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3. The longitudinal dynamics and natural history of clonal haematopoiesis

Author

Fabre, Margarete A., de Almeida, José Guilherme, Fiorillo, Edoardo, Mitchell, Emily, Damaskou, Aristi, Rak, Justyna, Orrù, Valeria, Marongiu, Michele, Chapman, Michael Spencer, Vijayabaskar, M. S., Baxter, Joanna, Hardy, Claire, Abascal, Federico, Williams, Nicholas, Nangalia, Jyoti, Martincorena, Iñigo, Campbell, Peter J., McKinney, Eoin F., Cucca, Francesco, Gerstung, Moritz, and Vassiliou, George S.

Published
2022
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4. The Women4Health (W4H) cohort: A unique cohort to study women-specific mechanisms of cardio-metabolic regulation

Author

Busonero, Fabio, primary, Lenarduzzi, Stefania, additional, Crobu, Francesca, additional, Gentile, Roberta Maria, additional, Carta, Andrea, additional, Cracco, Francesco, additional, Maschio, Andrea, additional, Camarda, Silvia, additional, Marongiu, Michele, additional, Zanetti, Daniela, additional, Conversano, Claudio, additional, Di Lorenzo, Giovanni, additional, Mazzà, Daniela, additional, De Seta, Francesco, additional, Girotto, Giorgia, additional, and Sanna, Serena, additional

Published
2024
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7. Implications of disease-modifying therapies for multiple sclerosis on immune cells and response to COVID-19 vaccination.

Author

Orrù, Valeria, Serra, Valentina, Marongiu, Michele, Lai, Sandra, Lodde, Valeria, Zoledziewska, Magdalena, Steri, Maristella, Loizedda, Annalisa, Lobina, Monia, Piras, Maria Grazia, Virdis, Francesca, Delogu, Giuseppe, Marini, Maria Giuseppina, Mingoia, Maura, Floris, Matteo, Masala, Marco, Castelli, M. Paola, Mostallino, Rafaela, Frau, Jessica, and Lorefice, Lorena

Subjects
COVID-19 vaccines, VACCINE effectiveness, BOOSTER vaccines, COVID-19 pandemic, DIMETHYL fumarate, NATALIZUMAB, FINGOLIMOD
Abstract

Introduction: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete. Methods: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization. Results and Discussion: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls. [ABSTRACT FROM AUTHOR]

Published
2024
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9. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, Zoledziewska, Magdalena, Agencia Estatal de Investigación (España), European Commission, Junta de Andalucía, Universidad de Sevilla, Fundación Ramón Areces, Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Abstract

Few genome-wide association studies (GWAS) analyzing genetic regulation of morphological traits of white blood cells have been reported. We carried out a GWAS of 12 morphological traits in 869 individuals from the general population of Sardinia, Italy. These traits, included measures of cell volume, conductivity and light scatter in four white-cell populations (eosinophils, lymphocytes, monocytes, neutrophils). This analysis yielded seven statistically significant signals, four of which were novel (four novel, PRG2, P2RX3, two of CDK6). Five signals were replicated in the independent INTERVAL cohort of 11 822 individuals. The most interesting signal with large effect size on eosinophil scatter (P-value = 8.33 x 10-32, beta = -1.651, se = 0.1351) falls within the innate immunity cluster on chromosome 11, and is located in the PRG2 gene. Computational analyses revealed that a rare, Sardinian-specific PRG2:p.Ser148Pro mutation modifies PRG2 amino acid contacts and protein dynamics in a manner that could possibly explain the changes observed in eosinophil morphology. Our discoveries shed light on genetics of morphological traits. For the first time, we describe such large effect size on eosinophils morphology that is relatively frequent in Sardinian population.

Published
2023

11. Patterns of Dietary Blood Markers Are Related to Frailty Status in the FRAILOMIC Validation Phase

Author

Henning, Thorsten, primary, Kochlik, Bastian, additional, Ara, Ignacio, additional, González-Gross, Marcela, additional, Fiorillo, Edoardo, additional, Marongiu, Michele, additional, Cucca, Francesco, additional, Rodriguez-Artalejo, Fernando, additional, Carnicero Carreño, Jose Antonio, additional, Rodriguez-Mañas, Leocadio, additional, Grune, Tilman, additional, and Weber, Daniela, additional

Published
2023
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13. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology

Author

Marongiu, Michele, primary, Pérez-Mejías, Gonzalo, additional, Orrù, Valeria, additional, Steri, Maristella, additional, Sidore, Carlo, additional, Díaz-Quintana, Antonio, additional, Mulas, Antonella, additional, Busonero, Fabio, additional, Maschio, Andrea, additional, Walter, Klaudia, additional, Tardaguila, Manuel, additional, Akbari, Parsa, additional, Soranzo, Nicole, additional, Fiorillo, Edoardo, additional, Gorospe, Myriam, additional, Schlessinger, David, additional, Díaz-Moreno, Irene, additional, Cucca, Francesco, additional, and Zoledziewska, Magdalena, additional

Published
2022
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14. Genetic Variants Regulating Immune Cell Levels in Health and Disease

Author

Orrù, Valeria, Steri, Maristella, Sole, Gabriella, Sidore, Carlo, Virdis, Francesca, Dei, Mariano, Lai, Sandra, Zoledziewska, Magdalena, Busonero, Fabio, Mulas, Antonella, Floris, Matteo, Mentzen, Wieslawa I., Urru, Silvana A.M., Olla, Stefania, Marongiu, Michele, Piras, Maria G., Lobina, Monia, Maschio, Andrea, Pitzalis, Maristella, Urru, Maria F., Marcelli, Marco, Cusano, Roberto, Deidda, Francesca, Serra, Valentina, Oppo, Manuela, Pilu, Rosella, Reinier, Frederic, Berutti, Riccardo, Pireddu, Luca, Zara, Ilenia, Porcu, Eleonora, Kwong, Alan, Brennan, Christine, Tarrier, Brendan, Lyons, Robert, Kang, Hyun M., Uzzau, Sergio, Atzeni, Rossano, Valentini, Maria, Firinu, Davide, Leoni, Lidia, Rotta, Gianluca, Naitza, Silvia, Angius, Andrea, Congia, Mauro, Whalen, Michael B., Jones, Chris M., Schlessinger, David, Abecasis, Gonçalo R., Fiorillo, Edoardo, Sanna, Serena, and Cucca, Francesco

Published
2013
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15. GWAS of genetic factors affecting white blood cell morphological parameters in Sardinians uncovers influence of chromosome 11 innate immunity gene cluster on eosinophil morphology.

Author

Marongiu, Michele, Pérez-Mejías, Gonzalo, Orrù, Valeria, Steri, Maristella, Sidore, Carlo, Díaz-Quintana, Antonio, Mulas, Antonella, Busonero, Fabio, Maschio, Andrea, Walter, Klaudia, Tardaguila, Manuel, Akbari, Parsa, Soranzo, Nicole, Fiorillo, Edoardo, Gorospe, Myriam, Schlessinger, David, Díaz-Moreno, Irene, Cucca, Francesco, and Zoledziewska, Magdalena

Published
2023
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16. The Longitudinal Dynamics and Natural History of Clonal Hematopoiesis

Author

Fabre, Margarete A, primary, Guillherme de Almeida, Jose, additional, Fiorillo, Edoardo, additional, Mitchell, Emily, additional, Damaskou, Aristi, additional, Rak, Justyna, additional, Orru, Valeria, additional, Marongiu, Michele, additional, Vijayabaskar, MS, additional, Baxter, Joanna E, additional, Hardy, Claire, additional, Abascal, Federico, additional, Spencer Chapman, Michael, additional, Williams, Nicholas, additional, Nangalia, Jyoti, additional, Martincorena, Inigo, additional, Campbell, Peter J, additional, Mckinney, Eoin F, additional, Cucca, Francesco, additional, Gerstung, Moritz, additional, and Vassiliou, George S, additional

Published
2021
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18. Age-related changes of the retinal microvasculature

Author

Orlov, Nikita V., primary, Coletta, Cristopher, additional, van Asten, Freekje, additional, Qian, Yong, additional, Ding, Jun, additional, AlGhatrif, Majd, additional, Lakatta, Edward, additional, Chew, Emily, additional, Wong, Wai, additional, Swaroop, Anand, additional, Fiorillo, Edoardo, additional, Delitala, Alessandro, additional, Marongiu, Michele, additional, Goldberg, Ilya G., additional, and Schlessinger, David, additional

Published
2019
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19. Mitogenome Diversity in Sardinians: A Genetic Window onto an Island's Past

Author

Olivieri, Anna, primary, Sidore, Carlo, additional, Achilli, Alessandro, additional, Angius, Andrea, additional, Posth, Cosimo, additional, Furtwängler, Anja, additional, Brandini, Stefania, additional, Capodiferro, Marco Rosario, additional, Gandini, Francesca, additional, Zoledziewska, Magdalena, additional, Pitzalis, Maristella, additional, Maschio, Andrea, additional, Busonero, Fabio, additional, Lai, Luca, additional, Skeates, Robin, additional, Gradoli, Maria Giuseppina, additional, Beckett, Jessica, additional, Marongiu, Michele, additional, Mazzarello, Vittorio, additional, Marongiu, Patrizia, additional, Rubino, Salvatore, additional, Rito, Teresa, additional, Macaulay, Vincent, additional, Semino, Ornella, additional, Pala, Maria, additional, Abecasis, Gonçalo R., additional, Schlessinger, David, additional, Conde-Sousa, Eduardo, additional, Soares, Pedro, additional, Richards, Martin B., additional, Cucca, Francesco, additional, and Torroni, Antonio, additional

Published
2017
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20. Personality traits and circadian blood pressure patterns: A seven year prospective study

Author

Terracciano, Antonio, Strait, James, Scuteri, Angelo, Meirelles, Osorio, Sutin, Angelina R., Tarasov, Kirill, Ding, Jun, Marongiu, Michele, Orru, Marco, Pilia, Maria Grazia, Cucca, Francesco, Lakatta, Edward, and Schlessinger, David

Subjects
Adult, Aged, 80 and over, Male, Personality Inventory, Blood Pressure, Blood Pressure Monitoring, Ambulatory, Middle Aged, Trust, Article, Circadian Rhythm, Young Adult, Logistic Models, Italy, Cardiovascular Diseases, Risk Factors, Impulsive Behavior, Odds Ratio, Humans, Female, Prospective Studies, Aged, Personality
Abstract

A nighttime dip in blood pressure is associated with decreased risk of cardiovascular morbidity and mortality. We examined whether personality traits predict nighttime dipping blood pressure.A community-based sample of 2848 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory and 7 years later were examined with 24-hour ambulatory blood pressure monitoring. The primary analyses examined the associations of personality traits with continuous and categorical measures of mean arterial, systolic, and diastolic blood pressure nighttime dipping.Agreeableness and conscientiousness were associated with more nocturnal blood pressure dipping (β = .05 [p = .025] and β = .07 [p.001], respectively) and lower systolic blood pressure at night (β = -.05 [p = .018] and β = -.03 [p = .072], respectively). Nondippers were particularly more impulsive (p = .009), less trusting (p = .004), and less self-disciplined (p = .001), but there was no significant association between nocturnal dipping blood pressure and trait anxiety (p = .78) or depression (p = .59). The associations were stronger when comparing extreme dippers (nighttime drop ≥ 20%) to reverse dippers (nighttime increase in blood pressure). Indeed, scoring 1 standard deviation higher on conscientiousness was associated with approximately 40% reduced risk of reverse dipping (odds ratio = 1.43, confidence interval = 1.08-1.91).We found evidence that reduced nighttime blood pressure dipping is associated with antagonism and impulsivity-related traits but not with measures of emotional vulnerability. The strongest associations were found with conscientiousness, a trait that may have a broad impact on cardiovascular health.

Published
2014

21. The longitudinal dynamics and natural history of clonal haematopoiesis

Author

Margarete A. Fabre, José Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, Michael Spencer Chapman, M. S. Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas Williams, Jyoti Nangalia, Iñigo Martincorena, Peter J. Campbell, Eoin F. McKinney, Francesco Cucca, Moritz Gerstung, George S. Vassiliou, Orrù, Valeria [0000-0002-6047-4625], Marongiu, Michele [0000-0002-7289-9815], Chapman, Michael Spencer [0000-0002-5320-8193], Abascal, Federico [0000-0002-6201-1587], Williams, Nicholas [0000-0003-3989-9167], Nangalia, Jyoti [0000-0001-7122-4608], Martincorena, Iñigo [0000-0003-1122-4416], Campbell, Peter J [0000-0002-3921-0510], Gerstung, Moritz [0000-0001-6709-963X], Vassiliou, George [0000-0003-4337-8022], Apollo - University of Cambridge Repository, and Vassiliou, George S [0000-0003-4337-8022]

Subjects
141, Aging, Multidisciplinary, Genome, Human, article, 692/699/67/1990/283/1897, 45/23, Middle Aged, 631/208/737, Clone Cells, 631/114/2397, 692/699/67/1990/1673, Mutation, Humans, Longitudinal Studies, 45/100, Clonal Hematopoiesis, 692/499, Phylogeny, Aged
Abstract

Funder: European Research Council, Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

Published
2022

22. Height-reducing variants and selection for short stature in Sardinia

Author

Ioanna Tachmazidou, Ramaiah Nagaraja, Diego Ortega-Del Vecchyo, Nicholas J. Timpson, George Dedoussis, Maristella Steri, Fabio Busonero, Alessandro P Delitala, Ginevra Biino, Federico Murgia, Gonçalo R. Abecasis, Kirk E. Lohmueller, Charleston W. K. Chiang, John Novembre, Serena Sanna, Joseph Marcus, Robert H. Lyons, Antonella Mulas, Matteo Floris, Eleftheria Zeggini, Maria Pina Concas, Michele Marongiu, Andrea Maschio, Magdalena Zoledziewska, Simona Vaccargiu, Nicole Soranzo, Sergio Uzzau, Andrea Angius, Antonella Meloni, David Schlessinger, Carlo Sidore, Chris Jones, Francesco Cucca, Zoledziewska, Magdalena, Sidore, Carlo, Chiang, Charleston W. K., Sanna, Serena, Mulas, Antonella, Steri, Maristella, Busonero, Fabio, Marcus, Joseph H., Marongiu, Michele, Maschio, Andrea, Del Vecchyo, Diego Ortega, Floris, Matteo, Meloni, Antonella, Delitala, Alessandro, Concas, MARIA PINA, Murgia, Federico, Biino, Ginevra, Vaccargiu, Simona, Nagaraja, Ramaiah, Lohmueller, Kirk E., Timpson, Nicholas J., Soranzo, Nicole, Tachmazidou, Ioanna, Dedoussis, George, Zeggini, Eleftheria, Uzzau, Sergio, Jones, Chri, Lyons, Robert, Angius, Andrea, Abecasis, Goncalo R., Novembre, John, Schlessinger, David, Cucca, Francesco, Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Male, Population genetics, Genome-wide association study, Body Height, Carrier Proteins, Founder Effect, Gene Frequency, Genome-Wide Association Study, Genotype, Haplotypes, High-Throughput Nucleotide Sequencing, KCNQ1 Potassium Channel, Laron Syndrome, Genetic Variation, Selection, Genetic, Genetics, 0302 clinical medicine, 80 and over, Haplotype, Longitudinal Studies, Non-U.S. Gov't, 10. No inequality, Aged, 80 and over, Islands, 0303 health sciences, Research Support, Non-U.S. Gov't, Middle Aged, Italy, Female, medicine.symptom, Adult, Biology, Research Support, Short stature, Article, N.I.H, 03 medical and health sciences, Young Adult, Research Support, N.I.H., Extramural, Genetic, Genetic drift, Journal Article, medicine, Humans, Allele, Selection, Allele frequency, 030304 developmental biology, Aged, Extramural, Minor allele frequency, Carrier Protein, 030217 neurology & neurosurgery, Founder effect
Abstract

We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus

Published
2015

23. The Women4Health cohort: a unique cohort to study women-specific mechanisms of cardio-metabolic regulation.

Author

Busonero F, Lenarduzzi S, Crobu F, Gentile RM, Carta A, Cracco F, Maschio A, Camarda S, Marongiu M, Zanetti D, Conversano C, Di Lorenzo G, Mazzà D, De Seta F, Girotto G, and Sanna S

Abstract

Aims: Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context., Methods and Results: Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders., Conclusion: The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Published
2024
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