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3. A metagenome-wide association study of HIV disease progression in HIV controllers

Author

Real, Luis Miguel, Sáez, María E., Corma-Gómez, Anais, Gonzalez-Pérez, Antonio, Thorball, Christian, Ruiz, Rocío, Jimenez-Leon, María Reyes, Gonzalez-Serna, Alejandro, Gasca-Capote, Carmen, Bravo, María José, Royo, José Luis, Perez-Gomez, Alberto, Camacho-Sojo, María Inés, Gallego, Isabel, Vitalle, Joana, Bachiller, Sara, Gutierrez-Valencia, Alicia, Vidal, Francisco, Fellay, Jacques, Lichterfeld, Mathias, and Ruiz-Mateos, Ezequiel

Published
2023
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4. The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study)

Author

Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica, Junta de Andalucía, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Servicio Andaluz de Salud, Royo, José Luis [0000-0003-2024-4363], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis Miguel [0000-0003-4932-7429], Martín-Sierra, Carmen, Bravo, María José, Sáez, María Eugenia, Rojas, Itziar de, Santos, Marta, Martín-Carmona, Jesica, Corma-Gómez, Anaïs, González-Serna, Alejandro, Royo, José Luis, Pineda, Juan A., Rivero, Antonio, Rivero-Juárez, Antonio, Macías, Juan, Real, Luis Miguel, Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica, Junta de Andalucía, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (España), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Servicio Andaluz de Salud, Royo, José Luis [0000-0003-2024-4363], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis Miguel [0000-0003-4932-7429], Martín-Sierra, Carmen, Bravo, María José, Sáez, María Eugenia, Rojas, Itziar de, Santos, Marta, Martín-Carmona, Jesica, Corma-Gómez, Anaïs, González-Serna, Alejandro, Royo, José Luis, Pineda, Juan A., Rivero, Antonio, Rivero-Juárez, Antonio, Macías, Juan, and Real, Luis Miguel

Abstract

[Background & aims] It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV)., [Objective] To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype., [Patients and methods] In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0., [Results] It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition., [Conclusions] Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

Published
2024

5. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

Author

Abdelnour, C., Aguilera, N., Alarcon, E., Alegret, M., Benaque, A., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Corbatón, A., de Rojas, I., Diego, S., Espinosa, A., Gailhajenet, A., García González, P., Gil, S., Guitart, M., González Pérez, A., Hernández, I., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M.T., Marquié, M., Mauleón, A., Monté-Rubio, G., Montrreal, L., Moreno-Grau, S., Moreno, M., Orellana, A., Ortega, G., Pancho, A., Pelejà, E., Pérez-Cordon, A., Pineda, J.A., Preckler, S., Quintela, I., Real, L.M., Rodríguez-Gómez, O., Rosende-Roca, M., Ruiz, A., Ruiz, S., Sáez, M.E., Sanabria, A., Santos-Santos, M.A., Serrano-Rios, M., Sotolongo-Grau, O., Tárraga, L., Valero, S., Vargas, L., Adarmes-Gómez, A.D., Alarcón-Martín, E., Álvarez, I., Álvarez, V., Amer-Ferrer, Goo, Antequera, M., Antúnez, C., Baquero, M., Bernal, M., Blesa, R., Buiza-Rueda, D., Bullido, M.J., Burguera, J.A., Calero, M., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., del Ser, T., Diez-Fairen, M., Fortea, J., Franco, E., Frank-García, A., García-Alberca, J.M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Espinosa, Labrador, Lage, C., Legaz, A., Lleó, A., López de Munáin, A., López-García, S., Macias, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martín Montes, A., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Menéndez-González, M., Mir, P., Molinuevo, J.L., Pastor, A.B., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Piñol Ripoll, G., Rábano, A., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Royo, J.L., A, Ruiz, Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vivancos, L., Moreno-Grau, Sonia, de Rojas, Itziar, Hernández, Isabel, Quintela, Inés, Montrreal, Laura, Alegret, Montserrat, Hernández-Olasagarre, Begoña, Madrid, Laura, González-Perez, Antonio, Maroñas, Olalla, Rosende-Roca, Maitée, Mauleón, Ana, Vargas, Liliana, Lafuente, Asunción, Abdelnour, Carla, Rodríguez-Gómez, Octavio, Gil, Silvia, Santos-Santos, Miguel Ángel, Espinosa, Ana, Ortega, Gemma, Sanabria, Ángela, Pérez-Cordón, Alba, Cañabate, Pilar, Moreno, Mariola, Preckler, Silvia, Ruiz, Susana, Aguilera, Nuria, Pineda, Juan Antonio, Macías, Juan, Alarcón-Martín, Emilio, Sotolongo-Grau, Oscar, Marquié, Marta, Monté-Rubio, Gemma, Valero, Sergi, Benaque, Alba, Clarimón, Jordi, Bullido, Maria Jesus, García-Ribas, Guillermo, Pástor, Pau, Sánchez-Juan, Pascual, Álvarez, Victoria, Piñol-Ripoll, Gerard, García-Alberca, Jose Maria, Royo, José Luis, Franco, Emilio, Mir, Pablo, Calero, Miguel, Medina, Miguel, Rábano, Alberto, Ávila, Jesús, Antúnez, Carmen, Real, Luis Miguel, Orellana, Adelina, Carracedo, Ángel, Sáez, María Eugenia, Tárraga, Lluís, Boada, Mercè, and Ruiz, Agustín

Published
2019
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8. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, Pérez-Tur, Jordi [0000-0002-9111-1712], European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis Miguel, Piñol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustín, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK

Published
2023

9. Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Author

Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ace Alzheimer Center Barcelona, Grifols, Fundación la Caixa, European Commission, European Alzheimer's Disease DNA BioBank, García-González, Pablo, Rojas, Itziar de, Moreno-Grau, Sonia, Montrreal, Laura, Puerta, Raquel, Alarcón-Martín, Emilio, Quintela, Inés, Orellana, Adela, Andrade, Victor, Martino-Adami, Pamela V., Heilmann-Heimbach, Stefanie, Gómez-Garre, Pilar, Periñán, María Teresa, Álvarez, Ignacio, Díez-Fairen, Mónica, Nuñez-Llaves, Raul, Olivé-Roig, Claudia, García-Ribas, Guillermo, Menéndez-González, Manuel, Martínez, Carmen, Aguilar Barberá, Miquel, Buongiorno, Maria Teresa, Franco-Macías, Emilio, Sáez, María Eugenia, Cano, Amanda, Bullido, María Jesús, Real, Luis Miguel, Rodríguez-Rodríguez, Eloy, Royo, José Luis, Álvarez, Victoria, Pastor, Pau, Piñol-Ripoll, Gerard, Mir, Pablo, Calero, Miguel, Medina-Padilla, Miguel, Sánchez-Juan, Pascual, Carracedo, Ángel, Valero, Sergi, Hernández, Isabel, Tárraga, Lluís, Ramírez, Alfredo, Boada, Mercè, Ruiz, Agustín, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ace Alzheimer Center Barcelona, Grifols, Fundación la Caixa, European Commission, European Alzheimer's Disease DNA BioBank, García-González, Pablo, Rojas, Itziar de, Moreno-Grau, Sonia, Montrreal, Laura, Puerta, Raquel, Alarcón-Martín, Emilio, Quintela, Inés, Orellana, Adela, Andrade, Victor, Martino-Adami, Pamela V., Heilmann-Heimbach, Stefanie, Gómez-Garre, Pilar, Periñán, María Teresa, Álvarez, Ignacio, Díez-Fairen, Mónica, Nuñez-Llaves, Raul, Olivé-Roig, Claudia, García-Ribas, Guillermo, Menéndez-González, Manuel, Martínez, Carmen, Aguilar Barberá, Miquel, Buongiorno, Maria Teresa, Franco-Macías, Emilio, Sáez, María Eugenia, Cano, Amanda, Bullido, María Jesús, Real, Luis Miguel, Rodríguez-Rodríguez, Eloy, Royo, José Luis, Álvarez, Victoria, Pastor, Pau, Piñol-Ripoll, Gerard, Mir, Pablo, Calero, Miguel, Medina-Padilla, Miguel, Sánchez-Juan, Pascual, Carracedo, Ángel, Valero, Sergi, Hernández, Isabel, Tárraga, Lluís, Ramírez, Alfredo, Boada, Mercè, and Ruiz, Agustín

Abstract

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.

Published
2023

10. A metagenome-wide association study of HIV disease progression in HIV controllers

Author

Junta de Andalucía, Instituto de Salud Carlos III, European Commission, Consejo Superior de Investigaciones Científicas (España), Real, Luis Miguel, Sáez, María Eugenia, Corma-Gómez, Anaïs, González-Pérez, Antonio, Thorball, Christian, Ruiz, Rocío, Jiménez-León, María Reyes, González-Serna, Alejandro, Gasca-Capote, Carmen, Bravo, María José, Royo, José Luis, Pérez-Gómez, Alberto, Camacho-Sojo, María Inés, Gallego, Isabel, Vitallé, Joana, Bachiller, Sara, Gutiérrez Valencia, Alicia, Vidal, Francisco, Fellay, Jacques, Lichterfeld, Mathias, Ruiz-Mateos, Ezequiel, Swiss HIV Cohort Study, Junta de Andalucía, Instituto de Salud Carlos III, European Commission, Consejo Superior de Investigaciones Científicas (España), Real, Luis Miguel, Sáez, María Eugenia, Corma-Gómez, Anaïs, González-Pérez, Antonio, Thorball, Christian, Ruiz, Rocío, Jiménez-León, María Reyes, González-Serna, Alejandro, Gasca-Capote, Carmen, Bravo, María José, Royo, José Luis, Pérez-Gómez, Alberto, Camacho-Sojo, María Inés, Gallego, Isabel, Vitallé, Joana, Bachiller, Sara, Gutiérrez Valencia, Alicia, Vidal, Francisco, Fellay, Jacques, Lichterfeld, Mathias, Ruiz-Mateos, Ezequiel, and Swiss HIV Cohort Study

Abstract

[Summary] Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Published
2023

11. Genetic Associations between Modifiable Risk Factors and Alzheimer Disease

Author

Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, Danish Heart Foundation, Lundbeck Foundation, Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J, Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M, Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, Van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, Van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, and Frikke-Schmidt, Ruth

Abstract

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39106 participants with clinically diagnosed AD and 401577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK B

Published
2023

12. Moderate exercise reveals the influence of ACTN3 R577X and ACE I/D polymorphisms on physical performance in non-athlete active subjects

Author

Alvero-Cruz, Jose Ramón, primary, Alarcón-Martín, Emilio, additional, García-Romero, Jerónimo, additional, Ruiz-Galdon, Maximiliano, additional, Carrillo-Albornoz-Gil, Margarita, additional, Polvillo, Rocío, additional, González, Irene, additional, Reyes-Engel, Armando, additional, and Royo, José Luis, additional

Published
2023
Full Text
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13. Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease

Author

European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR), Luo, Jiao, Thomassen, Jesper Qvist, Bellenguez, Celine, Grenier-Boley, Benjamin, Rojas, Itziar de, Castillo, Atahualpa, Parveen, Kayenat, Kucukali, Fahri, Nicolas, Aude, Peters, Oliver, Schneider, Anja, Dichgans, Martin, Rujescu, Dan, Scherbaum, Norbert, Jurgen, Deckert, Riedel-Heller, Steffi, Hausner, Lucrezia, Molina Porcel, Laura, Duzel, Emrah, Grimmer, Timo, Wiltfang, Jens, Heilmann-Heimbach, Stefanie, Moebus, Susanne, Tegos, Thomas, Scarmeas, Nikolaos, Clarimón, Jordi, Moreno, Fermín, Pérez-Tur, Jordi, Bullido, Maria J., Pastor, Pau, Sánchez-Valle, Raquel, Álvarez, Victoria, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Mir, Pablo, Real, Luis M., Pinol-Ripoll, Gerard, García-Alberca, José María, Royo, José Luis, Rodríguez-Rodríguez, Eloy, Soininen, Hilkka, Kuulasmaa, Teemu, Mendonça, Alexandre de, Mehrabian, Shima, Hort, Jakub, Vyhnalek, Martin, van der Lee, Sven, Graff, Caroline, Papenberg, Goran, Giedraitis, Vilmantas, Boland, Anne, Bacq-Daian, Delphine, Deleuze, Jean-Francois, Nicolas, Gael, Dufouil, Carole, Pasquier, Florence, Hanon, Olivier, Debette, Stephanie, Grunblatt, Edna, Popp, Julius, Benussi, Luisa, Galimberti, Daniela, Arosio, Beatrice, Mecocci, Patrizia, Solfrizzi, Vincenzo, Parnetti, Lucilla, Squassina, Alessio, Tremolizzo, Lucio, Borroni, Barbara, Nacmias, Benedetta, Sorbi, Sandro, Caffarra, Paolo, Seripa, Davide, Rainero, Innocenzo, Daniele, Antonio, Masullo, Carlo, Spalletta, Gianfranco, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick, Magda, Tsolaki, Rossi, Giacomina, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Andreassen, Ole A., Hiltunen, Mikko, Van Duijn, Cornelia, Sims, Rebecca, van der Flier, Wiesje, Ruiz, Agustin, Ramírez, Alfredo, Lambert, Jean-Charles, Frikke-Schmidt, Ruth, European Research Council, Instituto de Salud Carlos III, and Pérez-Tur, Jordi

Subjects
Aged, 80 and over, Male, Causality, epidemiology [Alzheimer Disease], Risk Factors, Cholesterol, HDL, Humans, ethyl 4-azidophenyl-1,4-dithiobutyrimidate, Female, genetics [Alzheimer Disease], ddc:610, Aged
Abstract

17 páginas, 3 figuras, 2 tablas. Material suplementario accesible en : https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2805006, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., The work for this manuscript was further supported by the CoSTREAM project (www.costream.eu) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 667375. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’).

Published
2023

14. Supplemental Online Content. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

Author

Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Le Guen, Yann, Belloy, Michael E, Grenier-Boley, Benjamin, de Rojas, Itziar, Castillo-Morales, Atahualpa, Jansen, Iris, Nicolas, Aude, Bellenguez, Céline, Dalmasso, Carolina, Küçükali, Fahri, Eger, Sarah J, Jürgen, Deckert, Kuulasmaa, Teemu, van der Lugt, Aad, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonça, Alexandre, Moebus, Susanne, Nacmias, Benedetta, Nicolas, Gael, Olaso, Robert, Papenberg, Goran, Parnetti, Lucilla, Pasquier, Florence, Peters, Oliver, Pijnenburg, Yolande A L, Popp, Julius, Rainero, Innocenzo, Ramakers, Inez, Riedel-Heller, Steffi, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Soininen, Hilkka, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Tegos, Thomas J, Tremolizzo, Lucio, Verhey, Frans, Vyhnalek, Martin, Wiltfang, Jens, Boada, Mercè, García-González, Pablo, Puerta, Raquel, Real, Luis Miguel, Álvarez, Victoria, Bullido, María J., Clarimón, Jordi, García-Alberca, José María, Mir, Pablo, Moreno, Fermín, Pastor, Pau, Piñol-Ripoll, Gerard, Molina-Porcel, Laura, Pérez-Tur, Jordi, Rodríguez Martínez, Eloy, Royo, José Luis, Sánchez-Valle, Raquel, Dichgans, Martin, Rujescu, Dan, Rasmussen, Katrine Laura, Thomassen, Jesper Qvist, Deleuze, Jean-François, He, Zihuai, Napolioni, Valerio, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., van Duijn, Cornelia, Tsolaki, Magda, Sánchez-Juan, Pascual, Sleegers, Kristel, Ingelsson, Martin, Rossi, Giacomina, Hiltunen, Mikko, Sims, Rebecca, van der Flier, Wiesje M., Ramírez, Alfredo, Andreassen, Ole A., Frikke-Schmidt, Ruth, Williams, Julie, Ruiz, Agustín, Lambert, Jean-Charles, Greicius, Michael D, Arosio, Beatrice, Benussi, Luisa, Boland, Anne, Borroni, Barbara, Caffarra, Paolo, Daian, Delphine, Daniele, Antonio, Debette, Stéphanie, Dufouil, Carole, Düzel, Emrah, Galimberti, Daniela, Giedraitis, Vilmantas, Grimmer, Timo, Graff, Caroline, Grünblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, and Hort, Jakub

Abstract

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Published
2022

16. Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Author

Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macias, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, Garcia-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sanchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis M., Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquie, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, Ruiz, Agustín, Instituto de Salud Carlos III, Unión Europea, Grifols (Spain), Fundación La Caixa, Fundació ACE, Centro de Investigación Biomédica en Red - CIBERNED (Enfermedades Neurodegenerativas), Fundación Reina Sofía, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Universidad de Cantabria, Rojas, Itziar de, Calero, Miguel, Menéndez-González, Manuel, Díez-Fairen, Mónica, Rábano, Alberto, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Bullido, María Jesús, Álvarez, Victoria, Real, Luis M., Medina, Miguel, Butler, Christopher R., Sáez, María Eugenia, Carracedo, Ángel, Ruiz, Agustín, and UAM. Departamento de Biología Molecular

Subjects
SARS-CoV-2, COVID-19, GWAS, GR@ACE/DEGESCO, dementia, APOE, Medicine (miscellaneous), Biología y Biomedicina / Biología, Article, Medicine
Abstract

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis., We would like to thank patients and controls who participated in this project. The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa’, Fundació ACE, and CIBERNED. The Vallecas Project is supported by Queen Sofia Foundation and the Instituto de Salud Carlos III. The position held by SA-L is funded by Instituto de Salud Carlos III (Co-funded by European Social Fund “Investing in your future”) Sara Borrell Contract (CD19/00232). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, accessed date: 1 October 2021, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. This research has been conducted using the COVID-19 Host Genetic Initiative public resource obtained through the web site (https://www.covid19hg.org/results/, accessed date: 1 October 2021).

Published
2021

17. The Genetic Research in Alzheimer Disease (GERALD) Initiative Finds rs9320913 as a Neural eQTL of lincRNA AL589740.1

Author

Lopez-Gutierrez, Lidia, primary, García-Alberca, José María, additional, Mendoza, Silvia, additional, Gris, Esther, additional, De la Guía, María Paz, additional, Marin-Carmona, José Manuel, additional, Alarcón-Martín, Emilio, additional, Lobato, Almudena, additional, Cruz-Gamero, Jose Manuel, additional, Cura, Laura, additional, Ocejo, Olga, additional, Torrecilla, Javier, additional, Nieto, María Dolores, additional, Urbano, Concepción, additional, Pareja, Nuria, additional, Luque, Macarena, additional, García-Peralta, María, additional, Carrillejo, Rosario, additional, and Royo, José Luis, additional

Published
2021
Full Text
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18. Genomic characterization of host factors related to SARS-CoV-2 infection in people with dementia and control populations: the GR@ACE/DEGESCO study

Author

Universidad de Sevilla. Departamento de Medicina, Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Macías Sánchez, Juan, Pineda Vergara, Juan Antonio, Mir Rivera, Pablo, Ruiz, Agustín, Universidad de Sevilla. Departamento de Medicina, Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Macías Sánchez, Juan, Pineda Vergara, Juan Antonio, Mir Rivera, Pablo, and Ruiz, Agustín

Abstract

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Published
2021

19. Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Author

Instituto de Salud Carlos III, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Reina Sofía, European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macías Sánchez, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, García-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis Miguel, Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, Ruiz, Agustín, Instituto de Salud Carlos III, Grifols, La Caixa, Ace Alzheimer Center Barcelona, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Fundación Reina Sofía, European Commission, Rojas, Itziar de [0000-0002-2148-381X], Calero, Miguel [0000-0001-5366-3324], Menéndez-González, Manuel [0000-0002-5218-0774], Díez-Fairen, Mónica [0000-0003-1882-0309], Rábano, Alberto [0000-0001-9320-6566], Rodríguez-Rodríguez, Eloy [0000-0001-7742-677X], Álvarez, Ignacio [0000-0002-8537-3935], Bullido, María Jesús [0000-0002-6477-1117], Álvarez, Victoria [0000-0002-1916-2523], Real, Luis M. [0000-0003-4932-7429], Medina, Miguel [0000-0002-7016-5340], Butler, Christopher R. [0000-0002-7502-9284], Sáez, María Eugenia [0000-0001-9299-2534], Carracedo, Ángel [0000-0003-1085-8986], Ruiz, Agustín [0000-0003-2633-2495], Rojas, Itziar de, Hernández, Isabel, Montrreal, Laura, Quintela, Inés, Calero, Miguel, Royo, José Luis, Huerto Vilas, Raquel, González-Pérez, Antonio, Franco-Macías, Emilio, Macías Sánchez, Juan, Menéndez-González, Manuel, Frank-García, Ana, Díez-Fairen, Mónica, Lage, Carmen, García-Madrona, Sebastián, Aguilera, Nuria, García-González, Pablo, Puerta, Raquel, Sotolongo-Grau, Oscar, Alonso-Lana, Silvia, Rábano, Alberto, Arias Pastor, Alfonso, Pastor, Ana Belén, Corma-Gómez, Anaïs, Martin Montes, Ángel, Martínez Rodríguez, Carmen, Buiza-Rueda, Dolores, Periñán, María Teresa, Rodríguez-Rodríguez, Eloy, Álvarez, Ignacio, Rosas Allende, Irene, Pineda, Juan A., Bernal Sánchez-Arjona, María, Fernández-Fuertes, Marta, Mendoza, Silvia, Ser, Teodoro del, GR@ACE, DEGESCO Consortium, García-Ribas, Guillermo, Sánchez-Juan, Pascual, Pastor, Pau, Bullido, María Jesús, Álvarez, Victoria, Real, Luis Miguel, Mir, Pablo, Piñol-Ripoll, Gerard, García-Alberca, José María, Medina, Miguel, Orellana, Adelina, Butler, Christopher R., Marquié, Marta, Sáez, María Eugenia, Carracedo, Ángel, Tárraga, Lluís, Boada, Mercè, and Ruiz, Agustín

Abstract

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Published
2021

20. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Author

Instituto de Salud Carlos III, Grifols, La Caixa, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Rojas, Itziar de, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, N. L., Stringa, N., Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Rossi, Giacomina, Tankard, R. M., Wiltfang, J., Giegling, Ina, Seidu, N. M., Dalmasso, Maria Carolina, Benussi, A., Boschi, Silvia, Sáez, María Eugenia, Binetti, Giuliano, Royo, José Luis, Pérez-Tur, Jordi, Spalletta, Gianfranco, Corbaton-Anchuelo, A., Froelich, L., Satizabal, Claudia L., Hagg, S., Ortega, G., Peters, Oliver, Vogelgsang, Jonathan, Serrano-Rios, M., Gil, S., Djurovic, Srdjan, Van Dongen, Jasper, Deramecourt, V., Kalaria, R. N., Wang, L. S., Goldhardt, O., Charbonnier, Camille, Farotti, Lucia, Kornhuber, Johannes, Andreassen, Ole A., Álvarez, Victoria, Herrmann, Martin J., Pasquier, Florence, Calero, Miguel, Holmes, Clive, Haapasalo, Annakaisa, Scherbaum, Norbert, Scheltens, Philip, Caffarra, P., Pineda, Juan A., Del Ser, Teodoro, Hort, Jakub, Espinosa, A., Bullido, María Jesús, Hampel, Harald, Medina, Miguel, Williams, Julie, Sims, Rebecca, Martinez-Larrad, M. T., Riederer, Peter, Esiri, M., Botne Sando, S., Grunblatt, E., Hoffmann, Per, Hiltunen, Mikko, Kern, Silke, Mendoza, Silvia, Kilander, Lena, Jessen, F., Ghidoni, R., Giedraitis, Vilmantas, Molina-Porcel, Laura, Sánchez-Juan, Pascual, Schmid, Matthias, van Duijn, Cornelia M., Antonell, A., Mir, Pablo, Moreno, F., Ferreira, Catarina B., Skrobot, Olivia, Sanchez-Valle, R., Chene, G., Duron, Emmanuelle, Martin Montes, Ángel, Ciccone, Simona, Piñol-Ripoll, Gerard, Ngandu, Tiia, Dardiotis, Efthimios, Scherer, Martin, Arosio, Beatrice, Meggy, A., Sotolongo-Grau, Oscar, Selbaek, Geir, Aarsland, D., Seshadri, Sudha, Bailly, Henri, Sánchez-García, Florentino, Roberto, Natalia, Armstrong, Nicola J., Farrer, Lindsay A., Popp, Julius, Riedel-Heller, Steffi, Fernández-Fuertes, Marta, Scamosci, Michela, Alcolea, Daniel, Rosas Allende, Irene, Marquié, Marta, Benussi, Luisa, Ewers, Michael, Antúnez, Carmen, van Broeckhoven, Christine, Masullo, C., Vyhnalek, Martin, Bossu, Paola, Appollonio, I., Mayeux, R., Lerch, Ondrej, Rábano, Alberto, Quenez, Olivier, Schneider, Anja, Wallon, David, Macías Sánchez, Juan, PGC-ALZ consortia, Yang, Q., Helisalmi, Seppo, Huisman, M., Lambert, Jean-Charles, Kehoe, Patrick G., Heneka, Michael T., DEGESCO consortium, Papenberg, Goran, Lowenmark, M., Frikke-Schmidt, Ruth, Fornage, Myriam, Kunkle, Brian W., Heilmann-Heimbach, Stefanie, Posthuma, Danielle, Tremolizzo, Lucio, Amouyel, Philippe, Franco-Macías, Emilio, Munoz-Fernandez, C., Sorbi, Sandro, Küçükali, Fahri, Dionigi Rossi, P., Huerto Vilas, Raquel, Spallazzi, Marco, Alarcón-Martín, Emilio, Maier, Wolfgang, de Mendonça, Alexandre, The GR@ACE study group, Benaque, Alba, EADB contributors, IGAP (ADGC, CHARGE, EADI, GERAD), van der Lee, Sven J., DeStefano, Anita, Lleó, Alberto, Kosmidis, Mary H., Rongve, A., Nicolas, Gael, Escott-Price, Valentina, Tybjaerg-Hansen, Anne, Chillotti, Caterina, Pastor, Pau, Buiza-Rueda, Dolores, Alegret, Montserrat, Lage, Carmen, Holmans, Peter A., Polak, Thomas, Pastor, Ana Belén, Nöthen, Markus M., García-Ribas, Guillermo, Pijnenburg, Yolande A L, Vidal, Jean-Sebastien, Squassina, Alessio, Kuulasmaa, Teemu, Pericak-Vance, M. A., Pisanu, Claudia, Fliessbach, Klaus, Grimmer, Timo, Galimberti, Daniela, Parnetti, L., López de Munain, Adolfo, Soininen, Hilkka, Carracedo, Ángel, Deckert, Jurgen, Karlsson, I. K., Buerger, Katharina, Clark, Christopher, Cecchetti, Roberta, Fostinelli, Silvia, Deniz-Naranjo, M. C., Engelborghs, S., Álvarez, Ignacio, Sakka, Paraskevi, Thomassen, Jesper Qvist, Ramirez, A., Holstege, Henne, Marshall, Rachel, Haines, Jonathan L., Hulsman, Marc, Kleineidam, Luca, Ferri, E., Pérez-Cordon, Alba, Menéndez-González, Manuel, van der Flier, Wiesje M., Rainero, Innocenzo, Rujescu, D., Wagner, Michael, Corma-Gómez, Anaïs, Lebouvier, T., Ruiz, Agustín, Vandenberghe, Rik, Weinhold, Leonie, Padovani, Alessandro, Diehl-Schmid, Janine, Mead, Simon, Fenoglio, Chiara, Conti, Elisa, Díez-Fairen, Mónica, Fischer, Peter, Abdelnour, Carla, Giaccone, G., González-Pérez, Antonio, Hartmann, Annette M., Hadjigeorgiou, Georgios, Zulaica, M., Sleegers, Kristel, Martínez Rodríguez, Carmen, García-González, Pablo, Rubino, Elisa, Bis, Joshua C., Orellana, Adelina, Zetterberg, Henrik, Schellenberg, Gerard D., Borroni, Barbara, Sanabria, Angela, Fortea, J., Reynolds, C. A., Gelpi, E., Bernal Sánchez-Arjona, María, Boerwinkle, Eric, Mather, K. A., Jian, X., Saltvedt, Ingvild, Frank-García, Ana, Rosende-Roca, Maitee, Kinhult Stahlbom, Anne, Hanon, Olivier, Skoog, Ingmar, Kivipelto, Miia, Lehtisalo, Jenni, García-Alberca, José María, Dufouil, Carole, Bellenguez, Celine, Ingelsson, Martin, Nacmias, B., Spottke, Annika, Ullgren, Abbe, Hausner, Lucrezia, Arias Pastor, Alfonso, Tsolaki, Magda, Seripa, Davide, Naj, A. C., Clarimón, Jordi, Nordestgaard, Borge G., Valero, Sergi, van Schoor, N. M., Scarpini, E., Graff, Caroline, Boada, Mercè, Tagliavini, F., Scarmeas, N., García-Madrona, Sebastián, Yannakoulia, Mary, Banaj, Nerisa, Blennow, Kaj, Duzel, Emrah, Tárraga, Lluís, Lemstra, A. W., Morgan, K., Kok, A. A. L., Bessi, Valentina, Baquero, Miquel, Rodríguez-Rodríguez, Eloy, Cervera-Carles, Laura, Archetti, Silvana, Grande, Giulia, Dichgans, Martin, Arcaro, Marina, Blesa, Rafael, Real, Luis Miguel, Ikram, M. Arfan, Mangialasche, Francesca, Quintela, Inés, Instituto de Salud Carlos III, Grifols, La Caixa, European Research Council, Pérez-Tur, Jordi [0000-0002-9111-1712], Rojas, Itziar de, Moreno-Grau, Sonia, Tesi, Niccolo, Grenier-Boley, Benjamin, Andrade, Victor, Jansen, Iris E., Pedersen, N. L., Stringa, N., Zettergren, Anna, Hernández, Isabel, Montrreal, Laura, Rossi, Giacomina, Tankard, R. M., Wiltfang, J., Giegling, Ina, Seidu, N. M., Dalmasso, Maria Carolina, Benussi, A., Boschi, Silvia, Sáez, María Eugenia, Binetti, Giuliano, Royo, José Luis, Pérez-Tur, Jordi, Spalletta, Gianfranco, Corbaton-Anchuelo, A., Froelich, L., Satizabal, Claudia L., Hagg, S., Ortega, G., Peters, Oliver, Vogelgsang, Jonathan, Serrano-Rios, M., Gil, S., Djurovic, Srdjan, Van Dongen, Jasper, Deramecourt, V., Kalaria, R. N., Wang, L. S., Goldhardt, O., Charbonnier, Camille, Farotti, Lucia, Kornhuber, Johannes, Andreassen, Ole A., Álvarez, Victoria, Herrmann, Martin J., Pasquier, Florence, Calero, Miguel, Holmes, Clive, Haapasalo, Annakaisa, Scherbaum, Norbert, Scheltens, Philip, Caffarra, P., Pineda, Juan A., Del Ser, Teodoro, Hort, Jakub, Espinosa, A., Bullido, María Jesús, Hampel, Harald, Medina, Miguel, Williams, Julie, Sims, Rebecca, Martinez-Larrad, M. T., Riederer, Peter, Esiri, M., Botne Sando, S., Grunblatt, E., Hoffmann, Per, Hiltunen, Mikko, Kern, Silke, Mendoza, Silvia, Kilander, Lena, Jessen, F., Ghidoni, R., Giedraitis, Vilmantas, Molina-Porcel, Laura, Sánchez-Juan, Pascual, Schmid, Matthias, van Duijn, Cornelia M., Antonell, A., Mir, Pablo, Moreno, F., Ferreira, Catarina B., Skrobot, Olivia, Sanchez-Valle, R., Chene, G., Duron, Emmanuelle, Martin Montes, Ángel, Ciccone, Simona, Piñol-Ripoll, Gerard, Ngandu, Tiia, Dardiotis, Efthimios, Scherer, Martin, Arosio, Beatrice, Meggy, A., Sotolongo-Grau, Oscar, Selbaek, Geir, Aarsland, D., Seshadri, Sudha, Bailly, Henri, Sánchez-García, Florentino, Roberto, Natalia, Armstrong, Nicola J., Farrer, Lindsay A., Popp, Julius, Riedel-Heller, Steffi, Fernández-Fuertes, Marta, Scamosci, Michela, Alcolea, Daniel, Rosas Allende, Irene, Marquié, Marta, Benussi, Luisa, Ewers, Michael, Antúnez, Carmen, van Broeckhoven, Christine, Masullo, C., Vyhnalek, Martin, Bossu, Paola, Appollonio, I., Mayeux, R., Lerch, Ondrej, Rábano, Alberto, Quenez, Olivier, Schneider, Anja, Wallon, David, Macías Sánchez, Juan, PGC-ALZ consortia, Yang, Q., Helisalmi, Seppo, Huisman, M., Lambert, Jean-Charles, Kehoe, Patrick G., Heneka, Michael T., DEGESCO consortium, Papenberg, Goran, Lowenmark, M., Frikke-Schmidt, Ruth, Fornage, Myriam, Kunkle, Brian W., Heilmann-Heimbach, Stefanie, Posthuma, Danielle, Tremolizzo, Lucio, Amouyel, Philippe, Franco-Macías, Emilio, Munoz-Fernandez, C., Sorbi, Sandro, Küçükali, Fahri, Dionigi Rossi, P., Huerto Vilas, Raquel, Spallazzi, Marco, Alarcón-Martín, Emilio, Maier, Wolfgang, de Mendonça, Alexandre, The GR@ACE study group, Benaque, Alba, EADB contributors, IGAP (ADGC, CHARGE, EADI, GERAD), van der Lee, Sven J., DeStefano, Anita, Lleó, Alberto, Kosmidis, Mary H., Rongve, A., Nicolas, Gael, Escott-Price, Valentina, Tybjaerg-Hansen, Anne, Chillotti, Caterina, Pastor, Pau, Buiza-Rueda, Dolores, Alegret, Montserrat, Lage, Carmen, Holmans, Peter A., Polak, Thomas, Pastor, Ana Belén, Nöthen, Markus M., García-Ribas, Guillermo, Pijnenburg, Yolande A L, Vidal, Jean-Sebastien, Squassina, Alessio, Kuulasmaa, Teemu, Pericak-Vance, M. A., Pisanu, Claudia, Fliessbach, Klaus, Grimmer, Timo, Galimberti, Daniela, Parnetti, L., López de Munain, Adolfo, Soininen, Hilkka, Carracedo, Ángel, Deckert, Jurgen, Karlsson, I. K., Buerger, Katharina, Clark, Christopher, Cecchetti, Roberta, Fostinelli, Silvia, Deniz-Naranjo, M. C., Engelborghs, S., Álvarez, Ignacio, Sakka, Paraskevi, Thomassen, Jesper Qvist, Ramirez, A., Holstege, Henne, Marshall, Rachel, Haines, Jonathan L., Hulsman, Marc, Kleineidam, Luca, Ferri, E., Pérez-Cordon, Alba, Menéndez-González, Manuel, van der Flier, Wiesje M., Rainero, Innocenzo, Rujescu, D., Wagner, Michael, Corma-Gómez, Anaïs, Lebouvier, T., Ruiz, Agustín, Vandenberghe, Rik, Weinhold, Leonie, Padovani, Alessandro, Diehl-Schmid, Janine, Mead, Simon, Fenoglio, Chiara, Conti, Elisa, Díez-Fairen, Mónica, Fischer, Peter, Abdelnour, Carla, Giaccone, G., González-Pérez, Antonio, Hartmann, Annette M., Hadjigeorgiou, Georgios, Zulaica, M., Sleegers, Kristel, Martínez Rodríguez, Carmen, García-González, Pablo, Rubino, Elisa, Bis, Joshua C., Orellana, Adelina, Zetterberg, Henrik, Schellenberg, Gerard D., Borroni, Barbara, Sanabria, Angela, Fortea, J., Reynolds, C. A., Gelpi, E., Bernal Sánchez-Arjona, María, Boerwinkle, Eric, Mather, K. A., Jian, X., Saltvedt, Ingvild, Frank-García, Ana, Rosende-Roca, Maitee, Kinhult Stahlbom, Anne, Hanon, Olivier, Skoog, Ingmar, Kivipelto, Miia, Lehtisalo, Jenni, García-Alberca, José María, Dufouil, Carole, Bellenguez, Celine, Ingelsson, Martin, Nacmias, B., Spottke, Annika, Ullgren, Abbe, Hausner, Lucrezia, Arias Pastor, Alfonso, Tsolaki, Magda, Seripa, Davide, Naj, A. C., Clarimón, Jordi, Nordestgaard, Borge G., Valero, Sergi, van Schoor, N. M., Scarpini, E., Graff, Caroline, Boada, Mercè, Tagliavini, F., Scarmeas, N., García-Madrona, Sebastián, Yannakoulia, Mary, Banaj, Nerisa, Blennow, Kaj, Duzel, Emrah, Tárraga, Lluís, Lemstra, A. W., Morgan, K., Kok, A. A. L., Bessi, Valentina, Baquero, Miquel, Rodríguez-Rodríguez, Eloy, Cervera-Carles, Laura, Archetti, Silvana, Grande, Giulia, Dichgans, Martin, Arcaro, Marina, Blesa, Rafael, Real, Luis Miguel, Ikram, M. Arfan, Mangialasche, Francesca, and Quintela, Inés

Abstract

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

Published
2021

21. Straightforward protocol for allele-specific chromatin conformation capture

Author

Ministerio de Economía y Competitividad (España), European Research Council, European Commission, Fundación BBVA, Acemel, Rafael D., Tena, Juan J., Gómez-Skarmeta, José Luis, Fibla, Joan, Royo, José Luis, Ministerio de Economía y Competitividad (España), European Research Council, European Commission, Fundación BBVA, Acemel, Rafael D., Tena, Juan J., Gómez-Skarmeta, José Luis, Fibla, Joan, and Royo, José Luis

Abstract

A key advance in our understanding of gene regulation came with the finding that the genome undergoes three-dimensional nuclear folding in a genetically determined process. This 3D conformation directly influences the association between enhancers and their target promoters. This complex interplay has been proven to be essential for gene regulation, and genetic variants affecting this process have been associated to human diseases. The development of new technologies that quantify these DNA interactions represented a revolution in the field. High throughput techniques like HiC provide a general picture of chromatin topology. However, they often lack resolution to evidence subtle effects that single nucleotide polymorphisms exert over the contacts between cis-regulatory regions and target promoters. Here we propose a cost-efficient approach to perform allele-specific chromatin conformation analysis. As a proof of concept, we analyzed the impact of a common deletion mapping between SIRPB1 promoter and one of its downstream enhancers.

Published
2021

22. Enriquecimiento de aceite oliva virgen extra con astaxantina de Xanthophyllomyces dendrorhous

Author

Rivera Royo, José Luis, Sánchez Gimeno, Ana Cristina, and Raso Pueyo, Javier

Abstract

El objetivo de este trabajo ha sido obtener aceite de oliva enriquecido con un extracto de astaxantina y comprobar cómo influye en su calidad.El enriquecimiento se realizó incorporando un extracto de astaxantina obtenido a partir de un cultivo de levadura Xanthophyllomyces dendrorhous, previamente tratado con la tecnología de pulsos eléctricos de alto voltaje (PEAV) y sometido a un proceso de extracción hasta obtener un extracto concentrado de astaxantina.No se observaron cambios significativos en el aceite enriquecido durante el período de duración del estudio en algunos parámetros físico-químicos del aceite, como la acidez, el índice de peróxidos y los coeficientes de extinción en el ultravioleta, pero en cambio en las medidas de color sí que se observaron cambios significativos.El enriquecimiento sí que generó variaciones significativas de los parámetros nutricionales del aceite. Por un lado, al incrementar el contenido en carotenoides se incrementó la capacidad antioxidante del aceite y, por otro lado, los carotenoides ejercieron un efecto protector sobre los polifenoles presentes en el aceite de oliva, afectando de forma positiva a su capacidad antioxidante

Published
2020

23. Association of complementC3d receptor 2genotypes with the acquisition of HIV infection in a trial of recombinant glycoprotein 120 vaccine

Author

Ministerio de Economía y Competitividad (España), Asociación Universitaria Iberoamericana de Postgrado (España), Meza, Giovanna, Expósito, Almudena, Royo, José Luis, Ruiz-García, Celia, Sánchez-Arcas, Beatriz, Marquez, Francisco J., Gómez-Vidal, María Amparo, Omar, Mohamed, Sinangil, Faruk, Higgins, Keith, Forthal, Donald, Real, Luis Miguel, Caruz, Antonio, Ministerio de Economía y Competitividad (España), Asociación Universitaria Iberoamericana de Postgrado (España), Meza, Giovanna, Expósito, Almudena, Royo, José Luis, Ruiz-García, Celia, Sánchez-Arcas, Beatriz, Marquez, Francisco J., Gómez-Vidal, María Amparo, Omar, Mohamed, Sinangil, Faruk, Higgins, Keith, Forthal, Donald, Real, Luis Miguel, and Caruz, Antonio

Abstract

[Objectives]: Complement C3d receptor 2 (CR2) is the main receptor for complement protein C3d and plays an important role in adaptive immune responses. CR2 genetic variants are associated with susceptibility to systemic lupus erythematosus as well as to HIV-1 infection. In addition, CR2 function can be subverted by HIV-1 for an efficient entry into target cells; in a process known as antibody-dependent enhancement of viral infection. We sought to determine the association between CR2 gene variants with HIV-1 acquisition after vaccination with recombinant gp120 protein (Vax004 clinical trial)., [Design and methods]: This is a retrospective cross-sectional study, comprising male volunteers of European ancestry including infected (n = 273) and uninfected (n = 402) vaccinees and placebo, who were genotyped for three single nucleotide polymorphisms (SNPs) in the CR2 gene region., [Results]: An interaction was observed between the baseline sexual behavior and the SNP rs3813946 for higher risk of infection in vacinees (interaction term P = 0.02). This SNP was associated with increased susceptibility to HIV-1 infection after vaccination in volunteers with low behavioral risk odds ratio (95% confidence interval): 5.5 (1.4–21.7) P = 0.006 but not vaccinees with high behavioral risk or volunteers given placebo (P = 0.7). Moreover, CR2 genotype was strongly associated with the rate of HIV-1 acquisition after vaccination in low-risk volunteers [hazard odds ratio (95% confidence interval): 3.3 (1.6–7.0), P = 0.001]., [Conclusion]: The current study suggests that CR2 may play a role in HIV-1 acquisition after vaccination with rgp120 proteins.

Published
2020

28. Synthesis and Characterization of Elongated-Shaped Silver Nanoparticles as a Biocompatible Anisotropic SERS Probe for Intracellular Imaging: Theoretical Modeling and Experimental Verification

Author

Caro, Carlos, Quaresma, Pedro, Pereira, Eulália, Franco, Jaime M., Pernia Leal, Manuel, García-Martín, María L., Royo, José Luis, Oliva, José M., Merkling, Patrick J., Zaderenko, Paula, Pozo, David, Franco, Ricardo, Caro, Carlos, Quaresma, Pedro, Pereira, Eulália, Franco, Jaime M., Pernia Leal, Manuel, García-Martín, María L., Royo, José Luis, Oliva, José M., Merkling, Patrick J., Zaderenko, Paula, Pozo, David, and Franco, Ricardo

Abstract

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 107) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.

Published
2019

29. Dysmorphic contribution of neurotransmitter and neuroendocrine system polymorphisms to subtherapeutic mood states

Author

González, Irene, Polvillo Hernández, Rocío, Ruiz‐Galdón, Maximiliano, Reyes‐Engel, Armando, Royo, José Luis, González, Irene, Polvillo Hernández, Rocío, Ruiz‐Galdón, Maximiliano, Reyes‐Engel, Armando, and Royo, José Luis

Abstract

[Objective]: From an evolutionary perspective, emotions emerged as rapid adaptive reactions that increase survival rates. Current psychobiology includes the consideration that genetic changes affecting neuroendocrine and neurotransmission pathways may also be affecting mood states. Following this hypothesis, abnormal levels of any of the aminergic neurotransmitters would be of considerable importance in the development of a pathophysiological state. [Materials and Methods]: A total of 668 students from the School of Medicine of the University of Malaga (Average = 22.41 ± 3; 41% men) provided self‐report measures of mood states using POMS and GHQ‐28 questionnaires and buccal cells for genotyping 19 polymorphisms from 14 selected neurotransmitter pathways genes (HTR1A; HTR2A; HTR2C; HTR3B; TPH1; SLC18A1; SLC18A2; COMT; MAOA; MAOB) and neuroendocrine system (AVPR1B; OPRM1; BDNF; OXTR). [Results]: MAOA rs3788862 genotype correlates with decreasing levels of Tension among females (beta = −0.168, p‐value = 0.003) but it is neutral among males in this subscale. On the contrary, it correlates with lower GHQ‐28 depression scores among males (beta = −0.196, p‐value = 0.008). Equivalently, SLC18A1 and HTR2A variants correlated with anger and vigor scores, only among males. From the neuroendocrine system, OPRM1 rs1799971 correlated increasing levels of female's Anxiety, depression and Social Dysfunction scores. [Conclusion]: Our findings suggest that these polymorphisms contribute to define general population mood levels, although exhibiting a clear sexual dimorphism.

Published
2019

31. Estrogen receptor alpha gene variants are associated with Alzheimer's disease

Author

Boada, Mercé, Antunez, Carmen, López-Arrieta, Jesús, Caruz, Antonio, Moreno-Rey, Concha, Ramírez-Lorca, Reposo, Morón, Francisco Jesús, Hernández, Isabel, Mauleón, Ana, Rosende-Roca, Maiteé, Martínez-Lage, Pablo, Marín, Juan, Tárraga, Lluis, Alegret, Montserrat, Pedrajas, José Rafael, Urda, Nuria, Royo, José Luis, Saez, María Eugenia, Gayán, Javier, González-Pérez, Antonio, Real, Luis Miguel, Ruiz, Agustín, and Galán, José Jorge

Published
2012
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32. Effects of SHBG rs1799941 Polymorphism on Free Testosterone Levels and Hypogonadism Risk in Young Non-Diabetic Obese Males

Author

Castellano-Castillo, Daniel, primary, Royo, José Luis, additional, Martínez-Escribano, Ana, additional, Sánchez-Alcoholado, Lidia, additional, Molina-Vega, María, additional, Queipo-Ortuño, María Isabel, additional, Ruiz-Galdon, Maximiliano, additional, J. Álvarez-Millán, Juan, additional, Cabezas-Sanchez, Pablo, additional, Reyes-Engel, Armando, additional, Tinahones, Francisco J., additional, Cardona, Fernando, additional, and Fernandez-Garcia, José C., additional

Published
2019
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34. A common copy-number variant within SIRPB1 correlates with human out-of-Africa migration after genetic drift correction

Author

Royo, José Luis, Valls, Joan, Acemel, Rafael D., Gómez-Marín, Carlos, Pascual-Pons, Mariona, Lupiañez, Arantxa, Gómez-Skarmeta, José Luis, Fibla, Joan, Royo, José Luis, Valls, Joan, Acemel, Rafael D., Gómez-Marín, Carlos, Pascual-Pons, Mariona, Lupiañez, Arantxa, Gómez-Skarmeta, José Luis, and Fibla, Joan

Abstract

Previous reports have proposed that personality may have played a role on human Out-Of-Africa migration, pinpointing some genetic variants that were positively selected in the migrating populations. In this work, we discuss the role of a common copy-number variant within the SIRPB1 gene, recently associated with impulsive behavior, in the human Out-Of-Africa migration. With the analysis of the variant distribution across forty-two different populations, we found that the SIRPB1 haplotype containing duplicated allele significantly correlated with human migratory distance, being one of the few examples of positively selected loci found across the human world colonization. Circular Chromosome Conformation Capture (4C-seq) experiments from the SIRPB1 promoter revealed important 3D modifications in the locus depending on the presence or absence of the duplication variant. In addition, a 3’ enhancer showed neural activity in transgenic models, suggesting that the presence of the CNV may compromise the expression of SIRPB1 in the central nervous system, paving the way to construct a molecular explanation of the SIRPB1 variants role in human migration.

Published
2018

35. A Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection

Author

Jaimes-Bernal, Claudia, primary, Rallón, Norma, additional, Benito, José M, additional, Omar, Mohamed, additional, Gómez-Vidal, María Amparo, additional, Márquez, Francisco José, additional, Sánchez-Arcas, Beatriz, additional, Trujillo, Monte, additional, Royo, José Luis, additional, Saulle, Irma, additional, Biasin, Mara, additional, Rivero-Juárez, Antonio, additional, and Caruz, Antonio, additional

Published
2018
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37. Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection.

Author

Jaimes-Bernal, Claudia, Rallón, Norma, Benito, José M, Omar, Mohamed, Gómez-Vidal, María Amparo, Márquez, Francisco José, Sánchez-Arcas, Beatriz, Trujillo, Monte, Royo, José Luis, Saulle, Irma, Biasin, Mara, Rivero-Juárez, Antonio, and Caruz, Antonio

Subjects
SEXUALLY transmitted diseases, HIV, HEPATITIS C virus, VIRUS diseases, INFECTION
Abstract

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α–dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1–positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2–3.6; P =.004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3–3.2; P =.001). [ABSTRACT FROM AUTHOR]

Published
2019
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38. A Knockout IFNL4 Variant Is Associated With Protection From Sexually Transmitted HIV-1 Infection.

Author

Jaimes-Bernal, Claudia, Rallón, Norma, Benito, José M, Omar, Mohamed, Gómez-Vidal, María Amparo, Márquez, Francisco José, Sánchez-Arcas, Beatriz, Trujillo, Monte, Royo, José Luis, Saulle, Irma, Biasin, Mara, Rivero-Juárez, Antonio, and Caruz, Antonio

Abstract

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001). [ABSTRACT FROM AUTHOR]

Published
2019
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39. Biocide nanostructures

Author

Zaderenko, Paula, Caro Salazar, Carlos Alberto, Sayagués, María Jesús, Royo, José Luis, and Polvillo Hernández, Rocío

Abstract

[EN] The invention relates to a method for producing nanostructures, comprising the following steps: a) preparing a suspension comprising at least one semiconductive metal oxide, activated carbon and at least one compound of a noble metal; and b) adding a reducing agent to the suspension obtained in step (a)., [ES] Esta invención se refiere a un procedimiento de obtención de nanoestructuras que comprende las siguientes etapas:a) preparación de una suspensión que comprende al menos un óxido metálico semiconductor, carbón activo y al menos un compuesto de un metal noble;y b) adición de un agente reductor a la suspensión obtenida en la etapa (a)., Universidad Pablo de Olavide, Consejo Superior de Investigaciones Científicas, A1 Solicitud de patente con informe sobre el estado de la técnica

Published
2014

40. Nanoestructuras biocidas

Author

Zaderenko, Paula, Caro Salazar, Carlos Alberto, Sayagués, María Jesús, Royo, José Luis, and Polvillo Hernández, Rocío

Abstract

Esta invención se refiere a un procedimiento de obtención de nanoestructuras que comprende las siguientes etapas: a) preparación de una suspensión que comprende al menos un óxido metálico semiconductor, carbón activo y al menos un compuesto de un metal noble; y b) adición de un agente reductor a la suspensión obtenida en la etapa (a)., Universidad Pablo de Olavide, Consejo Superior de Investigaciones Científicas, B1 Patente sin examen previo

Published
2013

41. Comparative genomics of the Hedgehog loci in chordates and the origins of Shh regulatory novelties

Author

Irimia, Manuel, Royo, José Luis, Burguera, Demian, Maeso, Ignacio, Gómez-Skarmeta, José Luis, Garcia-Fernàndez, Jordi, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Institución Catalana de Investigación y Estudios Avanzados, and Junta de Andalucía

Subjects
animal structures, Embryo, Nonmammalian, Green Fluorescent Proteins, Molecular Sequence Data, Chromosome Mapping, Gene Expression Regulation, Developmental, Genetic Variation, Genomics, Sequence Analysis, DNA, Zebrafish Proteins, Synteny, Article, Animals, Genetically Modified, Species Specificity, Chordata, Nonvertebrate, embryonic structures, Animals, Hedgehog Proteins, Cloning, Molecular, In Situ Hybridization, Phylogeny, Zebrafish
Abstract

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareALike 3.0 Unported License., The origin and evolution of the complex regulatory landscapes of some vertebrate developmental genes, often spanning hundreds of Kbp and including neighboring genes, remain poorly understood. The Sonic Hedgehog (Shh) genomic regulatory block (GRB) is one of the best functionally characterized examples, with several discrete enhancers reported within its introns, vast upstream gene-free region and neighboring genes (Lmbr1 and Rnf32). To investigate the origin and evolution of this GRB, we sequenced and characterized the Hedgehog (Hh) loci from three invertebrate chordate amphioxus species, which share several early expression domains with Shh. Using phylogenetic footprinting within and between chordate lineages, and reporter assays in zebrafish probing >30 Kbp of amphioxus Hh, we report large sequence and functional divergence between both groups. In addition, we show that the linkage of Shh to Lmbr1 and Rnf32, necessary for the unique gnatostomate-specific Shh limb expression, is a vertebrate novelty occurred between the two whole-genome duplications., M.I., D.B., I.M. and J.G.-F. were funded by Grants BFU2005-00252 and BMC2008-03776 and BMC2011-23291 from the Spanish Ministry of Science and Innovation, and J.G.F. by the ICREA Academia Prize. M.I., D.B. and I.M. held FPI, APIF-UB and FPU fellowships, respectively. J.-L.G.-S. and J.L.R. were supported by Grants BFU2010-14839, CSD2007-00008875 (MEC), and CVI 3488 (Junta de Andalucía). JLR holds a JAE-Doc grant from the National Research Council, founded by Social European Funds.

Published
2012

42. Nanoestructuras biocidas

Author

Zaderenko, Paula, Caro Salazar, Carlos Alberto, Sayagués, María Jesús, Royo, José Luis, Polvillo Hernández, Rocío, Zaderenko, Paula, Caro Salazar, Carlos Alberto, Sayagués, María Jesús, Royo, José Luis, and Polvillo Hernández, Rocío

Abstract

Esta invención se refiere a un procedimiento de obtención de nanoestructuras que comprende las siguientes etapas: a) preparación de una suspensión que comprende al menos un óxido metálico semiconductor, carbón activo y al menos un compuesto de un metal noble; y b) adición de un agente reductor a la suspensión obtenida en la etapa (a).

Published
2014

43. Prokaryotische genregulation: Aspirin als regulator der genexpression

Author

Becker, Pablo Daniel and Royo, José Luis

Abstract

[EN]: Salicylate-dependent control circuit based on nahR/Psal::xylS2 regulates the expression of the heterologous gene downstream the Pm promoter in vivo., [DE]: Ein Salicylat-abhängiger Kontrollschalter basierend auf dem regulatorischen Modul nahR/Psal::xylS2 und dem Gen von Interesse unter Kontrolle des Pm-Promotors reguliert die Genexpression in vivo.

Published
2008

45. O4-04-04: TOWARD FINE MAPPING AND FUNCTIONAL CHARACTERIZATION OF GENOME-WIDE ASSOCIATION STUDY-IDENTIFIED LOCUS RS74615166 (TRIP4) FOR ALZHEIMER'S DISEASE

Author

Ruiz, Agustín, primary, Heilmann, Stefanie, additional, Leber, Markus, additional, Becker, Tim, additional, Toliat, Mohammad, additional, Royo, José Luis, additional, Wagner, Holger, additional, Thelen, Mathias, additional, Hernandez, Isabel, additional, Alegret, Montse, additional, Mauleón, Ana, additional, Espinosa, Ana, additional, Rosende-Roca, Maitée, additional, Lacour, André, additional, Grau, Oscar Sotolongo, additional, Breteler, Monique M.B., additional, Jessen, Frank, additional, Tarraga, Lluis, additional, Becker, Julian, additional, Nürnberg, Peter, additional, Nöthen, Markus, additional, Maier, Wolfgang, additional, Boada, Mercè, additional, and Ramirez, Alfredo, additional

Published
2014
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47. Zebrafish as a model organism to study host–pathogen interactions

Author

Consejo Superior de Investigaciones Científicas (España), European Commission, Medina, Carlos, Royo, José Luis, Consejo Superior de Investigaciones Científicas (España), European Commission, Medina, Carlos, and Royo, José Luis

Abstract

Zebrafish have been extensively used in biomedical research as a model to study vertebrate development but it is only recently that it has also been adopted into varied fields such as immunology and host–pathogen interactions. Zebrafish have a rapid life cycle, small size and the adults exhibit no territorial behavior in relatively dense cages. Under standard conditions each female lays an average of a hundred eggs per clutch, providing a large number of larvae per week. Their transparency during early life stages allows real time visualization of the different organs, which makes them especially suitable for the study of bacterial host–pathogen interactions. Traditionally, these studies have been technically challenging in higher organisms, given the loss of control over the bacteria once the pathogen infects its host. Here we describe an emerging approach to monitor Salmonella typhimurium infection progression using in vivo fluorescence upon parenteral infection. We have engineered Salmonella with the Cascade expression system; an efficient method to voluntarily activate bacterial heterologous gene expression at any point during infection once inside the Zebrafish macrophages, using a non-toxic inducer.

Published
2013

48. Comparative genomics of the Hedgehog loci in chordates and the origins of Shh regulatory novelties

Author

Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Institución Catalana de Investigación y Estudios Avanzados, Junta de Andalucía, Irimia, Manuel, Royo, José Luis, Burguera, Demian, Maeso, Ignacio, Gómez-Skarmeta, José Luis, Garcia-Fernàndez, Jordi, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Institución Catalana de Investigación y Estudios Avanzados, Junta de Andalucía, Irimia, Manuel, Royo, José Luis, Burguera, Demian, Maeso, Ignacio, Gómez-Skarmeta, José Luis, and Garcia-Fernàndez, Jordi

Abstract

The origin and evolution of the complex regulatory landscapes of some vertebrate developmental genes, often spanning hundreds of Kbp and including neighboring genes, remain poorly understood. The Sonic Hedgehog (Shh) genomic regulatory block (GRB) is one of the best functionally characterized examples, with several discrete enhancers reported within its introns, vast upstream gene-free region and neighboring genes (Lmbr1 and Rnf32). To investigate the origin and evolution of this GRB, we sequenced and characterized the Hedgehog (Hh) loci from three invertebrate chordate amphioxus species, which share several early expression domains with Shh. Using phylogenetic footprinting within and between chordate lineages, and reporter assays in zebrafish probing >30 Kbp of amphioxus Hh, we report large sequence and functional divergence between both groups. In addition, we show that the linkage of Shh to Lmbr1 and Rnf32, necessary for the unique gnatostomate-specific Shh limb expression, is a vertebrate novelty occurred between the two whole-genome duplications.

Published
2012

49. Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer

Author

Royo, José Luis, Gómez-Skarmeta, José Luis, Heath, Karen Elise, Royo, José Luis, Gómez-Skarmeta, José Luis, and Heath, Karen Elise

Abstract

[Background]: SHOX, located in the pseudoautosomal region 1 (PAR1) of the sexual chromosomes, encodes a transcription factor implicated in human growth. Defects in SHOX or its enhancers have been observed in ~60% of Leri-Weill dyschondrosteosis (LWD) patients, a skeletal dysplasia characterised by short stature and/or the characteristic Madelung deformity, and in 2e5% of idiopathic short stature (ISS). To identify the molecular defect in the remaining genetically undiagnosed LWD and ISS patients, this study screened previously unanalysed PAR1 regions in 124 LWD and 576 ISS probands. [Methods]: PAR1 screening was undertaken by multiplex ligation dependent probe amplification (MLPA). Copy number alterations were subsequently confirmed and delimited by locus-specific custom-designed MLPA, array comparative genomic hybridisation (CGH) and breakpoint junction PCR/sequencing. [Results]: A recurrent PAR1 deletion downstream of SHOX spanning 47543 bp with identical breakpoints was identified in 19 LWD (15.3%) and 11 ISS (1.9%) probands, from 30 unrelated families. Eight evolutionarily conserved regions (ECRs 1e8) identified within the deleted sequence were evaluated for SHOX regulatory activity by means of chromosome conformation capture (3C) in chicken embryo limbs and luciferase reporter assays in human U2OS osteosarcoma cells. The 3C assay indicated potential SHOX regulatory activity by ECR1, which was subsequently confirmed to act as a SHOX enhancer, operating in an orientation and position independent manner, in human U2OS cells. [Conclusions]: This study has identified the first recurrent PAR1 deletion in LWD and ISS, which results in the loss of a previously uncharacterised SHOX enhancer. The loss of this enhancer may decrease SHOX transcription, resulting in LWD or ISS due to SHOX haploinsufficiency.

Published
2012

50. Engineered Salmonella allows real-time heterologous gene expression monitoring within infected zebrafish embryos

Author

Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía y Competitividad (España), Medina, Carlos, Santero, Eduardo, Gómez-Skarmeta, José Luis, Royo, José Luis, Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), Ministerio de Economía y Competitividad (España), Medina, Carlos, Santero, Eduardo, Gómez-Skarmeta, José Luis, and Royo, José Luis

Abstract

Microbial host–pathogen interactions have been traditionally well studied at genetic and physiological levels, but cell-resolution analyses have been particularly scarce. This has been especially remarkable for intracellular parasites for two major reasons: first, the inherent loss of bacteria traceability once infects its hosts; second and more important, the limited availability of genetic tools that allow a tight regulated expression of bacterial virulence genes once inside the host tissues. Here we present novel data supporting the use of zebrafish embryos to monitor Salmonella enterica serovar Thyphimurium infection. Intravenous infection of Salmonella can be easily monitored using in vivo fluorescence that allows the visualization of free-swimming bacteria through the circulatory system. Moreover, we have engineered Salmonella to voluntarily activate heterologous gene expression at any point during infection once inside the zebrafish macrophages using a salicylate-based expression system. This approach allows real-time cell-resolution in vivo monitoring of the infection. All together, this approach paves the road to cell-based resolution experiments that would be harder to mimic in other vertebrate infection models.

Published
2012

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