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1. Social deprivation and SARS-CoV-2 testing: a population-based analysis in a highly contrasted southern France region

Author

Jordi Landier, Léa Bassez, Marc-Karim Bendiane, Pascal Chaud, Florian Franke, Steve Nauleau, Fabrice Danjou, Philippe Malfait, Stanislas Rebaudet, and Jean Gaudart

Subjects
testing, access to health care, deprivation, COVID-19, geoepidemiology, France, Public aspects of medicine, RA1-1270
Abstract

BackgroundTesting was the cornerstone of the COVID-19 epidemic response in most countries until vaccination became available for the general population. Social inequalities generally affect access to healthcare and health behaviors, and COVID-19 was rapidly shown to impact deprived population more drastically. In support of the regional health agency in Provence-Alpes-Côte d’Azur (PACA) in South-Eastern France, we analyzed the relationship between testing rate and socio-demographic characteristics of the population, to identify gaps in testing coverage and improve targeting of response strategies.MethodsWe conducted an ecological analysis of SARS-CoV-2/COVID-19 testing rate in the PACA region, based on data aggregated at the finest spatial resolution available in France (IRIS) and by periods defined by public health implemented measures and major epidemiological changes. Using general census data, population density, and specific deprivation indices, we used principal component analysis followed by hierarchical clustering to define profiles describing local socio-demographic characteristics. We analyzed the association between these profiles and testing rates in a generalized additive multilevel model, adjusting for access to healthcare, presence of a retirement home, and the age profile of the population.ResultsWe identified 6 socio-demographic profiles across the 2,306 analyzed IRIS spatial units: privileged, remote, intermediate, downtown, deprived, and very deprived (ordered by increasing social deprivation index). Profiles also ranged from rural (remote) to high density urban areas (downtown, very deprived). From July 2020 to December 2021, we analyzed SARS-CoV-2/COVID-19 testing rate over 10 periods. Testing rates fluctuated strongly but were highest in privileged and downtown areas, and lowest in very deprived ones. The lowest adjusted testing rate ratios (aTRR) between privileged (reference) and other profiles occurred after implementation of a mandatory healthpass for many leisure activities in July 2021. Periods of contextual testing near Christmas displayed the largest aTRR, especially during the last periods of 2021 after the end of free convenience testing for unvaccinated individuals.ConclusionWe characterized in-depth local heterogeneity and temporal trends in testing rates and identified areas and circumstances associated with low testing rates, which the regional health agency targeted specifically for the deployment of health mediation activities.

Published
2023
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2. A Sparse Mixture-of-Experts Model With Screening of Genetic Associations to Guide Disease Subtyping

Author

Marie Courbariaux, Kylliann De Santiago, Cyril Dalmasso, Fabrice Danjou, Samir Bekadar, Jean-Christophe Corvol, Maria Martinez, Marie Szafranski, and Christophe Ambroise

Subjects
mixture of experts model, disease subtyping, clinical data, longitudinal data, genotyping, high dimension, Genetics, QH426-470
Abstract

Motivation: Identifying new genetic associations in non-Mendelian complex diseases is an increasingly difficult challenge. These diseases sometimes appear to have a significant component of heritability requiring explanation, and this missing heritability may be due to the existence of subtypes involving different genetic factors. Taking genetic information into account in clinical trials might potentially have a role in guiding the process of subtyping a complex disease. Most methods dealing with multiple sources of information rely on data transformation, and in disease subtyping, the two main strategies used are 1) the clustering of clinical data followed by posterior genetic analysis and 2) the concomitant clustering of clinical and genetic variables. Both of these strategies have limitations that we propose to address.Contribution: This work proposes an original method for disease subtyping on the basis of both longitudinal clinical variables and high-dimensional genetic markers via a sparse mixture-of-regressions model. The added value of our approach lies in its interpretability in relation to two aspects. First, our model links both clinical and genetic data with regard to their initial nature (i.e., without transformation) and does not require post-processing where the original information is accessed a second time to interpret the subtypes. Second, it can address large-scale problems because of a variable selection step that is used to discard genetic variables that may not be relevant for subtyping.Results: The proposed method was validated on simulations. A dataset from a cohort of Parkinson’s disease patients was also analyzed. Several subtypes of the disease and genetic variants that potentially have a role in this typology were identified.Software availability: The R code for the proposed method, named DiSuGen, and a tutorial are available for download (see the references).

Published
2022
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3. Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease

Author

Sabine Prud'hon, Samir Bekadar, Agnès Rastetter, Justine Guégan, Florence Cormier-Dequaire, Lucette Lacomblez, Graziella Mangone, Hana You, Mailys Daniau, Yannick Marie, Hélène Bertrand, Suzanne Lesage, Sophie Tezenas Du Montcel, Mathieu Anheim, Alexis Brice, Fabrice Danjou, and Jean-Christophe Corvol

Subjects
Parkinson's disease (PD), dopamine agonists (DA), impulse control disorders (ICD), pharmacogenetics, exome sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.

Published
2020
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4. IFNL3 polymorphisms and HCV infection in patients with beta thalassemia

Author

Raffaella Origa, Giuseppe Marceddu, Fabrice Danjou, Luciana Perseu, Stefania Satta, Franca Rosa Demartis, Antonio Piga, Filomena Longo, Maria-Eliana Lai, Stefania Vacquer, and Renzo Galanello

Subjects
Transfusion-borne infections, Virus C, IL28B, Viral clearance, Viral persistence, Specialties of internal medicine, RC581-951
Abstract

Background and relationale for the study. Genome-wide association studies have identified host genetic variation to be critical for spontaneous clearance and treatment response in patients infected with hepatitis C virus. Recently, the role of the IFNL3 polymorphisms in influencing the spontaneous clearance of HCV, the response to interferon and the progression of liver fibrosis, was also demonstrated in patients with thalassemia major infected by genotype 1b. In the present study we retrospectively analyzed 368 anti-HCV positive patients with beta-thalassemia at two Italian major centers in Cagliari and Torino.Results. C/C variant of polymorphism rs12979860 was related to response to interferon treatment and, above all, to spontaneous clearance of the virus. However, the positive predictive power was stronger for viral persistence than spontaneous clearance and in such respect the TT allele was more predictive than CC. The methylation associated polymorphism rs4803221 had independent effects with respect to rs12979860 and the haplotype tagged by SNP rs12979860 and rs4803221 significantly could improve the viral clearance prediction in infected patients. Neither necroinflammation or bilirubin values in the chronic phase of the hepatitis C were related to IFNL3 polymorphisms. No relation among IFNL3 polymorphisms and fibrosis stage directly shown by the liver biopsy was found.Conclusions. Also in thalassemia the SNPs on chromosome 19q13 closely associates with spontaneous and treatment-induced HCV clearance. The viral clearance prediction is significantly improved by the haplotype tagged by SNP rs12979860 and rs4803221. Neither necroinflammation, bilirubin values or fibrosis stage seem to be related to IFNL3 polymorphisms.

Published
2015
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6. A genetic score for the prediction of beta-thalassemia severity

Author

Fabrice Danjou, Marcella Francavilla, Franco Anni, Stefania Satta, Franca-Rosa Demartis, Lucia Perseu, Matteo Manca, Maria Carla Sollaino, Laura Manunza, Elisabetta Mereu, Giuseppe Marceddu, Serge Pissard, Philippe Joly, Isabelle Thuret, Raffaella Origa, Joseph Borg, Gian Luca Forni, Antonio Piga, Maria Eliana Lai, Catherine Badens, Paolo Moi, and Renzo Galanello

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.−158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R2=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P

Published
2015
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8. Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion

Author

Fabrice Danjou, Franco Anni, Lucia Perseu, Stefania Satta, Carlo Dessì, Maria Eliana Lai, Paolo Fortina, Marcella Devoto, and Renzo Galanello

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background The clinical and hematologic features of β-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of β-thalassemia as assessed by the patients’ age at first transfusion.Design and Methods We studied the effect of seven loci in a cohort of 316 Sardinian patients with β0-thalassemia. In addition to characterizing the β-globin gene mutations, α-globin gene defects and HBG2:g.−158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion.Results According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell’s concordance index=0.72; Cox & Snell R2=0.394) and demonstrated that most of the model’s discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.−158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R2=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population.Conclusions This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of β0-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.

Published
2012
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10. Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Author

Ole A. Andreassen, Vivianna M. Van Deerlin, David Simon, Claire E. Wegel, Guido Alves, Ruwani Wijeyekoon, Jodi Maple-Grødem, Alastair J. Noyce, Roger A. Barker, Bart P.C. van de Warrenburg, Peter Heutink, Shirley Eberly, J. Raphael Gibbs, Alexis Brice, Kumaraswamy Naidu Chitrala, Lasse Pihlstrøm, Marlies van Nimwegen, Khanh-Dung H. Nguyen, Ganqiang Liu, Bernard Ravina, Clemens R. Scherzer, Jean-Christophe Corvol, Bastiaan R. Bloem, Jacobus J. van Hilten, Karol Estrada, Faraz Faghri, Jonathan R. Evans, Daniel Weintraub, Ole-Bjørn Tysnes, Aaron G. Day-Williams, Hampton L. Leonard, Jonggeol J. Kim, Fabrice Danjou, David P. Breen, Samantha J. Hutten, Andrew B. Singleton, Hirotaka Iwaki, Peggy Auinger, Mike A. Nalls, Kirsten M. Scott, Dena G. Hernandez, Mathias Toft, Jacqueline Rick, Caroline H. Williams-Gray, and Cornelis Blauwendraat

Subjects
0301 basic medicine, Oncology, Apolipoprotein E, Male, Parkinson's disease, Disease, genetics [Glucosylceramidase], etiology [Cognitive Dysfunction], Cohort Studies, 0302 clinical medicine, genetics [Parkinson Disease], Medicine, Longitudinal Studies, Cognitive decline, Aged, 80 and over, Hazard ratio, Parkinson Disease, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], LRRK2, Phenotype, Neurology, genetics [Organic Cation Transport Proteins], Disease Progression, Glucosylceramidase, GBA, Female, psychology [Cognitive Dysfunction], psychology [Parkinson Disease], Adult, medicine.medical_specialty, Organic Cation Transport Proteins, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Risk Assessment, Article, 03 medical and health sciences, Antigens, CD, Internal medicine, Humans, Cognitive Dysfunction, ddc:610, genomewide association study, Aged, business.industry, genetics [Cognitive Dysfunction], Odds ratio, medicine.disease, genetics [Antigens, CD], 030104 developmental biology, Cross-Sectional Studies, Expression quantitative trait loci, genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2], Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study
Abstract

Item does not contain fulltext BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for alpha-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. (c) 2019 International Parkinson and Movement Disorder Society.

Published
2019

11. Genome-wide association study of Parkinson’s disease progression biomarkers in 12 longitudinal patients’ cohorts

Author

David P. Breen, Samantha J. Hutten, Alastair J. Noyce, Dena G. Hernandez, Kumaraswamy Naidu Chitrala, Lasse Pihlstrøm, Jacqueline Rick, Mathias Toft, Mike A. Nalls, Ganqiang Liu, Karol Estrada, Jean-Christophe Corvol, Marlies van Nimwegen, Bernard Ravina, Shirley Eberly, Aaron G. Day-Williams, Jonathan R. Evans, Peter Heutink, Claire E. Wegel, Ole-Bjørn Tysnes, J. Raphael Gibbs, Bart P.C. van de Warrenburg, Peggy Auinger, Alexis Brice, Hirotaka Iwaki, Clemens R. Scherzer, Jonggeol J. Kim, Jodi Maple-Grødem, Kirsten M. Scott, Fabrice Danjou, Daniel Weintraub, H. Nguyen Khanh-Dung, Jacobus J. van Hilten, Roger A. Barker, Caroline H. Williams-Gray, Hampton L. Leonard, Cornelis Blauwendraat, David Simon, Andrew B. Singleton, Faraz Faghri, Guido Alves, Ruwani Wijeyekoon, Ole A. Andreassen, Vivianna M. Van Deerlin, and Bastiaan R. Bloem

Subjects
Oncology, medicine.medical_specialty, Parkinson's disease, business.industry, Genome-wide association study, Disease, medicine.disease, LRRK2, Clinical trial, Internal medicine, Expression quantitative trait loci, medicine, Missense mutation, Cognitive decline, business
Abstract

BackgroundSeveral reports have identified different patterns of Parkinson’s disease progression in individuals carrying missense variants in theGBAorLRRK2genes. The overall contribution of genetic factors to the severity and progression of Parkinson’s disease, however, has not been well studied.ObjectivesTo test the association between genetic variants and the clinical features and progression of Parkinson’s disease on a genome-wide scale.MethodsWe accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes.ResultsTwo variants were genome-wide significant. Rs382940(T>A), within the intron ofSLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL forADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinson’s risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports ofGBAcoding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, andAPOEE4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.ConclusionsWe identified novel genetic factors associated with heterogeneity of progression in Parkinson’s disease. The results provide new insights into the pathogenesis of Parkinson’s disease as well as patient stratification for clinical trials.

Published
2019
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12. Genetic risk of Parkinson disease and progression:: An analysis of 13 longitudinal cohorts

Author

Peggy Auinger, David Simon, Ganqiang Liu, Daniel Weintraub, Alexis Brice, Bart P.C. van de Warrenburg, Jacqueline Rick, Bernard Ravina, Kirsten M. Scott, Hampton L. Leonard, Fabrice Danjou, Caroline H. Williams-Gray, Faraz Faghri, Hirotaka Iwaki, Ole-Bjørn Tysnes, Cornelis Blauwendraat, Lasse Pihlstrøm, Clemens R. Scherzer, Marlies van Nimwegen, Jacobus J. van Hilten, Alastair J. Noyce, Samantha J. Hutten, Mike A. Nalls, Vivianna M. van Deerlin, Peter Heutink, Roger A. Barker, Karol Estrada, Jonathan R. Evans, Aaron G. Day-Williams, Shirley Eberly, Andrew B. Singleton, Jean-Christophe Corvol, David P. Breen, Dena G. Hernandez, Khanh-Dung H. Nguyen, Bastiaan R. Bloem, Claire E. Wegel, Jodi Maple-Grødem, Mathias Toft, Guido Alves, Ruwani Wijeyekoon, Leonard, Hampton L [0000-0003-2390-8110], Maple-Grødem, Jodi [0000-0001-7142-0078], Pihlstrøm, Lasse [0000-0002-7635-8645], Faghri, Faraz [0000-0001-5744-8728], Alves, Guido [0000-0003-0630-2870], Danjou, Fabrice [0000-0002-4976-2327], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Aging, medicine.medical_specialty, 32 Biomedical and Clinical Sciences, Disease, Neurodegenerative, 3105 Genetics, Article, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Clinical Research, Internal medicine, Genetics, medicine, 2.1 Biological and endogenous factors, ddc:610, Genetic variability, Parkinson, Allele, Genetics (clinical), 2 Aetiology, Parkinson's Disease, business.industry, Prevention, Hazard ratio, Neurosciences, Odds ratio, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], LRRK2, Brain Disorders, 3. Good health, nevrologi, 030104 developmental biology, Medical disciplines: 700::Clinical medical disciplines: 750::Neurology: 752 [VDP], Neurological, Neurology (clinical), business, 030217 neurology & neurosurgery, 31 Biological Sciences, Cohort study
Abstract

ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance ofGBAon phenotypes.GBAvariants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations ofGBAvariants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant nearLRRK2and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant inPMVKand the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated withTMEM175variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region ofGPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region ofCCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particularGBAvariants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

Published
2018

13. LRP10 in α-synucleinopathies

Author

Demis A Kia, Marya S Sabir, Sarah Ahmed, Joanne Trinh, Sara Bandres-Ciga, Alastair J Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Manuela Tan, Henry Houlden, Huw R Morris, Helene Plun-Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, Jose Bras, John Quinn, Kin Y Mok, Kerri J. Kinghorn, Kimberley Billingsley, Nicholas W Wood, Patrick Lewis, Sebastian Schreglmann, Rita Guerreiro, Ruth Lovering, Lea R'Bibo, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott-Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean-Christophe Corvol, Maria Martinez, Claudia Schulte, Kathrin Brockmann, Javier Simón-Sánchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark R Cookson, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, Raphael J. Gibbs, Dena G Hernandez, Kendall Van Keuren-Jensen, Joshua M. Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolo E. Mencacci, Codrin Lungu, Andrew B Singleton, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan-Or, Guy A. Rouleau, Jacobus J van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Miquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Francisco J. Barrero, Jesús A. Bergareche Yarza, Inmaculada Bernal-Bernal, Marta Blazquez, Marta Bonilla-Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Jordi Clarimón, Monica Diez-Farien, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Mario Ezquerra, Cici Feliz, Manel Fernández, Rubén Fernández-Santiago, Ciara Garcia, Pedro García-Ruiz, Pilar Gómez-Garre, Maria Jose Gomez Heredia, Isabel Gonzalez-Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Silvia Jesús, Adriano Jimenez-Escrig, Jaime Kulisevsky, Miguel A. Labrador-Espinosa, Jose L. Lopez-Sendon, Adolfo López de Munain Arregui, Daniel Macias, Irene Martínez Torres, Juan Marín, Maria Jose Marti, Juan Carlos Martínez- Castrillo, Carlota Méndez-del-Barrio, Manuel Menéndez González, Marina Mata, Adolfo Mínguez, Pablo Mir, Elisabet Mondragon Rezola, Esteban Muñoz, Javier Pagonabarraga, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Javier Ruiz-Martínez, Clara Ruz, Antonio Sanchez Rodriguez, María Sierra, Esther Suarez-Sanmartin, Cesar Tabernero, Juan Pablo Tartari, Cristina Tejera-Parrado, Eduard Tolosa, Francesc Valldeoriola, Laura Vargas-González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrom, Mathias Toft, Sulev Koks, Pille Taba, and Sharon Hassin-Baer

Subjects
Lewy Body Disease, Genetic Linkage, Humans, Dementia, Lewy Bodies, Parkinson Disease, Neurology (clinical)
Published
2018

14. Hypothermic pulsatile preservation of kidneys from uncontrolled deceased donors after cardiac arrest - a retrospective study

Author

Vannary Meas Yedid, Thomas Rimmelé, Alexandre Faure, Palmina Petruzzo, Xavier Matillon, Lionel Badet, Emmanuel Morelon, Ricardo Codas, Olivier Thaunat, Maud Rabeyrin, Fabrice Danjou, William Hanf, Claire Delsuc, Service d'Urologie et Chirurgie de la Transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital Saint Camille, Department of Medical Sciences, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Lymphocytes B effecteurs et à mémoire – Effector and memory B cells, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Transplantation, Néphrologie et Immunologie Clinique [Hôpital Edouard Herriot, HCL], Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service d'anesthésie-réanimation [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Département de Pathologie [CHU Lyon-Sud - HCL], Analyse d'images biologiques - Biological Image Analysis (BIA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Alpes-Léman - CHAL, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Graft Rejection, Male, Time Factors, medicine.medical_treatment, 030232 urology & nephrology, Pulsatile flow, 030230 surgery, outcomes, Cohort Studies, 0302 clinical medicine, Warm Ischemia, Kidney transplantation, uncontrolled deceased donors, Graft Survival, Statistics, Organ Preservation, perfusion machine, Treatment Outcome, Anesthesia, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Perfusion, medicine.medical_specialty, Tissue and Organ Procurement, Risk Assessment, Statistics, Nonparametric, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, Resistance Index, Extracorporeal membrane oxygenation, medicine, Humans, Nonparametric, Cardiopulmonary resuscitation, Retrospective Studies, Transplantation, Inulin Clearance, business.industry, Retrospective cohort study, medicine.disease, Kidney Transplantation, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Surgery, Heart Arrest, Linear Models, business, donor management, Follow-Up Studies
Abstract

Kidneys from uncontrolled donors after cardiac arrest (uDCD) suffer from a period of warm ischemia between cardiac arrest and cold flushing. Aim of the study was to evaluate renal outcomes of uDCD kidneys selected on the basis of renal Resistance Index (RI) and its influence on graft function and survival. The study included 44 kidneys procured from 26 uDCD starting 1.1.2006 until 31.12.2013. The donors (Maastricht category II) underwent cardiopulmonary resuscitation by assisted ventilation and chest compression; the organs were preserved with “in situ” cold perfusion or a normothermic regional perfusion. All kidneys were perfused on hypothermic (1-4°C) pulsatile perfusion machine (RM3, Waters Medical System) and discarded when RI≥0.5 mmHg/mL/min after 6 hours of perfusion. There was one (2.2%) primary non-function, while 37 recipients (84.1%) experienced delayed graft function. Graft survival was 97.6% at 1 and 3 post-transplantation years. Linear regression models showed that lower values of RI at the end of perfusion were associated to higher values of MDRD at 3 (p=0.049) and 6 months after transplantation (p=0.010) and to higher values of inulin clearance at 1 year (p=0.030). RI showed to be a useful tool to select uDCD kidneys allowing to achieve good clinical results. This article is protected by copyright. All rights reserved.

Published
2017

15. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci

Author

Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)

Subjects
Netherlands Twin Register (NTR), Erythrocytes, Genome-wide association study, UNCERTAINTY, Regulatory Sequences, Nucleic Acid, VARIANTS, ANNOTATION, COLORECTAL-CANCER, Histones, 0302 clinical medicine, BINDING, Cluster Analysis, Myeloid Cells, Genetics (clinical), Genetics, hematological trait, 0303 health sciences, Chromosome Mapping, MRP4 ABCC4, Chromatin, Nucleosomes, Phenotype, Organ Specificity, 030220 oncology & carcinogenesis, Blood Platelets, Quantitative Trait Loci, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, DYNAMIN 3, 03 medical and health sciences, Quantitative Trait, Heritable, MEGAKARYOCYTES, Humans, Cell Lineage, ddc:610, GENOME-WIDE ASSOCIATION, Enhancer, Transcription factor, Gene, ChIA-PET, 030304 developmental biology, Research, Genetic Variation, DNA, Chromatin Assembly and Disassembly, Genetic architecture, Gene Expression Regulation, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Published
2013

16. GENOME-WIDE ASSOCIATION ANALYSES BASED ON WHOLE-GENOME SEQUENCING IN SARDINIA PROVIDE INSIGHTS INTO REGULATION OF HEMOGLOBIN LEVELS

Author

Eleonora Porcu, Fabio Busonero, Andrea Angius, Swee Lay Thein, Antonella Mulas, Maristella Steri, Giorgio Pistis, Mauro Pala, Paolo Moi, Lucia Perseu, Stephan Menzel, Carlo Sidore, Magdalena Zoledziewska, Serena Sanna, Lidia Leoni, Sarah Metrustry, Manuela Uda, Andrea Maschio, Susanna Barella, Gonçalo R. Abecasis, David Schlessinger, Renzo Galanello, Maristella Pitzalis, Fabrice Danjou, Francesco Cucca, and Tim D. Spector

Subjects
Adult, Male, Genotype, Genotyping Techniques, Genome-wide association study, beta-Globins, Polymorphism, Single Nucleotide, Article, Hemoglobins, alpha-Globins, Genetic variation, Genetics, Humans, Genotyping, Whole genome sequencing, Islands, biology, Genome, Human, Genetic Variation, Sequence Analysis, DNA, Middle Aged, NFIX, Italy, Multigene Family, biology.protein, Human genome, Female, Genome-Wide Association Study
Abstract

We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.

Published
2015

17. A genetic score for the prediction of beta-thalassemia severity

Author

Franco Anni, Marcella Francavilla, Elisabetta Mereu, Joseph Borg, Philippe Joly, Gian Luca Forni, Isabelle Thuret, Serge Pissard, Franca Rosa Demartis, Catherine Badens, Matteo Manca, Stefania Satta, Laura Manunza, Paolo Moi, Renzo Galanello, A. Piga, Maria Carla Sollaino, Giuseppe Marceddu, Fabrice Danjou, Maria Eliana Lai, Raffaella Origa, Lucia Perseu, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Star*AgroEnergy Research Unit, Department of Agriculture, Food and Environment, Università degli Studi di Foggia - University of Foggia, Centre de Recherche et d'Innovation sur le Sport (EA647) (CRIS), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Male, Oncology, Genetics -- Study and teaching, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Genome-wide association study, Kaplan-Meier Estimate, beta-Globins, Biology, Quantitative trait locus, Bioinformatics, Polymorphism, Single Nucleotide, Severity of Illness Index, Blood -- Transfusion, Chromosome polymorphism, Internal medicine, Fetal hemoglobin, Severity of illness, medicine, Humans, Blood Transfusion, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Receiver operating characteristic, beta-Thalassemia, Genetic Variation, Beta thalassemia, Retrospective cohort study, Articles, Hematology, Prognosis, Thalassemia -- Diagnosis, medicine.disease, 3. Good health, Phenotype, Genetic Loci, Mutation, Cohort, DNA, Intergenic, Female
Abstract

Clinical and hematologic characteristics of beta(β)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and fetal hemoglobin production modulators (HBG2:g.-158C>T polymorphism, HBS1L-MYB intergenic region and the BCL11A). We characterized 54 genetic variants at these five loci robustly associated with the amelioration of beta-thalassemia phenotype, to build a predictive score of severity using a representative cohort of 890 β-thalassemic patients. Using Cox proportional hazard analysis on a training set, we assessed the effect of these loci on the age at which patient started regular transfusions, built a Thalassemia Severity Score, and validated it on a testing set. Discriminatory power of the model was high (C-index=0.705; R(2)=0.343) and the validation conducted on the testing set confirmed its predictive accuracy with transfusion-free survival probability (P, peer-reviewed

Published
2014

18. Current growth patterns in children and adolescents with thalassemia major

Author

Maria Loreta Foschini, Fabrice Danjou, Sandro Loche, Anna Demurtas, Raffaella Origa, Paolo Moi, Antonietta Zappu, Giovan Battista Leoni, Maddalena Morittu, Carlo Dessì, and Valeria Orecchia

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Blood transfusion, Adolescent, Body height, Thalassemia, medicine.medical_treatment, Immunology, MEDLINE, Deferoxamine, 030204 cardiovascular system & hematology, Biochemistry, Short stature, 03 medical and health sciences, Child Development, 0302 clinical medicine, medicine, Humans, Blood Transfusion, Child, business.industry, beta-Thalassemia, Cell Biology, Hematology, Adolescent Development, medicine.disease, Child development, Body Height, Child, Preschool, Female, medicine.symptom, Adolescent development, business, 030215 immunology
Abstract

To the editor: Although the cause of short stature in children with thalassemia major is not well understood, it is believed to be multifactorial.[1][1] Many different factors including iron overload, intensive use of iron chelators, and gonadal damage may interact, making it difficult to

Published
2016

19. International survey of T2* cardiovascular magnetic resonance in -thalassemia major

Author

Ana Almeida, Jane S. Hankins, Fernando Kay, Alexis A. Thompson, George Kontoghiorges, Chi Kong Li, John Paul Carpenter, Wing Y. Au, Mohsen Saleh Elalfy, M.D. Cappellini, Fabrice Danjou, Vassilis Ladis, Mirella Rangelova, Gian Luca Forni, Taigang He, J Malcolm Walker, Paul D. W. Kirk, Ru San Tan, Jameela Sathar, Michael Roughton, Lee Lee Chan, Shahina Daar, Tuncay Hazirolan, Andreas Michos, Meng-Yao Lu, Catherine Badens, Denka Stoyanova, Isabelle Thuret, Demetra Vini, Ali T. Taher, Manuela Merelles-Pulcini, V. John B. Porter, Ibrahim Al-Nasser, Winnie C.W. Chu, Amal El-Beshlawy, Antonis Kattamis, Lisa J. Anderson, Lia Wahidiyat, Valeria Kaleva, Georgi Tonev, Selen Bayraktaroglu, Renzo Galanello, Juliano L Fernandes, Shau Yin Ha, Khawla Belhoul, Dudley J. Pennell, Yesim Aydinok, Janet L. Kwiatkowski, Marouso Drossou, P. Joy Ho, Vassilios Perifanis, and Ege Üniversitesi

Subjects
medicine.medical_specialty, Internationality, Iron Overload, Thalassemia, Magnetic Resonance Imaging, Cine, Cohort Studies, Internal medicine, Humans, Medicine, Heart Failure, medicine.diagnostic_test, business.industry, Data Collection, beta-Thalassemia, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, International survey, Beta thalassemia, Magnetic resonance imaging, Articles, Hematology, medicine.disease, ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS, ComputingMethodologies_PATTERNRECOGNITION, Heart failure, Cohort, Cardiology, InformationSystems_MISCELLANEOUS, business, β thalassemia major, Cohort study
Abstract

PubMed ID: 23812939, Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*?10ms), 22.8% had moderate myocardial iron (T2* 10-20ms) and 56.6% of patients had no iron loading (T2*>20ms). There was significant geographical variation in myocardial iron loading (24.8-52.6%; P

Published
2013

20. A genome-wide association study by ImmunoChip reveals potential modifiers in myelodysplastic syndromes

Author

Giancarlo Latte, Claudio Fozza, Attilio Gabbas, Antonio Galleu, Magdalena Zoledziewska, Fausto Dore, Lucia Gemma Delogu, Paolo Casula, Antonella Mulas, Emanuele Angelucci, Fabrice Danjou, Eleonora Gaviano, Giovanni Caocci, Giovanna Corda, Anna Angela Di Tucci, Maurizio Roberto Longinotti, Giorgio La Nasa, Francesco Cucca, and Salvatore Contini

Subjects
Cancer Research, Genotype, Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Immunomodulation, 03 medical and health sciences, Alleles, Computational Biology, Humans, Meta-Analysis as Topic, Myelodysplastic Syndromes, Genetic Predisposition to Disease, Genome-Wide Association Study, 0302 clinical medicine, Genetics, Allele, Polymorphism, education, Molecular Biology, Gene, Genotyping, Genetic association, education.field_of_study, Cell Biology, Hematology, Single Nucleotide, 030220 oncology & carcinogenesis, Methylenetetrahydrofolate reductase, biology.protein, 030215 immunology
Abstract

Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 ( p = 1.16 × 10 −12 ), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10 −6 and 3.34 × 10 −6 , are situated in the methylene tetrahydrofolate reductase ( MTHFR ) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.

Published
2016

21. Genetic modifiers of -thalassemia and clinical severity as assessed by age at first transfusion

Author

Fabrice Danjou, Renzo Galanello, Franco Anni, Lucia Perseu, Paolo Fortina, Marcella Devoto, Carlo Dessì, Stefania Satta, and Maria Eliana Lai

Subjects
Adult, Genetic Markers, Male, Oncology, fetal hemoglobin, medicine.medical_specialty, Adolescent, Thalassemia, Single-nucleotide polymorphism, beta-Globins, Biology, Gene mutation, Polymorphism, Single Nucleotide, Severity of Illness Index, thalassemia intermedia, Cohort Studies, beta-thalassemia, alpha-Globins, hemic and lymphatic diseases, Internal medicine, Severity of illness, medicine, Humans, Blood Transfusion, Genotyping, Proportional Hazards Models, Genetics, Proportional hazards model, Age Factors, Nuclear Proteins, Beta thalassemia, Hematology, Middle Aged, genetic modifiers, medicine.disease, DNA Fingerprinting, Survival Analysis, Repressor Proteins, thalassemia major, Genetic Loci, Genetic marker, DNA, Intergenic, Female, Original Articles and Brief Reports, Carrier Proteins
Abstract

Background The clinical and hematologic features of β-thalassemia are modulated by different factors, resulting in a wide range of clinical severity. The main factors are the type of disease-causing mutation and the ability to produce α-globin and γ-globin chains. In the present study we investigated the respective contributions of known modifiers to the prediction of the clinical severity of β-thalassemia as assessed by the patients’ age at first transfusion.Design and Methods We studied the effect of seven loci in a cohort of 316 Sardinian patients with β0-thalassemia. In addition to characterizing the β-globin gene mutations, α-globin gene defects and HBG2:g.−158C>T polymorphism, we genotyped two different markers in the BCL11A gene and three in the HBS1L-MYB intergenic region using single nucleotide polymorphism microarrays, imputation and direct genotyping. We performed Cox proportional hazard analysis of the time to first transfusion.Results According to the resulting model, we were able to explain phenotypic severity to a large extent (Harrell’s concordance index=0.72; Cox & Snell R2=0.394) and demonstrated that most of the model’s discriminatory ability is attributable to the genetic variants affecting fetal hemoglobin production (HBG2:g.−158C>T, BCL11A and HBS1L-MYB loci: C-index=0.68, R2=0.272), while the remaining is due to α-globin gene defects and gender. Consequently, significantly distinct survival curves can be described in our population.Conclusions This detailed analysis clarifies the impact of genetic modifiers on the clinical severity of the disease, measured by time to first transfusion, by determining their relative contributions in a homogeneous cohort of β0-thalassemia patients. It may also support clinical decisions regarding the beginning of transfusion therapy in patients with β-thalassemia.

Published
2012

22. A decisional algorithm to start iron chelation in patients with beta thalassemia

Author

Susanna Barella, Raffaella Origa, Paolo Moi, Carlo Dessì, Michela Marcias, Renzo Galanello, Elisabetta Defraia, Maria Loreta Foschini, Maddalena Morittu, Zvi Ioav Cabantchik, Giovan Battista Leoni, Fabrice Danjou, and Nicolina Giagu

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pediatrics, Iron Overload, Iron, Thalassemia, Iron Chelating Agents, Gastroenterology, Iron chelation, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Chelation, In patient, Serum ferritin, biology, business.industry, beta-Thalassemia, Infant, Beta thalassemia, Hematology, medicine.disease, Ferritin, ROC Curve, Child, Preschool, biology.protein, Erythrocyte Transfusion, business, Algorithms
Abstract

Since the implementation of deferrioxamine for the treatment of thalassemia major, it has been customary to initiate chelation after the first 10–20 transfusions or when serum ferritin reached over 1000 mcg/L.[1][1] However, in non-chronically-transfused thalassemia patients, ferritin

Published
2014

24. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers

Author

Nicholas J. Timpson, George Dedoussis, Brendan Tarrier, Alan Kwong, Gonçalo R. Abecasis, Charleston W. K. Chiang, Serena Sanna, Riccardo Berutti, Chris Jones, Andrea Angius, Eleftheria Zeggini, Ramaiah Nagaraja, Giorgio Pistis, Hyun Min Kang, Andrea Maschio, Maristella Steri, Paolo Gasparini, Eleonora Porcu, Silvia Naitza, Christine Brennan, Magdalena Zoledziewska, Carlo Sidore, Christian Fuchsberger, Francesco Cucca, Giovanni Malerba, Vicente Diego Ortega Del Vecchyo, Nicole Soranzo, Sergio Uzzau, Rossano Atzeni, Robert H. Lyons, Antonella Mulas, Jie Huang, John Novembre, Frederic Reinier, David Schlessinger, Jennifer L. Bragg-Gresham, Fabio Busonero, Fabrice Danjou, Daniela Toniolo, Maristella Pitzalis, Sidore, Carlo, Busonero, Fabio, Maschio, Andrea, Porcu, Eleonora, Naitza, Silvia, Zoledziewska, Magdalena, Mulas, Antonella, Pistis, Giorgio, Steri, Maristella, Danjou, Fabrice, Kwong, Alan, Del Vecchyo, Vicente Diego Ortega, Chiang, Charleston W. K., Bragg Gresham, Jennifer, Pitzalis, Maristella, Nagaraja, Ramaiah, Tarrier, Brendan, Brennan, Christine, Uzzau, Sergio, Fuchsberger, Christian, Atzeni, Rossano, Reinier, Frederic, Berutti, Riccardo, Huang, Jie, Timpson, Nicholas J., Toniolo, Daniela, Gasparini, Paolo, Malerba, Giovanni, Dedoussis, George, Zeggini, Eleftheria, Soranzo, Nicole, Jones, Chri, Lyons, Robert, Angius, Andrea, Kang, Hyun M., Novembre, John, Sanna, Serena, Schlessinger, David, Cucca, Francesco, Abecasis, Gonçalo R., Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Female, Founder Effect, Gene Frequency, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genotype, Geography, Haplotypes, Humans, Inflammation Mediators, Italy, Lipids, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult, Genetic Variation, Genetics, Haplotype, 80 and over, Non-U.S. Gov't, Inflammation Mediator, Exome sequencing, Genome, Research Support, Non-U.S. Gov't, Single Nucleotide, Lipid, Inflammatory biomarkers, Sequence Analysis, Human, Population, Biology, Research Support, DNA sequencing, Article, N.I.H, Research Support, N.I.H., Extramural, Journal Article, 1000 Genomes Project, Polymorphism, Genetic variants, Extramural, Biomarker, DNA, Genetic architecture, Founder effect
Abstract

We report similar to 17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, similar to 76,000 variants common in our sample (frequency >5%) are rare elsewhere (

Published
2015

25. Beta-thalassemia: from genotype to phenotype

Author

Renzo Galanello, Fabrice Danjou, and Franco Anni

Subjects
Male, Repressor, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb, Polymorphism (computer science), hemic and lymphatic diseases, medicine, Humans, Registries, Nuclear protein, Mutation, beta-Thalassemia, Nuclear Proteins, Beta thalassemia, Hematology, medicine.disease, Molecular biology, Repressor Proteins, medicine.anatomical_structure, Female, Brief Reports, Bone marrow, Genotype to phenotype, Carrier Proteins
Abstract

A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) β-thalassemia mutations; (ii) the XmnI SNP; (iii) the −3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region.

Published
2011

26. The V736A TMPRSS6 polymorphism influences liver iron concentration in nontransfusion-dependent thalassemias

Author

Marianna Serrenti, Fabrice Danjou, Milena Cau, Maria Addis, Susanna Barella, Raffaella Origa, and Roberta Chessa

Subjects
TMPRSS6, Liver Iron Concentration, medicine.medical_specialty, Thalassemia, Non transfusion dependent thalassemia, Hematology, Biology, medicine.disease, Liver metabolism, Endocrinology, Membrane protein, Polymorphism (materials science), TMPRSS6 gene, Internal medicine, medicine
Published
2015

27. Impact of heart magnetic resonance imaging on chelation choices, compliance with treatment and risk of heart disease in patients with thalassaemia major

Author

Renzo Galanello, Raffaella Origa, Gildo Matta, Carlo Dessì, GiovanBattista Leoni, Patrizio Bina, Maddalena Morittu, Fabrice Danjou, S. Cossa, Elisabetta Defraia, and Maria Loreta Foschini

Subjects
Adult, Male, Risk, medicine.medical_specialty, Iron Overload, Heart disease, Pyridones, Iron, Deferoxamine, Iron Chelating Agents, Benzoates, Sampling Studies, Young Adult, Predictive Value of Tests, Internal medicine, Medicine, Humans, In patient, Deferiprone, Patient compliance, Heart Failure, medicine.diagnostic_test, Thalassaemia major, Dose-Response Relationship, Drug, business.industry, Myocardium, beta-Thalassemia, Transfusion Reaction, Magnetic resonance imaging, Arrhythmias, Cardiac, Hematology, Triazoles, medicine.disease, Magnetic Resonance Imaging, Chelation Therapy, Compliance (physiology), Deferasirox, ROC Curve, Heart failure, Area Under Curve, Cohort, Cardiology, Patient Compliance, Drug Therapy, Combination, Female, business
Abstract

Summary This study aimed to verify the impact of heart magnetic resonance imaging on chelation choices and patient compliance in a single-institution cohort as well as its predictive value for heart failure and arrhythmias. Abnormal cardiac T2* values determined changes in treatment in most subjects. Heart T2* was confirmed to be highly predictive over 1 year for heart failure and arrhythmias. The choice of chelation regimens known to remove heart iron efficiently was not sufficient by itself to influence the risk. Compliance with treatment had a more remarkable role.

Published
2013

28. Seventy-five genetic loci influencing the human red blood cell

Author

Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Published
2012

29. A randomized study comparing IGL-1 to the University of Wisconsin preservation solution in liver transplantation

Author

Fédérica, Dondéro, Catherine, Paugam-Burtz, Fabrice, Danjou, Jeanick, Stocco, Francois, Durand, and Jacques, Belghiti

Subjects
Adult, Aged, 80 and over, Male, Adenosine, Adolescent, Allopurinol, Organ Preservation Solutions, Organ Preservation, Middle Aged, Glutathione, Tissue Donors, Liver Transplantation, Young Adult, Raffinose, Treatment Outcome, Liver, Liver Function Tests, Humans, Insulin, Female, Postoperative Period, Prospective Studies, Child, Aged
Abstract

Institut Georges Lopez-1 (IGL-1) is a new preservation solution with lower potassium and lower viscosity than University Wisconsin solution (UW). These characteristics which improve liver preservation lead us to evaluate clinical effects of IGL-1 in a randomized controlled study with UW.From June 2007 to July 2009, after exclusion of partial graft, combined transplantation and fulminant hepatic failure, 140 deceased donor allografts were randomly assigned to IGL-1 (n=48) or UW (n=92) solution. Variables concerning donors and recipients were collected including liver tests (total serum bilirubin, prothrombin time and transaminases) were analyzed until postoperative day 30. Incidences of hepatic artery thrombosis (HAT), primary non function (PNF) and biliary non anastomotic strictures (NAS) were analyzed. The comparative analysis of costs was realized.Donor and recipients characteristics were similar in both groups. Volume of preservation solution utilized for harvesting was identical. Duration of cold ischemia (472±142 vs. 477±122 min), surgery (427±97 vs. 437±94 min) and proportion of extended criteria donor was similar. Postoperative kinetic and level liver tests were similar. Rate of PNF (2% vs. 4%), early retransplantation (6% vs. 7%), incidence of biliary NAS (2% vs. 3%) and HAT (6% vs. 4%) were similar. Mean intensive care unit (ICU) stay was similar (5.6 vs. 6.1 days). However costs related to preservation solution for one liver procurement were 992.0 for IGL-1 vs. 1609.0 Euros for UW.Results of this randomized study shows that the efficacy and safety of IGL-1 are comparable to those of the reference UW with a lower cost.

Published
2010

30. Worldwide survey of T2* cardiovascular magnetic resonance in Thalassaemia

Author

Juliano L Fernandes, Tuncay Hazirolan, Ibrahim Al-Nasser, Mirella Rangelova, Taigang He, Paul D. W. Kirk, Lisa J. Anderson, Amal El-Beshlawy, Shahina Daar, Renzo Galanello, John-Paul Carpenter, Andreas Michos, Vassilis Ladis, Yesim Aydinok, Mohsen Saleh Elalfy, Demetra Vini, Malcolm Walker, Ana G. Almeida, Marouso Drossou, Gian Luca Forni, Vassilios Perifanis, John B. Porter, Fabrice Danjou, Antonis Kattamis, and Dudley J. Pennell

Subjects
Moderate to severe, Medicine(all), medicine.medical_specialty, Pediatrics, lcsh:Diseases of the circulatory (Cardiovascular) system, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, medicine.disease, Medical care, lcsh:RC666-701, Internal medicine, Heart failure, Cohort, medicine, Cardiology, Cardiac iron, Oral Presentation, Radiology, Nuclear Medicine and imaging, Chelation therapy, Cardiology and Cardiovascular Medicine, business, Angiology
Abstract

Results Overall, 57.5% of patients had no significant iron loading (T2* >20ms), 22.6% had moderate cardiac iron (10ms 50%) in South-East Asia had cardiac iron (T2* >20ms) at baseline. At the time of the first scan, 100 patients (3.3%) had confirmed heart failure, the majority of whom (77.0%) had myocardial T2*

Published
2011

31. Effect of Iron Chelators on Cardiac Iron Assessed by MR T2* in Thalassemia Major

Author

Raffaella Origa, Gian Luca Forni, Fabrice Danjou, Filomena Longo, Renzo Galanello, Maria Eliana Lai, Annalisa Agus, and Antonio Piga

Subjects
medicine.medical_specialty, Pathology, Ejection fraction, Dose, Thalassemia, Immunology, Deferasirox, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, chemistry.chemical_compound, chemistry, Internal medicine, medicine, Cardiology, Chelation therapy, Siderosis, Complication, Deferiprone, medicine.drug
Abstract

Introduction: Cardiac iron overload secondary to red blood cell transfusion is a common complication of thalassemia major despite the wide use of chelation therapy and cardiac disease still account for up to 70% of deaths in these patients. Furthermore, myocardial siderosis can be accurately assessed by cardiovascular magnetic resonance (CMR) using T2* sequence. Available chelators seem to have unique profiles of organ iron removal. We report a retrospective analysis of the effect of three available chelators on cardiac iron in patients with thalassemia major. Methods: Fifty-two patients on subcutaneous desferrioxamine (DFO), 28 on deferiprone (DFP) and 28 on deferasirox (DFX) are included in the study. DFO was administered at a mean dosage of 36 ± 8 mg/kg/d for 10 to 14 hours per day for 21 ± 13 months, DFP at 86 ± 10 mg/kg/d for 23 ± 12 months and DFX at 27 ± 6mg/kg/d for 15 ± 5 months. T2* was measured according to Westwood et al (2005). Entry criteria included in each patient a value of T2* lower than 20 ms at baseline or at final assessment. Left ventricular ejection fraction (LVEF) was measured by echocardiography. Results: At baseline, the 3 treatment groups did not show any significant difference in age blood consumption and cardiac T2* (DFO group: 13.4 ± 4.5 ms, DFP 13.9 ± 3.7 and DFX 12.8 ± 3.7; p=0.573).. At the last evaluation mean cardiac T2* was slightly increased in patients on DFO (13.9 ± 8.6 ms, p=0.8) and in those on DFX (13.8 ± 4.4 ms, p=0.04), while was substantially increased in patients on DFP (21.7 ± 9.2 ms, p=0.001). To correct for the different duration of treatment we calculated the percentage monthly cardiac T2* changes that were significantly higher in patients on DFP (1,84 ± 1.94), as compared to patients on DFO (0.2 3 ± 2.15) or DFX (0.45 ± 1.49) (p Conclusions: In this retrospective study monotherapy with deferiprone was significantly more effective than desferrioxamine and deferasirox in alleviating myocardial siderosis in patients with beta-thalassemia major. Further studies are needed to understand if the cardiac T2* changes are influenced by the chelator dosages.

Published
2008

32. Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs

Author

Maristella Steri, Christine Brennan, Eleonora Porcu, Carlo Sidore, Fabio Busonero, Matt McGue, Fabrice Danjou, Antonella Mulas, Serena Sanna, Magdalena Zoledziewska, Michael B. Miller, Maria Francesca Urru, Andrea Angius, Gonçalo R. Abecasis, Marco Marcelli, Maristella Pitzalis, Sandra Lai, Robert H. Lyons, David Schlessinger, Hyun Min Kang, Scott I. Vrieze, Francesco Cucca, Chris Jones, William G. Iacono, Giorgio Pistis, and Andrea Maschio

Subjects
Genotype, Cost-Benefit Analysis, Minnesota, Population, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, White People, Gene Frequency, Statistics, Genetics, Humans, 1000 Genomes Project, education, Allele frequency, Genotyping, Genetics (clinical), Genetic association, education.field_of_study, Genome, Human, Haplotype, Sequence Analysis, DNA, Genetics, Population, Haplotypes, Italy, Research Design, Imputation (genetics), Genome-Wide Association Study
Abstract

The utility of genotype imputation in genome-wide association studies is increasing as progressively larger reference panels are improved and expanded through whole-genome sequencing. Developing general guidelines for optimally cost-effective imputation, however, requires evaluation of performance issues that include the relative utility of study-specific compared with general/multipopulation reference panels; genotyping with various array scaffolds; effects of different ethnic backgrounds; and assessment of ranges of allele frequencies. Here we compared the effectiveness of study-specific reference panels to the commonly used 1000 Genomes Project (1000G) reference panels in the isolated Sardinian population and in cohorts of European ancestry including samples from Minnesota (USA). We also examined different combinations of genome-wide and custom arrays for baseline genotypes. In Sardinians, the study-specific reference panel provided better coverage and genotype imputation accuracy than the 1000G panels and other large European panels. In fact, even gene-centered custom arrays (interrogating ~200 000 variants) provided highly informative content across the entire genome. Gain in accuracy was also observed for Minnesotans using the study-specific reference panel, although the increase was smaller than in Sardinians, especially for rare variants. Notably, a combined panel including both study-specific and 1000G reference panels improved imputation accuracy only in the Minnesota sample, and only at rare sites. Finally, we found that when imputation is performed with a study-specific reference panel, cutoffs different from the standard thresholds of MACH-Rsq and IMPUTE-INFO metrics should be used to efficiently filter badly imputed rare variants. This study thus provides general guidelines for researchers planning large-scale genetic studies.

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