaplin, Alice; Casas, Rosa; Salcedo-Bellido, Inmaculada; Tojal-Sierra, Lucas; Rosa Bernal-Lopez, Maria; Vazquez-Ruiz, Zenaida; Asensio, Eva M; Goday, Albert; Peña-Orihuela, Patricia J; Signes-Pastor, Antonio J; Garcia-Arellano, Ana; Fito, Montserrat; Babio, Nancy; Salas-Salvado, Jordi
Introduction: The principal source of exposure to Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) in humans comes from food intake. PCDD/Fs, are a family of potential endocrine disruptors and have been associated with different chronic diseases such as diabetes and hypertension. However, studies assessing the relationship between dietary exposure to PCDD/Fs and adiposity or obesity status in a middle-aged population are limited. Objective: To assess cross-sectionally and longitudinally the associations between estimated dietary intake (DI) of PCDD/Fs and body mass index (BMI), waist circumference, and the prevalence/incidence of obesity and abdominal obesity in a middle-aged population. Methods: In 5899 participants aged 55-75 years (48% women) living with overweight/obesity from the PREDIMED-plus cohort, PCDD/Fs DI was estimated using a 143-item validated food-frequency questionnaire, and the levels of food PCDD/F expressed as Toxic Equivalents (TEQ). Consequently, cross-sectional and prospective associations between baseline PCDD/Fs DI (in pgTEQ/week) and adiposity or obesity status were assessed at baseline and after 1-year follow-up using multivariable cox, logistic or linear regression models. Results: Compared to participants in the first PCDD/F DI tertile, those in the highest tertile presented a higher BMI (β-coefficient [confidence interval]) (0.43kg/m2 [0.22; 0.64]; P-trend <0.001), a higher waist circumference (1.11 cm [0.55; 1.66]; P-trend <0.001), and a higher prevalence of obesity and abdominal obesity (1.05 [1.01; 1.09] and 1.02 [1.00; 1.03]; P-trend = 0.09 and 0.027, respectively). In the prospective analysis, participants in the top PCDD/F DI baseline tertile showed an increase in waist circumference compared with those in the first tertile after 1-year of follow-up (β-coefficient 0.37 cm [0.06; 0.70]; P-trend = 0.015). Conclusion: Higher DI of PCDD/Fs was positively associated with adiposity parameters and obesity status at baseline and with changes in waist circumference after 1-year of follow-up in subjects living with overweight/obesity. Further large prospective studies using a different population with longer follow-up periods are warranted in the future to strengthen our results.
Association of adiposity and its changes over time with COVID-19 risk in older adults with overweight/obesity and metabolic syndrome: a longitudinal evaluation in the PREDIMED-Plus cohort
(BioMed Central (BMC), 2023-10-13) Shyam, Sangeetha; García-Gavilán, Jesús Francisco; Paz-Graniel, Indira; Gaforio, José J; Martínez-González, Miguel Ángel; Corella, Dolores; Martínez, J Alfredo; Alonso-Gómez, Ángel M; Wärnberg, Julia; Vioque, Jesus; Romaguera, Dora; López-Miranda, José; Estruch, Ramon; Tinahones, Francisco J; Lapetra, José; Serra-Majem, Lluis; Bueno-Cavanillas, Aurora; Tur, Josep A; Sanchez, Vicente Martin; Pintó, Xavier; Matía-Martín, Pilar; Vidal, Josep; Vazquez, Clotilde; Daimiel, Lidia; Ros, Emilio; Fernandez-Aranda, Fernando; Nishi, Stephanie K; Garcia-Regata, Oscar; Toledo, Estefanía; Asensio, Eva M; Castañer, Olga; Garcia-Rios, Antonio; Torres-Collado, Laura; Gómez-Gracia, Enrique; Zulet, M Angeles; Goñi-Ruiz, Nuria; Casas, Rosa; Cano-Ibáñez, Naomi; Tojal-Sierra, Lucas; Gómez-Perez, A M; Sorli, Jose V; Cinza-Sanjurjo, Sergio; Martín-Peláez, Sandra; Peña-Orihuela, Patricia J; Oncina-Canovas, Alejandro; Perez-Araluce, Rafael; Zomeño, María Dolores; Chaplin, Alice; Delgado-Rodríguez, Miguel; Babio, Nancy; Fitó, Montserrat; Salas-Salvado, Jordi
Background: Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. Methods: This analysis included 6874 men and women (aged 55-75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5-6 years before the pandemic and their changes at the visit prior to censoring. Results: At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. Conclusions: In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19. Trial registration: This study is registered at the International Standard Randomized Controlled Trial (ISRCT; http://www.isrctn.com/ISRCTN89898870).
A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype
(Frontiers Media, 2022) Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel; Cárcel-Márquez, Jara; Muiño, Elena; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledós, Miquel; Llucià-Carol, Laia; Sobrino, Tomas; Campos, Francisco; Castillo, José; Freijo Guerrero, Maria del Mar; Arenillas, Juan Francisco; Obach, Victor; Álvarez-Sabín, José; Molina, Carlos A; Ribo, Marc; Jiménez-Conde, Jordi; Roquer, Jaume; Muñoz-Narbona, Lucia; Lopez-Cancio, Elena; Millán, Mònica; Diaz Navarro, Rosa; Vives-Bauza, Cristofol; Serrano-Heras, Gemma; Segura, Tomas; Ibañez, Laura; Heitsch, Laura; Delgado, Pilar; Dhar, Rajat; Krupinski, Jerzy; Delgado-Mederos, Raquel; Prats-Sánchez, Luis; Camps-Renom, Pol; Blay, Natalia; Sumoy, Lauro; de Cid, Rafael; Montaner, Joan; Cruchaga, Carlos; Lee, Jin-Moo; Martí-Fàbregas, Joan; Fernandez-Cadenas, Israel
Background: Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification. Methods: Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10-8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort. Results: We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension. Conclusion: The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.
Daptomycin Plus Fosfomycin Versus Daptomycin Alone for Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis: A Randomized Clinical Trial
(Oxford University Press, 2021-05-01) Pujol, Miquel; Miró, José María; Shaw, Evelyn; Aguado, José María; San-Juan, Rafael; Puig-Asensio, Mireia; Pigrau, Carles; Calbo, Esther; Montejo, Miguel; Rodriguez-Alvarez, Regino; Garcia-Pais, Maria-Jose; Pintado, Vicente; Escudero-Sanchez, Rosa; Lopez-Contreras, Joaquin; Morata, Laura; Montero, Milagros; Andres, Marta; Pasquau, Juan; Arenas, Maria-del-Mar; Padilla, Belen; Murillas, Javier; Jover-Saenz, Alfredo; Lopez-Cortes, Luis Eduardo; Garcia-Pardo, Graciano; Gasch, Oriol; Videla, Sebastian; Hereu, Pilar; Tebe, Cristian; Pallares, Natalia; Sanllorente, Mireia; Dominguez, Maria-Angeles; Camara, Jordi; Ferrer, Ana; Padulles, Ariadna; Cuervo, Guillermo; Carratalà, Jordi; MRSA Bacteremia (BACSARM) Trial Investigators
Background. We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods. A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results. of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions. Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events.
RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-07) Muiño, Elena; Carcel-Marquez, Jara; Carrera, Caty; Llucia-Carol, Laia; Gallego-Fabrega, Cristina; Cullell, Natalia; Lledos, Miquel; Castillo, Jose; Sobrino, Tomas; Campos, Francisco; Rodriguez-Castro, Emilio; Millan, Monica; Muñoz-Narbona, Lucia; Bustamante, Alejandro; Lopez-Cancio, Elena; Ribo, Marc; Alvarez-Sabin, Jose; Jimenez-Conde, Jordi; Roquer, Jaume; Giralt-Steinhauer, Eva; Soriano-Tarraga, Carolina; Vives-Bauza, Cristofol; Diaz Navarro, Rosa; Tur Campos, Silvia; Obach, Victor; Arenillas, Juan Francisco; Segura, Tomas; Serrano-Heras, Gemma; Marti-Fabregas, Joan; Delgado-Mederos, Raquel; Camps-Renom, Pol; Prats-Sanchez, Luis; Guisado, Daniel; Guasch, Marina; Marin, Rebeca; Martinez-Domeno, Alejandro; Freijo Guerrero, Maria del Mar; Moniche, Francisco; Cabezas, Juan Antonio; Castellanos, Mar; Krupinsky, Jerzy; Strbian, Daniel; Tatlisumak, Turgut; Thijs, Vincent; Lemmens, Robin; Slowik, Agnieszka; Pera, Joanna; Heitsch, Laura; Ibañez, Laura; Cruchaga, Carlos; Dhar, Rajat; Lee, Jin-Moo; Montaner, Joan; Fernandez-Cadenas, Israel; International Stroke Genetic Consortium; Spanish Stroke Genetic Consortium
Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 x 10(-8)) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 x 10(-8)) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-beta, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.
Effectiveness of a Multicomponent Intervention in Primary Care That Addresses Patients with Diabetes Mellitus with Two or More Unhealthy Habits, Such as Diet, Physical Activity or Smoking: Multicenter Randomized Cluster Trial (EIRA Study)
(Multidisciplinary Digital Publishing Institute (MDPI), 2021-06) Represas-Carrera, Francisco; Couso-Viana, Sabela; Mendez-Lopez, Fatima; Masluk, Barbara; Magallon-Botaya, Rosa; Recio-Rodriguez, Jose I; Pombo, Haizea; Leiva Rus, Alfonso; Gil-Girbau, Montserrat; Motrico, Emma; Marti-Lluch, Ruth; Gude, Francisco; Claveria, Ana
Introduction: We evaluated the effectiveness of an individual, group and community intervention to improve the glycemic control of patients with diabetes mellitus aged 45-75 years with two or three unhealthy life habits. As secondary endpoints, we evaluated the inverventions' effectiveness on adhering to Mediterranean diet, physical activity, sedentary lifestyle, smoking and quality of life. Method: A randomized clinical cluster (health centers) trial with two parallel groups in Spain from January 2016 to December 2019 was used. Patients with diabetes mellitus aged 45-75 years with two unhealthy life habits or more (smoking, not adhering to Mediterranean diet or little physical activity) participated. Centers were randomly assigned. The sample size was estimated to be 420 people for the main outcome variable. Educational intervention was done to improve adherence to Mediterranean diet, physical activity and smoking cessation by individual, group and community interventions for 12 months. Controls received the usual health care. The outcome variables were: HbA1c (main), the Mediterranean diet adherence score (MEDAS), the international diet quality index (DQI-I), the international physical activity questionnaire (IPAQ), sedentary lifestyle, smoking >= 1 cigarette/day and the EuroQuol questionnaire (EVA-EuroQol5D5L). Results: In total, 13 control centers (n = 356) and 12 intervention centers (n = 338) were included with similar baseline conditions. An analysis for intention-to-treat was done by applying multilevel mixed models fitted by basal values and the health center: the HbA1c adjusted mean difference = -0.09 (95% CI: -0.29-0.10), the DQI-I adjusted mean difference = 0.25 (95% CI: -0.32-0.82), the MEDAS adjusted mean difference = 0.45 (95% CI: 0.01-0.89), moderate/high physical activity OR = 1.09 (95% CI: 0.64-1.86), not living a sedentary lifestyle OR = 0.97 (95% CI: 0.55-1.73), no smoking OR = 0.61 (95% CI: 0.54-1.06), EVA adjusted mean difference = -1.26 (95% CI: -4.98-2.45). Conclusions: No statistically significant changes were found for either glycemic control or physical activity, sedentary lifestyle, smoking and quality of life. The multicomponent individual, group and community interventions only showed a statistically significant improvement in adhering to Mediterranean diet. Such innovative interventions need further research to demonstrate their effectiveness in patients with poor glycemic control.
HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer
(Nature Publishing Group, 2023) Olivera-Salguero, Rubén; Seguí, Elia; Cejalvo, Juan Miguel; Oliveira, Mafalda; Tolosa, Pablo; Vidal, Maria; Malumbres Martinez, Marcos; Gavilá, Joaquín; Saura, Cristina; Pernas, Sonia; López, Rafael; Margelí, Mireia; Balmaña, Judith; Muñoz, Montserrat; Blancas, Isabel; Boni, Valentina; Ciruelos, Eva; Galve, Elena; Perelló, Antonia; Sánchez-Bayona, Rodrigo; de la Cruz, Susana; de la Hoya, Miguel; Galván, Patricia; Sanfeliu, Esther; Gonzalez-Farre, Blanca; Sirenko, Valeria; Blanch-Torras, Aura; Canes, Jordi; Masanas, Helena; Olmos, Rosa; Forns, Margarita; Prat, Aleix; Casas, Ana; Pascual, Tomás; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III
BACKGROUND: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. TRIAL DESIGN: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment. CLINICAL TRIAL REGISTRATION: www.soltihope.com, identifier NCT04497285.
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
(Nature Publishing Group, 2023-05) Pairo-Castineira, Erola; Rawlik, Konrad; Bretherick, Andrew D; Qi, Ting; Wu, Yang; Nassiri, Isar; McConkey, Glenn A; Zechner, Marie; Klaric, Lucija; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Richmond, Anne; Millar, Jonathan; Russell, Clark D; Malinauskas, Tomas; Thwaites, Ryan; Morrice, Kirstie; Keating, Sean; Maslove, David; Nichol, Alistair; Semple, Malcolm G; Knight, Julian; Shankar-Hari, Manu; Summers, Charlotte; Hinds, Charles; Horby, Peter; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Openshaw, Peter J M; Begg, Colin; Walsh, Timothy; Tenesa, Albert; Flores, Carlos; Riancho, José A; Rojas-Martinez, Augusto; Lapunzina, Pablo; Yang, Jian; Ponting, Chris P; Wilson, James F; Vitart, Veronique; Abedalthagafi, Malak; Luchessi, Andre D; Parra, Esteban J; Cruz, Raquel; Carracedo, Ángel; Fawkes, Angie; Murphy, Lee; Rowan, Kathy; Pereira, Alexandre C; Law, Andy; Fairfax, Benjamin; Hendry, Sara Clohisey; Baillie, J Kenneth; Sepsis Research (the Fiona Elizabeth Agnew Trust); Intensive Care Society; Wellcome Trust; UK Research and Innovation; Department of Health and Social Care (DHSC); BBSRC Institute Program Support Grant; Edinburgh Clinical Academic Track (ECAT) programm; Health Data Research UK; RCUK Innovation Fellowship from the National Productivity Investment Fund; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Fundacion Amancio Ortega; Fundación Canaria Instituto de Investigación Sanitaria de Canarias; Centro National de Genotipado (CEGEN); Centro de Supercomputacion de Galicia (CESGA); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)
Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights
(Elsevier, 2023-07) Koutros, Stella; Kiemeney, Lambertus A; Pal Choudhury, Parichoy; Milne, Roger L; Lopez de Maturana, Evangelina; Ye, Yuanqing; Joseph, Vijai; Florez-Vargas, Oscar; Dyrskjøt, Lars; Figueroa, Jonine; Dutta, Diptavo; Giles, Graham G; Hildebrandt, Michelle A T; Offit, Kenneth; Kogevinas, Manolis; Weiderpass, Elisabete; McCullough, Marjorie L; Freedman, Neal D; Albanes, Demetrius; Kooperberg, Charles; Cortessis, Victoria K; Karagas, Margaret R; Johnson, Alison; Schwenn, Molly R; Baris, Dalsu; Furberg, Helena; Bajorin, Dean F; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Kraft, Peter; Porru, Stefano; Carta, Angela; Bishop, Timothy; Southey, Melissa C; Matullo, Giuseppe; Fletcher, Tony; Kumar, Rajiv; Taylor, Jack A; Lamy, Philippe; Prip, Frederik; Kalisz, Mark; Weinstein, Stephanie J; Hengstler, Jan G; Selinski, Silvia; Harland, Mark; Teo, Mark; Kiltie, Anne E; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schned, Alan; Lenz, Petra; Riboli, Elio; Brennan, Paul; Tjønneland, Anne; Otto, Thomas; Ovsiannikov, Daniel; Volkert, Frank; Vermeulen, Sita H; Aben, Katja K; Galesloot, Tessel E; Turman, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J; Hohensee, Chancellor; Hunt, Rebecca; Patel, Alpa V; Huang, Wen-Yi; Thorleifsson, Gudmar; Gago-Dominguez, Manuela; Amiano, Pilar; Golka, Klaus; Stern, Mariana C; Yan, Wusheng; Liu, Jia; Li, Shengchao Alfred; Katta, Shilpa; Hutchinson, Amy; Hicks, Belynda; Wheeler, William A; Purdue, Mark P; McGlynn, Katherine A; Kitahara, Cari M; Haiman, Christopher A; Greene, Mark H; Rafnar, Thorunn; Chatterjee, Nilanjan; Chanock, Stephen J; Wu, Xifeng; Real, Francisco X; Silverman, Debra T; Garcia-Closas, Montserrat; Stefansson, Kari; Prokunina-Olsson, Ludmila; Malats, Nuria; Rothman, Nathaniel; NIH - National Cancer Institute (NCI) (Estados Unidos); Radboud University Medical Center; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Canadian Institutes of Health Research (CIHR) Cancer Council Victoria; National Health and Medical Research Council (Australia)
Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. Design, setting, and participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. Outcome measurements and statistical analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. Results and limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. Patient summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.
Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain
(Nature Publishing Group, 2020-02-18) Cullell, Natalia; Carrera, Caty; Muino, Elena; Torres-Aguila, Nuria-Paz; Carcel-Marquez, Jara; Gonzalez-Sanchez, Jonathan; Gallego-Fabrega, Cristina; Molina, Jessica; Besora, Sarah; Sotoca, Javier; Buongiorno, Maria-Teresa; Jimenez-Conde, Jordi; Giralt-Steinhauer, Eva; de Torres-Chacon, Reyes; Montaner, Joan; Mancha, Fernando; Cabezas, Juan A; Marti-Fabregas, Joan; Prats-Sanchez, Luis; Camps-Renom, Pol; Purroy, Francisco; Cambray, Serafi; Freijo Guerrero, Maria del Mar; Vives-Bauza, Cristofol; Tur Campos, Silvia; Font, Maria-Angels; Lopez-Cancio, Elena; Hernandez-Perez, Maria; Obach, Victor; Calleja, Ana; Arenillas, Juan Francisco; Rodriguez-Yanez, Manuel; Castillo, Jose; Sobrino, Tomas; Fernandez-Cadenas, Israel; Krupinski, Jerzy
Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms in CYP2C9 and VKORC1 previously associated with acenocoumarol maintenance dose in a Genome-Wide Association study (GWAs) in Dutch population are associated with stroke recurrence, intracranial haemorrhage (ICH) and acenocoumarol maintenance dose in a Spanish population. We performed a GWAs using Human Core Exome-chip (Illumina) in 78 patients stroke patients treated with acenocoumarol for secondary prevention enrolled as part of the prospective investigator-initiated study (IIS) SEDMAN Study. Patients were followed-up a median of 12.8 months. Three and eight patients had recurrent stroke and ICH events, respectively. We found 14 of the 49 published variants associated with acenocoumarol maintenance dose (p<0.05). Six polymorphisms were associated with stroke recurrence and four variants with ICH (p<0.05). In conclusion, variants in VKORC1 and CYP2C9 are associated with acenocoumarol maintenance dose, stroke recurrence and ICH in a Spanish cohort. These results highlight the relevance of studying pharmacogenetics associated with efficacy and safety of anticoagulant drugs and justify studies with larger sample size and different ethnic populations.
Detection of MET Alterations Using Cell Free DNA and Circulating Tumor Cells from Cancer Patients
(Multidisciplinary Digital Publishing Institute (MDPI), 2020-02) Mondelo-Macia, Patricia; Rodriguez-Lopez, Carmela; Valina, Laura; Aguin, Santiago; Leon-Mateos, Luis; Garcia-Gonzalez, Jorge; Abalo, Alicia; Rapado-Gonzalez, Oscar; Suarez-Cunqueiro, Mercedes; Diaz-Lagares, Angel; Curiel, Teresa; Calabuig-Farinas, Silvia; Azkárate, Aitor; Obrador-Hevia, Antonia; Abdulkader, Ihab; Muinelo-Romay, Laura; Diaz-Pena, Roberto; Lopez-Lopez, Rafael
MET alterations may provide a potential biomarker to evaluate patients who will benefit from treatment with MET inhibitors. Therefore, the purpose of the present study is to investigate the utility of a liquid biopsy-based strategy to assess MET alterations in cancer patients. We analyzed MET amplification in circulating free DNA (cfDNA) from 174 patients with cancer and 49 healthy controls and demonstrated the accuracy of the analysis to detect its alteration in patients. Importantly, a significant correlation between cfDNA concentration and MET copy number (CN) in cancer patients (r = 0.57, p <10(-10)) was determined. Furthermore, we evaluated two approaches to detect the presence of MET on circulating tumor cells (CTCs), using the CellSearch((R)) and Parsortix systems and monitored patients under anti-EGFR treatment (n = 30) combining both cfDNA and CTCs analyses. This follow-up provides evidence for the potential of MET CN assessment when patients develop resistance to anti-EGFR therapy and a significant association between the presence of CTCs MET+ and the Overall Survival (OS) in head and neck cancer patients (P = 0.05; HR = 6.66). In conclusion, we develop specific and noninvasive assays to monitor MET status in cfDNA/CTCs and demonstrate the utility of plasma MET CN determination as a biomarker for monitoring the appearance of resistance to anti-EGFR therapy.
Surveillance of invasive pneumococcal disease in Spain exploring the impact of the COVID-19 pandemic (2019-2023)
(Elsevier, 2024-06-19) Perez-Garcia, Covadonga; Sempere, Julio; Miguel, Sara de; Hita, Samantha; Úbeda, Aída; Vidal-Alcántara, Erick Joan; Llorente, Joaquín; Limia, Aurora; Gil-de-Miguel, Ángel; Sanz, Juan Carlos; Martinón-Torres, Federico; Ardanuy, Carmen; Domenech Lucas, Mirian; Yuste, Jose Enrique; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Merck, Sharp & Dohme
Objectives: Dynamic trends of invasive pneumococcal disease (IPD) including the evolution of prevalent serotypes are very useful to evaluate the impact of current and future pneumococcal conjugate vaccines (PCVs) and the rise of non-vaccine serotypes. In this study, we include epidemiological patterns of S. pneumoniae before and after COVID-19 pandemic. Methods: We characterized all national IPD isolates from children and adults received at the Spanish Pneumococcal Reference Laboratory during 2019-2023. Results: In the first pandemic year 2020, we found a general reduction in IPD cases across all age groups, followed by a partial resurgence in children in 2021 but not in adults. By 2022, IPD cases in children had returned to pre-pandemic levels, and partially in adults. In 2023, IPD rates surpassed those of the last pre-pandemic year. Notably, the emergence of serotype 3 is of significant concern, becoming the leading cause of IPD in both pediatric and adult populations over the last two years (2022-2023). Increase of serotype 4 in young adults occurred in the last epidemiological years. Conclusions: The COVID-19 pandemic led to a temporary decline in all IPD cases during 2020 attributable to non-pharmaceutical interventions followed by a subsequent rise. Employing PCVs with broader coverage and/or enhanced immunogenicity may be critical to mitigate the marked increase of IPD.
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
(Nature Publishing Group, 2024-02-19) Pérez-Jurado, Luis Alberto; Cáceres, Alejandro; Balagué-Dobón, Laura; Esko, Tonu; López de Heredia, Miguel; Quintela, Inés; Cruz, Raquel; Lapunzina, Pablo; Carracedo, Ángel; SCOURGE Cohort Group; González, Juan R; Meijome, Xose M; Brochado-Kith, Oscar; Ceballos, Francisco C; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Martin-Vicente, Maria; Resino, Salvador; Virseda-Berdices, Ana; Government of Catalonia (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Estonian Research Council; Instituto de Salud Carlos III; Amancio Ortega Foundation; Banco Santander
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.

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