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1. Small-area distribution of multiple sclerosis incidence in western France: in search of environmental triggers

Author

Karima Hammas, Gilles Edan, Morgane Lannes, J. Yaouanq, Jean-François Viel, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), French Ministry of Health [PHRC API 09-41], and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Adult, Male, medicine.medical_specialty, General Computer Science, Scan statistic, Population, Geographic Mapping, Disease, lcsh:Computer applications to medicine. Medical informatics, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Epidemiology, medicine, Humans, 030212 general & internal medicine, Registries, education, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, education.field_of_study, business.industry, Environmental triggers, Incidence (epidemiology), Incidence, Research, Public Health, Environmental and Occupational Health, Small-area distribution, Environmental Exposure, Middle Aged, medicine.disease, General Business, Management and Accounting, Spatial cluster, Etiology, lcsh:R858-859.7, Residence, Female, France, business, 030217 neurology & neurosurgery, Demography, Follow-Up Studies
Abstract

International audience; Background: Despite intensive research over several decades, the etiology of multiple sclerosis (MS) remains poorly understood, although environmental factors are supposedly implicated. Our goal was to identify spatial clusters of MS incident cases at the small-area level to provide clues to local environmental risk factors that might cause or trigger the disease. Methods: A population-based and multi-stage study was performed in the French Brittany region to accurately ascertain the clinical onset of disease during the 2000-2004 period. The municipality of residence at the time of clinical onset was geocoded. To test for the presence of MS incidence clusters and to identify their approximate locations, we used a spatial scan statistic. We adjusted for socioeconomic deprivation, known to be strongly associated with increased MS incident rates, and scanned simultaneously for areas with either high or low rates. Sensitivity analyses (focusing on relapsing-remitting forms and/or places of residence available within the year following clinical onset) were performed. Results: A total of 848 incident cases of MS were registered in Brittany, corresponding to a crude annual incidence rate of 5.8 per 100,000 inhabitants. The spatial scan statistic did not find a significant cluster of MS incidence in either the primary analysis (p value >= 0.56) or in the sensitivity analyses (p value >= 0.16). Conclusion: The findings of this study indicate that MS incidence is not markedly affected across space, suggesting that in the years preceding the first clinical expression of the disease, no environmental trigger is operative at the small-area population level in the French Brittany region.

Published
2017
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2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences

Subjects
Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Published
2016
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3. ‘Clinically definite benign multiple sclerosis’, an unwarranted conceptual hodgepodge: evidence from a 30-year observational study

Author

M. Coustans, E. Le Page, Gilles Edan, J. Yaouanq, Joel Oger, Emmanuelle Leray, Neurosciences Cliniques, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes]-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], CHU Pontchaillou [Rennes]-CHU Pontchaillou [Rennes], University of British Columbia (UBC), Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service de Neurologie [Rennes] = Neurology [Rennes], Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, medicine.medical_specialty, Pediatrics, MESH: Multiple Sclerosis, Relapsing-Remitting, Long term follow up, MEDLINE, Outcome measurement, Clinical onset, Multiple sclerosis, Disability Evaluation, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, 030225 pediatrics, Benign multiple sclerosis, Humans, Medicine, Longitudinal Studies, MESH: Longitudinal Studies, 10. No inequality, Long-term follow-up, MESH: Humans, Benign form, business.industry, Disease progression, MESH: Disability Evaluation, MESH: Adult, Prognosis, medicine.disease, MESH: Male, 3. Good health, Surgery, Neurology, Disease Progression, Female, MESH: Disease Progression, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Observational study, Neurology (clinical), business, MESH: Female, 030217 neurology & neurosurgery
Abstract

Background: Benign multiple sclerosis (BMS) is a controversial concept which is still debated. However identification of this kind of patients is crucial to prevent them from unnecessary exposure to aggressive and/or long term medical treatments. Objectives: To assess two definitions of ‘clinically definite benign multiple sclerosis’ (CDBMS) using long-term follow-up data, and to look for prognostic factors of CDBMS. Methods: In 874 patients with definite relapsing–remitting MS, followed up for at least 10 years, disability was assessed using the Disability Status Scale (DSS). CDBMS was defined by either DSS score≤2 (CDBMS1 group) or DSS score≤ 3 (CDBMS2 group) at 10 years. We estimated the proportion of patients who were still benign at 20 and 30 years after clinical onset. Results: CDBMS frequency estimates were 57.7% and 73.9% when using CDBMS1 and CDBMS2 definitions, respectively. In the CDBMS1 group, only 41.7% (105/252) of cases were still benign 10 years later, and 41.1% (23/56) after an additional decade, while there were 53.8% (162/301) and 59.5% (44/74) respectively in the CDBMS2 group. Conclusions: This 30-year observational study, which is one of the largest published series, indicates that favourable 10-year disability scores of DSS 2 or 3 fail to ensure a long-term benign course of multiple sclerosis. After every decade almost half of the CDBMS were no longer benign. CDBMS, as currently defined, is an unwarranted conceptual hodgepodge. Other criteria using new biomarkers (genetic, biologic or MRI) should be found to detect benign cases of MS.

Published
2012
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4. Evidence for a two-stage disability progression in multiple sclerosis

Author

Gilles Edan, J. Yaouanq, David Laplaud, M. Coustans, Emmanuelle Le Page, Emmanuelle Leray, and Joel Oger

Subjects
education.field_of_study, medicine.medical_specialty, Proportional hazards model, business.industry, Multiple sclerosis, Population, Neurodegeneration, Original Articles, Disease, multiple sclerosis, medicine.disease, Central nervous system disease, disability progression, age, Internal medicine, medicine, Physical therapy, prognosis, Neurology (clinical), Stage (cooking), Young adult, education, business, course
Abstract

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, ‘Phase 1’, from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, ‘Phase 2’, from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan–Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26 273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (

Published
2010
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5. MGAT5 alters the severity of multiple sclerosis

Author

Filippo Martinelli-Boneschi, Federica Esposito, V. Debailleul, Jérôme Wojcik, Hadi Abderrahim, Gilles Edan, Giacomo P. Comi, J. Yaouanq, Boel Brynedal, Jan Hillert, Brynedal, B, Wojcik, J, Esposito, F, Debailleul, V, Yaouanq, J, MARTINELLI BONESCHI, F, Edan, G, Comi, Giancarlo, Hillert, J, and Abderrahim, H.

Subjects
Adult, Genetic Markers, Male, Glycosylation, Multiple Sclerosis, Genotype, DNA Mutational Analysis, Immunology, Population, Central nervous system, Nerve Tissue Proteins, Biology, N-Acetylglucosaminyltransferases, Severity of Illness Index, Genome, Cohort Studies, Disability Evaluation, Immune system, medicine, Demyelinating disease, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Genetic Testing, education, Gene, Oligonucleotide Array Sequence Analysis, Genetic association, education.field_of_study, Multiple sclerosis, Genetic Variation, medicine.disease, Europe, medicine.anatomical_structure, Neurology, Female, Neurology (clinical), Genome-Wide Association Study
Abstract

Multiple Sclerosis (MS) is a genetically complex immune mediated, demyelinating disease of the central nervous system. To date no genetic variants have been unambiguously linked to disease severity. We have conducted a genome wide screen, using Affymetrix Genechip® 500K technology, for severity in 1040 MS patients. Two markers within MGAT5 , a gene coding for a glycosylation enzyme, were found to be significantly associated with outcome in the screening as well as in an independent population (combined p -values: 2.8 × 10 − 6 and 1.5 × 10 − 7 ).

Published
2010
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6. Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis

Author

D A, Fernandes de Abreu, M C, Babron, M C I, Babron, I, Rebeix, C, Rebeix, C, Fontenille, J, Fontenille, J, Yaouanq, D, Yaouanq, D, Brassat, B, Brassat, B, Fontaine, F, Fontaine, F, Clerget-Darpoux, F, Jehan, and F, Feron

Subjects
Parents, Risk, Multiple Sclerosis, Genotype, Season of birth, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Calcitriol receptor, Gene Frequency, Risk Factors, medicine, Vitamin D and neurology, Humans, Genetic Predisposition to Disease, Prospective Studies, Risk factor, Promoter Regions, Genetic, Allele frequency, Pregnancy, business.industry, Incidence, Multiple sclerosis, Parturition, medicine.disease, Neurology, Immunology, Receptors, Calcitriol, France, Seasons, Neurology (clinical), business
Abstract

Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether: (1) a seasonality of birth was observed in French multiple sclerosis patients; (2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.

Published
2009
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7. HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis

Author

Gilles Edan, Marie-Claude Babron, M. Rosenheim, Bertrand Fontaine, Hervé Perdry, Gout C, Mehdi Alizadeh, J. Yaouanq, Emmanuelle Leray, Gilbert Semana, Emmanuelle Génin, Françoise Clerget-Darpoux, David Brassat, Cournu-Rebeix I, and Jérémie F. Cohen

Subjects
Adult, Male, Multiple Sclerosis, Adolescent, Multiple sclerosis, Immunology, HLA-DR Antigens, Disease, Human leukocyte antigen, Biology, medicine.disease, Natural history, Relapsing remitting, Genotype, Genetics, medicine, Humans, Female, Allele, Child, HLA-DRB1, Genetics (clinical), HLA-DRB1 Chains
Abstract

Most of the published works so far have aimed at finding genes associated with multiple sclerosis (MS) susceptibility. Very few studies have attempted to correlate disease features with DNA variants. In a well-characterized sample (651 patients) representative of multiple sclerosis natural history, we engaged a comprehensive study of the role of human leukocyte antigen (HLA) in the course of the disease. We investigated the role of HLA-DRB1*15 allele in samples stratified according to severity evaluated by the Multiple Sclerosis Severity Score (MSSS), time to reach EDSS 6.0 and disease type. We found that HLA-DRB1*15 genotype does not influence MS severity even among patients presenting with a given type of the disease. However, we show for the first time that HLA-DRB1*15 allele modulates the course of MS for relapsing-remitting (RR) onset patients likely by precipitating the secondary progressive (SP) phase.

Published
2008
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8. Register-based incidence of multiple sclerosis in Brittany (north-western France), 2000-2001

Author

Anne Kerbrat, P Hinault, Gilles Edan, M Merienne, Stéphanie Hamonic, Emmanuelle Leray, Isabelle Tron, J. Yaouanq, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), West Neuroscience Network of Excellence, West Neuroscience Network of Excellence (WENNE), Service d'Epidémiologie et de Santé Publique [Rennes] = Epidemiology and Public Health [Rennes], CHU Pontchaillou [Rennes], Observatoire Régional de Santé (ORS Bretagne), ORS Bretagne, Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Rennes] = Neurology [Rennes], École des Hautes Études en Santé Publique [EHESP] (EHESP), SERONO LaboratoriesFrench Ministry of Health. Grant Number: API 09-41, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), WENNE, CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), and Edan, Gilles

Subjects
Adult, Male, Register based, medicine.medical_specialty, Epidemiology, Population, Poser criteria, Multiple sclerosis, 03 medical and health sciences, Age Distribution, 0302 clinical medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Registries, 030212 general & internal medicine, Sex Distribution, education, education.field_of_study, business.industry, Medical record, Incidence (epidemiology), Incidence, Putative incident cases of MS, General Medicine, Middle Aged, medicine.disease, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Neurology (clinical), business, 030217 neurology & neurosurgery, Demography
Abstract

International audience; Objectives – To report on multiple sclerosis (MS) incidence in Brittany, north-western France. Materials & Methods – From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated. Results – Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/ probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32–5.51], 6.68 [4.75–8.60], and 2.21 [1.12–3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25–29 years and progressive onset MS at 40–44 years in women (20–24 years and 45–49 years in men, respectively). Conclusions – Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25-to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France.

Published
2015
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9. Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study

Author

Mehdi Alizadeh, Lisa F. Barcellos, Françoise Clerget-Darpoux, David Brassat, Marie Claude Babron, M. Clanet, Margaret A. Pericak-Vance, Robin R. Lincoln, Stephen L. Hauser, Isabelle Cournu-Rebeix, Gilbert Semana, Erwann Quelvennec, Emmanuelle Génin, Melissa E. Garcia, Jorge R. Oksenberg, Hélène Coppin, J. Yaouanq, Ariele Azoulay-Cayla, Gilles Edan, Jonathan L. Haines, Olivier Lyon-Caen, M.-P. Roth, Emmanuelle Duhamel, Jackie B. Rimmler, and Bertrand Fontaine

Subjects
Multiple Sclerosis, Genetic Linkage, Locus (genetics), Biology, Genetic determinism, Cellular and Molecular Neuroscience, Genetic linkage, Genetics, medicine, Humans, Genetic Predisposition to Disease, Multiplex, Cooperative Behavior, Allele, Genetics (clinical), HLA-DR Serological Subtypes, Multiple sclerosis, HLA-DR15, HLA-DR Antigens, medicine.disease, United States, Human genetics, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 3, France, Chromosomes, Human, Pair 19
Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.

Published
2004
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10. NOD2/CARD15 gene polymorphisms in Crohn's disease

Author

Laurent Siproudhis, PN d'Halluin, Brigitte Birebent, Stéphane Dreano, Jean-François Bretagne, Nathalie Heresbach-Le Berre, Jean Mosser, J. Yaouanq, Denis Heresbach, Alain Dabadie, Véronique Gicquel-Douabin, Gilbert Semana, and Michel Gosselin

Subjects
Adult, Male, Heterozygote, Adolescent, Population, Nod2 Signaling Adaptor Protein, Biology, Compound heterozygosity, Crohn Disease, Gene Frequency, Genotype, medicine, Humans, Genetic Predisposition to Disease, Allele, Child, education, Allele frequency, Aged, Analysis of Variance, education.field_of_study, Granuloma, Polymorphism, Genetic, Hepatology, Homozygote, Intracellular Signaling Peptides and Proteins, Gastroenterology, Odds ratio, Middle Aged, medicine.disease, digestive system diseases, Genotype frequency, Mutation, Immunology, Female, Carrier Proteins
Abstract

OBJECTIVES Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population. METHODS Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma). RESULTS Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma. CONCLUSIONS In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.

Published
2004
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11. Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients

Author

Gilles Edan, J. Yaouanq, Anne Kerbrat, Emmanuelle Leray, I Tron, Stéphanie Hamonic, Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Service de santé publique et d'épidémiologie, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), API 09-41, PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Edan, Gilles, Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Université de Rennes (UNIV-RENNES)-CentraleSupélec-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec, Service de Neurologie [Rennes], and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
Male, Pediatrics, Time Factors, MESH: Multiple Sclerosis, Relapsing-Remitting, Disease, multiple sclerosis, 0302 clinical medicine, cohort studies, Recurrence, MESH: Child, Epidemiology, Medicine, demyelinating diseases, 10. No inequality, Child, MESH: Aged, 0303 health sciences, education.field_of_study, Clinically isolated syndrome, MESH: Middle Aged, MESH: Follow-Up Studies, Middle Aged, Multiple Sclerosis, Chronic Progressive, 3. Good health, Natural history, Neurology, MESH: Young Adult, Cohort, Disease Progression, Female, epidemiology, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cohort study, Adult, medicine.medical_specialty, Adolescent, Population, MESH: Prognosis, 03 medical and health sciences, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Multiple Sclerosis, Chronic Progressive, education, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, business.industry, Multiple sclerosis, MESH: Time Factors, MESH: Adult, medicine.disease, MESH: Male, MESH: Recurrence, clinically isolated syndrome, Physical therapy, Neurology (clinical), prognosis, business, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

International audience; Background and purpose - Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort. Methods - A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected. Results - In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6. Conclusion(s) - Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive-onset MS group. This finding impacts the prognosis given to patients in clinical practice.

Published
2015
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12. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations

Author

J. Le Gall, Véronique David, G. Gandon, J. Yaouanq, Patricia Fergelot, and Anne-Marie Jouanolle

Subjects
Heterozygote, Candidate gene, Positional cloning, Genes, MHC Class I, Biology, medicine.disease_cause, Bioinformatics, Gene Frequency, HLA Antigens, Genetics, medicine, Humans, Missense mutation, Hemochromatosis Protein, Gene, Allele frequency, Genetics (clinical), Hemochromatosis, Mutation, Histocompatibility Antigens Class I, Homozygote, Membrane Proteins, medicine.disease, Haplotypes, Hereditary hemochromatosis, Chromosomes, Human, Pair 6, France
Abstract

The gene whose alteration causes hereditary hemochromatosis (HFE according to the international nomenclature) was, more than 20 years ago, shown to map to 6p21.3. It has since escaped all efforts to identify it by positional cloning strategies. Quite recently, a gene named HLA-H was reported as being responsible for the disease. Two missense mutations, Cys282Tyr (C282Y) and His63Asp (H63D), were observed, but no proof was produced that the gene described is the hemochromatosis gene. To validate this gene as the actual site of the alteration causing hemochromatosis, we decided to look for the two mutations in 132 unrelated patients from Brittany. Our results indicate that more than 92% of these patients are homozygous for the C282Y mutation, and that all 264 chromosomes but 5 carry either mutation. These findings confirm the direct implication of HLA-H in hemochromatosis.

Published
1997
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13. Evidence for Linkage Disequilibrium Between HLA-DRB1 Gene and Multiple Sclerosis

Author

Michel Clanet, E Quelvennec, S. Eichenbaum, Françoise Clerget-Darpoux, Gilles Edan, M.-P. Roth, Gilbert Semana, and J. Yaouanq

Subjects
Genetics, Linkage disequilibrium, Multidisciplinary, Multiple sclerosis, Haplotype, Disequilibrium, Biology, medicine.disease, Genome, Evolutionary biology, Genetic predisposition, medicine, medicine.symptom, Gene, HLA-DRB1
Abstract

In their Perspective “The future of genetic studies of complex human diseases ([13 Sept., p. 1516][1]), Neil Risch and Kathleen Merikangas emphasize that such studies might benefit greatly from approaches based on gametic disequilibrium. Recent genome scans ([1][2]) and our own data on human

Published
1997
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14. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author

H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. 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Valalentino, D. Guidetti, B. Buchwald, C. H. Lücking, D. Gauvreau, F. Pfaff, A. Ben Younes-Chennoufi, R. Kiefer, R. Massot, K. A. Hossmann, L. Werdelin, P. J. Baxter, U. Ziflo, S. Allaria, C. D. Marsden, M. Cabaret, S. P. Mueller, E. Calabrese, R. Colao, S. I. Bekkelund, M. Yilmaz, O. Oktem-Tanor, R. Gine, M. E. Scheulen, J. Beuuer, A. Melo, Z. Gulay, M. D. Have, C. Frith, D. Liberati, J. Gozlan, P. Rondot, Ch. Brunholzl, M. Pocchiari, J. Pena, L. Moiola, C. Salvadori, A. Cabello, T. Catarci, S. Webb, C. Dettmers, N. A. Gregson, Alexandra Durr, F. Iglesias, U. Knorr, L. Ferrini-Strambi, F. Kruggel, P. Allard, A. Coquerel, P. Genet, F. Vinuels, C. Oberwittler, A. Torbicki, P. Leffers, B. Renault, B. Fauser, C. Ciano, G. Uziel, J. M. Gibson, F. Anaya, C. Derouesné, C. N. Anagnostou, M. Kaido, W. Eickhoff, G. Talerico, M. L. Berthier, A. Capdevila, M. Alons, D. Rezek, E. Wondrusch, U. Kauerz, D. Mateo, M. A. Chornet, Holon, N. Pinsard, I. Doganer, E. Paoino, H. Strenge, C. Diaz, J. R. Brasic, W. Heide, I. Santilli, W. M. Korn, D. Selcuki, M. J. Barrett, D. Krieger, T. Leon, T. Houallah, M. Tournilhac, C. Nos, D. Chavot, F. Barbieri, F. J. Jimenez-Jimenez, J. Muruzabal, K. Poeck, A. Sennlaub, L. M. Iriarte, L. G. Lazzarino, C. Sanz, P. A. Fischer, S. D. Shorvon, R. Hoermann, F. Delecluse, M. Krams, O. Corabianu, F. H. Hochberg, Christopher J. Mathias, B. Debachy, C. M. Poser, L. Delodovici, A. Jimenez-Escrig, F. Baruzzi, F. Godenberg, D. Cucinotta, P. J. Garcia Ruiz, K. Maier-Hauff, P. R. Bar, R. Mezt, R. Jochens, S. Karakaneva, C. Roberti, E. Caballero, Joseph E. Parisi, M. Zamboni, T. Lacasa, B. Baklan, J. C. Gautier, J. A. Martinez-Matos, W. Pollmann, G. Thomas, L. Verze, E. Chleide, R. Alvarez Sala, I. Noel, E. Albuisson, O. Kastrup, S. I. Rapoport, H. J. Braune, H. Lörler, M. Le Merrer, A. Biraben, S. Soler, S. J. Taagholt, U. Meyding-Lamadé, K. Bleasdale-Barr, Isabella Moroni, Y. Campos, J. Matias-Guiu, G. Edan, M. G. Bousser, John B. Clark, J. Garcia de Yebenes, N. K. Olsen, P. Hitzenberger, S. Einius, Aj Thompson, Ch. J. Vecht, T. Crepin-Leblond, Klaus L. Leenders, A. Di Muzio, L. Georgieva, René Spiegel, K. Sabey, D. Ménégalli, J. Meulstee, U. Liszka, P. Giral, C. Sunol, J. M. Espadaler, A. D. Crockar, K. Varli, G. Giraud, P. J. Hülser, A. Benazzouz, A. Reggio, M. Salvatore, K. Genc, M. Kushnir, S. Barbieri, J. Ph. Azulay, M. Gianelli, N. Bathien, A. AlMemar, F. Hentati, I. Ragueneau, F. Chiarotti, R. C. F. Smits, A. K. Asbury, F. Lacruz, B. Muller, Alan J. Thompson, Gordon Smith, K. Schmidt, C. Daems Monpeun, Juergen Weber, A. Arboix, G. R. Fink, A. M. Cobo, M. Ait Kaci Ahmed, E. Gencheva, Israel-Biet, G. Schlaug, P. De Jonghe, Philip Scheltens, K. Toyka, P. Gonzalez-Porque, A. Cila, J. M. Fernandez, P. Augustin, J. Siclia, S. Medaglini, D. E. Ziogas, A. Feve, L. Kater, G. J. E. Rinkel, D. Leppert, Rüdiger J. Seitz, S. Ried, C. Turc-Carel, G. Smeyers, F. Godinho, M. Czygan, M. Rijntjes, E. Aversa, M. Frigo, Leif Østergaard, J. L. Munoz Blanco, A. Cruz-Matinez, J. De Reuck, C. Theillet, T. Barroso, V. Oikonen, Florence Lebert, M. Kilinc, C. Cordon-Cardon, G. Stoll, E. Thiery, F. Pulcinelli, J. Solski, M. Schmiegelow, L. J. Polman, P. Fernandez-Calle, C. Wikkelso, M. Ben Hamida, M. Laska, E. Kott, W. Sulkowski, C. Lucas, N. M. Bornstein, D. Schmitz, M. W. Lammers, A. de Louw, R. J. S. Wise, P. A. van Darn, C. Antozzi, P. Villanueva, P. H. E. Hilkens, C. Constantin, W. Ricart, A. Wolf, M. Gamba, P. Maguire, Alessandro Padovani, B. M. Patten, Marie Sarazin, H. Ackermann, L. Durelli, S. Timsit, Sebastian Jander, B. W. Scheithauer, G. Demir, J. P. Neau, P. Barbanti, A. Brand, N. AraÇ, V. Fischer-Gagnepain, R. Marchioli, G. Serratrice, C. Maugard-Louboutin, G. T. Spencer, D. Lücke, G. Mainardi, K. Harmant Van Rijckevorsel, G. B. Creel, R. Manzanares, Francesco Fortunato, A. May, J. Workman, K. Johkura, E. Fernandez, Carlo Colosimo, L. Calliauw, L. Bet, Félix F. Cruz-Sánchez, M. Dhib, H. Meinardi, F. Carrara, J. Kuehnen, C. Peiro, H. Lassmann, K. Skovgaard Olsen, A. McDonald, L. Sciulli, A. Cobo, A. Monticelli, B. Conrad, J. Bagunya, J. Benitez, V. Desnizza, B. Dupont, O. Delrieu, D. Moraes, J. J. Heimans, F. Garcia Rio, M. Matsumto, A. Fernandez, R. Nermni, R. Chalmers, M. J. Marchau, F. Aguado, P. Velupillai, P. J. Martin, P. Tassan, V. Demarin, A. Engelien, T. Gerriets, Comar, J. L. Carrasco, J. P. Pruvo, A. Lopez de Munain, D. Pavitt, J. Alarcon, Chris H. Polman, B. Guldin, N. Yeni, Hartmut Brückmann, N. Wilczak, H. Szwed, R. Causaran, G. Kyriazis, M. E. Westarp, M. Gasparini, N. Pecora, J. M. Roda, E. Lang, V. Scaioli, David R. Fish, D. Caputo, O. Gratzl, R. Mercelis, A. Perretti, G. Steimetz, I. Link, C. Rigoletto, A. Catafau, G. Lucotte, M. Buti, G. Fagiolari, A. Piqueras, C. Godinot, J. C. Meurice, Erodriguez J. Dominigo, F. Lionnet, H. Grzelec, David J. Brooks, P. M. G. Munro, F. X. Weilbach, M. Maiwald, W. Split, B. Widjaja-Cramer, V. Ozturk, J. Colas, E. Brizioli, J. Calleja, L. Publio, M. Desi, R. Soffietti, P. Cortinovis-Tourniaire, E. F. Gonano, G. Cavaletti, S. Uselli, K. Westerlind, H. Betuel, C. O. Dhiver, H. Guggenheim, M. Hamon, R. Fazio, P. Lehikoinen, A. Esser, B. Sadzot, G. Fink, Angelo Antonini, D. Bendahan, V. Di Carlo, G. Galardi, A. F. Boller, M. Aksenova, Del Fiore, V. de la Sayette, H. Chabriat, A. Nicoletti, A. Dilouya, M. L. Harpin, E. Rouillet, J. Stam, A. Wolters, M. R. Delgado, Eduardo Tolosa, G. Said, A. J. Lees, L. Rinaldi, A. Schulze-Bonhage, MA Ron, C. Lefebvre, E. W. Radü, R. Alvarez, M. L. Bots, P. Reganati, S. Palazzi, A. Poggi, N. J. Scolding, V. Sazdovitch, T. Moreau, E. Maes, M. A. Estelies, P. Petkova, Jose-Felix Marti-Masso, G De La Meilleure, N. Mullatti, M. Rodegher, N. C. Notermans, T. A. T. Warner, S. Aktan, J. P. Louboutin, L. Volpe, C. Scheidt, W. Aust, C. M. Wiles, U. Schneider, S. K. Braekken, W. R. Willems, K. Usuku, Peter M. Rothwell, C. Talamon, M. L. Sacchetti, A. Codina, M. H. Marion, A. Santoro, J. Roda, A. Bordoni, D. J. Taylor, S. Ertas, H. H. Emmen, J. Vichez, V. BesanÇon, R. E. Passingham, M. L. Malosio, A. Vérier, M. Bamberg, A. W. Hansen, E. Mostacero, G. Gaudriault, Marie Vidailhet, B. Birebent, K. Strijckmans, F. Giannini, T. Kammer, I. Araujo, J. Nowicki, E. Nikolov, A. Hutzelmann, R. Gherardi, J. Verroust, L. Austoni, A. Scheller, A. Vazquez, S. Matheron, H. Holthausen, J. M. Gerard, M. Bataillard, S. Dethy, V. H. Patterson, V. Ivanez, N. P. Hirsch, F. Ozer, M. Sutter, C. Jacomet, M. Mora, Bruno Colombo, A. Sarropoulos, T. H. Papapetropoulos, M. Schwarz, D. S. Dinner, N. Acarin, B. Iandolo, J. O. Riis, P. R. J. Barnes, F. Taroni, J. Kazenwadel, L. Torre, A. Lugaresi, I. L. Henriques, S. Pauli, S. Alfonso, Pedro Quesada, A. S. T. Planting, J. M. Castilla, Thomas Gasser, M. Van der Linden, A. Alfaro, E. Nobile-Orazio, G. Popova, W. Vaalburg, F. G. A. van der Mech, L. Williams, F. Medina, J. P. Vernant, J. Yaouanq, B. Storch-Hagenlocher, A. Potemkowski, R. Riva, M. H. Mahagne, M. Ozturk, Ve. Drory, N. Konic, C. Jungreis, A. Pou Serradell, J. L. Gauvrit, G. J. Chelune, S. Hermandez, T. Dingus, L. Hewer, Ch. Koch, M. N. Metz-Lutz, G. Parlato, M. Sinaki, Charles Pierrot-Deseilligny, H. C. Diener, J. Broeckx, J. Weill-Fulazza, M. L. Villar, M. Rizzo, O. Ganslandt, C. Duran, N. A. Fletcher, G. Di Giovacchino, Susan T. Iannaccone, C. Kolig, N. Fabre, H. A. Crockard, Rita Bella, M. Tazir, E. Papagiannuli, K. Overgaard, Emma Ciafaloni, I. Lorenzetti, F. Viader, P. A. H. Millac, I. Montiel, L. H. Visser, M. Palomar, P. L. Murgia, H. Pedersen, Rafael Blesa, S. Seddigh, W. O. Renier, I. Lemahieu, H. M. L. Jansen, L. Rosin, J. Galofre, K. Mattos, M. Pondal, G. M. Hadjigeorgiou, D. Francis, L. Cantin, D. Stegeman, M. Rango, A. B. M. F. Karim, S. Schraff, B. Castellotti, I. Iriarte, E. Laborde, T. J. Tjan, R. Mutani, D. Toni, B. Bergaasco, J. G. Young, C. Klotzsch, A. Zincone, X. Ducrocq, M. Uchuya, O. J. Kolar, A. Quattrone, T. Bauermann, Nereo Bresolin, J. Vallée, B. C. Jacobs, A. Campos, Werner Poewe, J. A. Villanueva, A. W. Kornhuber, A. Malafosse, E. Diez-Tejedor, G. Jungreia, M. J. A. Puchner, A. Komiyama, O. Saribas, V. Volpini, L. Geremia, S. Bressi, A. Nibbio, Timothy E. Bates, T. z. Tzonev, E. Ideman, G. A. Damlacik, G. Martino, G. Crepaldi, T. Martino, Kjell Någren, E. Idiman, D. Samuel, J. M. Perez Trullen, Y. van der Graaf, J. O. Thorell, M. J. M. Dupuis, E. Sieber, R. D'Alessandro, C. Cazzaniga, J. Faiss, A. Tanguy, A. Schick, I. Hoksergen, A. Cardozo, R. Shakarishvili, G. K. Wennlng, J. L. Marti-Vilalta, J. Weissenbach, I. L. Simone, Amalia C. Bruni, Darius J. Adams, C. Weiller, A. Pietrangeli, F. Croria, C. Vigo-Pelfrey, Patricia Limousin, A. Ducros, G. Conti, O. Lindvall, E. Richter, M. Zuffi, A. Nappo, T. Riise, J. Wijdenes, M. J. Fernandez, J. Rosell, P. Vermersh, S. Servidei, M. S. C. Verdugo, F. Gouttiere, W. Solbach, M. Malbezin, I. S. Watanabe, A. Tumac, W. I. McDonald, D. A. Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg

Subjects
Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published
1994
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16. REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction

Author

Julie Pilliod, Estelle Fedirko, Imed Feki, Didier Lacombe, Alexandra Durr, Perrine Charles, Cyril Goizet, Marie-Laure Martin-Negrier, Alexis Brice, Giovanni Benard, Sylvie Forlani, Eric LeGuern, Jean-François Pinel, Elisabeth Ollagnon-Roman, Rodrigue Rossignol, Giovanni Stevanin, Didier Hannequin, Annick Toutain, Stanislas Lyonnet, J. Yaouanq, Amir Boukhris, Emeline Mundwiller, Bertrand Fontaine, Anne-Marie Ouvrard-Hernandez, Cécile Cazeneuve, Christel Depienne, G. Sole, Isabelle Coupry, and Christelle Dussert

Subjects
Adult, Male, Mutation rate, Adolescent, Hereditary spastic paraplegia, Biology, Mitochondrion, Exon, Young Adult, Mutation Rate, Genetics, medicine, Humans, Multiplex ligation-dependent probe amplification, Child, Muscle, Skeletal, Gene, Genetics (clinical), Aged, Sequence Deletion, Cerebellar ataxia, Base Sequence, Spastic Paraplegia, Hereditary, Infant, Newborn, Infant, Membrane Transport Proteins, Middle Aged, medicine.disease, Phenotype, Mitochondria, Pedigree, Child, Preschool, Mutation, Female, medicine.symptom, Energy Metabolism
Abstract

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation-dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD-HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD-HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver-like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain. Hum Mutat 32:1118–1127, 2011. ©2011 Wiley-Liss, Inc.

Published
2010

17. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations

Author

Bertram Müller-Myhsok, Stephan Ripke, F. Müller-Sarnowski, C. Gout, S. Lutz, Marie-Claude Babron, Michel Clanet, F. Weber, Martin A. Kohli, J. Yaouanq, M. Knop, Peter Rieckmann, Marcus Ising, Isabelle Cournu-Rebeix, Manfred Uhr, Olivier Lyon-Caen, Gilles Edan, Antje Kroner, Bertrand Fontaine, Françoise Clerget-Darpoux, David Brassat, F. Holsboer, G. Semana, S. Mrejen, and Thomas Bettecken

Subjects
Adult, Male, Multiple Sclerosis, Genotype, Immunology, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Gene Frequency, Germany, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Allele frequency, Gene, Genetics (clinical), Aged, Receptors, Interleukin-7, Multiple sclerosis, Interleukin-2 Receptor alpha Subunit, Odds ratio, Middle Aged, medicine.disease, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Female, France
Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Published
2008

18. HLA class I gene polymorphism in genetic hemochromatosis

Author

Renée Fauchet, Jean-Yves Le Gall, Véronique David, Muriel Périchon, M. P. Font, J. Yaouanq, Anne-Marie Jouanolle, and Martine Blayau

Subjects
Genetics, Polymorphism, Genetic, biology, Histocompatibility Antigens Class I, EcoRI, Human leukocyte antigen, HindIII, medicine.disease, Molecular biology, Restriction fragment, EcoRV, HLA Antigens, medicine, biology.protein, Humans, Hemochromatosis, Gene polymorphism, Restriction fragment length polymorphism, Polymorphism, Restriction Fragment Length, Genetics (clinical)
Abstract

The authors have studied HLA class I polymorphism in an attempt to identify a genomic marker of the hemochromatosis gene. Five enzymes were used (HindIII, EcoRI, EcoRV, PvuII, and HincII) in 47-106 unrelated patients and 71-91 controls. Both populations were HLA-typed. The relationship between the restriction fragments and HLA-A antigens was considered. Comparison of the two groups revealed a significantly high frequency of one 14 kb EcoRI fragment among the HLA-A3 hemochromatosis patients. The fragment hybridizes to an HLA-A specific probe but not to an HLA-B specific probe, and is associated with the hemochromatosis gene, which is itself associated with HLA-A3.

Published
1990
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19. Long-term survival of patients with multiple sclerosis in West France

Author

Gilles Edan, J. Yaouanq, M. Coustans, E. Le Page, J. Chaperon, Emmanuelle Leray, Sean Patrick Morrissey, Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], CHU de Pontchaillou, Service de Neurologie [Rennes], Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Survival, Population, Kaplan-Meier Estimate, Standardized mortality rates, Clinical onset, Central nervous system disease, Multiple sclerosis, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, Cause of Death, Long term survival, Medicine, Humans, 030212 general & internal medicine, 10. No inequality, education, Cause of death, Aged, education.field_of_study, business.industry, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Prognosis, 3. Good health, Surgery, Neurology, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), France, business, 030217 neurology & neurosurgery, Sex ratio
Abstract

In France no data have been published about comparing survival in multiple sclerosis (MS) patients with the general French population. We estimated survival probabilities in MS patients from a major centre for MS in West France. We also compared MS survival with the general population and assessed prognostic parameters. All patients with MS onset after January 1976 and classified as dead or alive on 1 January 2004 were included. One thousand eight-hundred and seventy-nine patients (sex ratio W: M 2.3; relapsing/progressive onset 77.4%/22.6%) fulfilled these criteria, disease duration ranged from one to 28 years. By 2004, 68 patients died (51 due to MS) and the 15 and 25-year survival probabilities were 96% and 88%. Male gender, progressive course (either primary or secondary), polysymptomatic onset, and increased annual relapse rate during the first two years of MS were related to a worse prognosis. After a mean follow-up duration of 12.7 years since clinical onset, MS increased the number of deaths compared with the general population. However taking into account disability status, we found that less disabled MS patients had a better survival and highly disabled patients a worse survival (eight-fold increase of mortality) compared with the French population. Multiple Sclerosis 2007; 13: 865—874. http://msj.sagepub.com

Published
2007
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20. Non-C282Y familial iron overload: evidence for locus heterogeneity in haemochromatosis

Author

Anne-Marie Jouanolle, S Pinson, J Yaouanq, B Turlin, and H Plauchu

Subjects
Adult, Male, Candidate gene, Iron Overload, Genetic counseling, Locus (genetics), Biology, Genetic determinism, Genetic Heterogeneity, Locus heterogeneity, Genetics, medicine, Humans, Missense mutation, Cysteine, Genetics (clinical), Hemochromatosis, Genetic heterogeneity, Genetic Diseases, Inborn, Middle Aged, medicine.disease, Amino Acid Substitution, Tyrosine, Female, Research Article
Abstract

Haemochromatosis (HC) is an autosomal recessive disease with progressive iron overload leading to midlife onset of clinical complications. The causal gene (HFE) maps to 6p, in close linkage with the HLA class I genes. An HFE candidate gene recently identified has two missense mutations (C282Y and H63D) associated with the disease. Here we document the phenotypic and genetic analysis of a nuclear family comprising two sibs with symptomatic and massive iron overload before the age of 25. The disease seemed to be recessively transmitted and fitted the agreed criteria for haemochromatosis, but was neither associated with the C282Y and H63D mutations nor linked with HLA markers. Our data strongly support locus heterogeneity in haemochromatosis by showing evidence that the gene responsible for juvenile haemochromatosis (JH) does not map to 6p. In the absence of clear cut phenotypic distinction from typical haemochromatosis, patients below 30 years of age and C282Y negative should be considered as putative juvenile cases. This has practical implications in genetic counselling and family management.

Published
1998
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21. Genetic analysis of multiple sclerosis in Europeans: French data

Author

Emmanuelle Génin, Marie-Claude Babron, Bertrand Fontaine, Stephen Sawcer, Michel Clanet, Brigitte Birebent, Mehdi Alizadeh, Alastair Compston, Françoise Clerget-Darpoux, Gilles Edan, Gilbert Semana, Isabelle Cournu-Rebeix, J. Yaouanq, and Stéphane Dreano

Subjects
Linkage disequilibrium, Multiple Sclerosis, Genotype, International Cooperation, Immunology, Biology, Genetic analysis, Linkage Disequilibrium, Gene Frequency, medicine, Immunology and Allergy, Dna pools, Humans, Dna pooling, Genetic Testing, Prospective Studies, Allele frequency, Alleles, Genetics, Genome, Human, Multiple sclerosis, medicine.disease, Neurology, Case-Control Studies, Microsatellite, Neurology (clinical), Pooled dna, France, Microsatellite Repeats
Abstract

We report the results of a genome-wide screen for linkage disequilibrium (LD) in multiple sclerosis (MS) performed on 200 cases, 200 controls and 200 case–parent trios from France employing pooled DNA methodology. A total of 3510 microsatellite markers supplied through the GAMES collaborative were analysed and ranked according to their evidence for association. The most promising 117 markers were then followed up in a two-step validation process. In the first step, additional PCR of the DNA pools was performed in order to refine the ranking order. In the second step, markers were genotyped in individual cases and parents from the trio families. Seven markers showing nominally significant allele frequency differences between affected and unaffected emerged—D6S265, D12S1064, TNFa, D7S1824, D14S1426, D14S605 and D21S2051. These potential associations will require confirmation in further studies.

Published
2003

22. Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients

Author

Michel Clanet, Erwann Quelvennec, Emmanuelle Génin, Gilles Edan, Françoise Clerget-Darpoux, J. Yaouanq, Héloise Bougerie, Berta Martins Silva, Marie Claude Babron, Patrícia Maciel, Mehdi Alizadeh, Patricia Momigliano-Richiardi, Gilbert Semana, Roland S. Liblau, Maria Trojano, Brigitte Birebent, Bertrand Fontaine, Jorge Sequeiros, Alexandre Vasilescu, Isabelle Cournu-Rebeix, Fumihiko Matsuda, and Universidade do Minho

Subjects
Immunoconjugates, Multiple Sclerosis, Medicina Básica [Ciências Médicas], Immunoblotting, Disease, Major histocompatibility complex, Polymerase Chain Reaction, Abatacept, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Antigen, Antigens, CD, Genetic predisposition, medicine, Cytotoxic T cell, Humans, CTLA-4 Antigen, Genetic Predisposition to Disease, Promoter Regions, Genetic, 030304 developmental biology, DNA Primers, HLA-DR Serological Subtypes, 0303 health sciences, Science & Technology, Polymorphism, Genetic, biology, Multiple sclerosis, Haplotype, HLA-DR15, HLA-DR Antigens, medicine.disease, Antigens, Differentiation, 3. Good health, Neurology, Ciências Médicas::Medicina Básica, Immunology, biology.protein, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119-122, Fondation pour la Recherche Médicale (ARS 2.09 Bertrand Fontaine), by Association pour la Recherche sur la Sclérose en Plaques, by Italian Foundation for Multiple Sclerosis, by INSERM, and by the French Ministry of Research (Centre d'Investigations Cliniques Pitié‐Salpétrière and Centre de Resources Biologiques)

Published
2003

23. Familial screening for genetic haemochromatosis by means of DNA markers

Author

M. Perichon, Véronique David, Martine Blayau, A. El Kahloun, Pierre Pontarotti, J.-Y. Le Gall, V. Mauvieux, J. Yaouanq, Michael J. Chorney, and Anne-Marie Jouanolle

Subjects
Genetic Markers, Male, Locus (genetics), Biology, HindIII, Genetics, medicine, Humans, Genetic Testing, Allele, Genetics (clinical), Hemochromatosis, Genetic testing, medicine.diagnostic_test, Histocompatibility Antigens Class I, Haplotype, DNA, medicine.disease, Pedigree, Genetic marker, biology.protein, Female, Restriction fragment length polymorphism, DNA Probes, Polymorphism, Restriction Fragment Length, Research Article
Abstract

Genetic haemochromatosis (HFE) is a frequent and potentially fatal disease. Early phlebotomies may prevent complications. The recessive gene for HFE is unknown but closely linked to the HLA-A locus. No direct test for homozygosity for HFE is currently available, apart from HLA typing within the family of a patient with confirmed HFE. During a reverse genetic approach to identify the gene, we found three anonymous genomic probes (P3, P5, and I.82) derived from previously cloned YACs and physically mapped in the HLA class I region. P3 and P5 probes recognise 3 loci (P3A, P3B, P5) and I.82 one locus about 100 kb from HLA-A. Using five biallelic polymorphisms (I.82/BglII, P3B/EcoRV, P3B/PstI, P5/HindIII, P3A/PstI), we tested 198 HLA typed subjects from the families of 22 haemochromatosis patients. The information from the five polymorphisms was sufficient to identify unequivocally extended restriction haplotypes in all families. The restriction haplotypes cosegregate with the HFE allele and enable identification of genotypically identical sibs in all families studied. The linked DNA markers described in this article avoid the disadvantages of HLA serological typing and can be used in genetic counselling of HFE families.

Published
1992
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25. Familial factors influence disability in MS multiplex families. French Multiple Sclerosis Genetics Group

Author

D, Brassat, C, Azais-Vuillemin, J, Yaouanq, G, Semana, J, Reboul, I, Cournu, C, Mertens, G, Edan, O, Lyon-Caen, M, Clanet, and B, Fontaine

Subjects
Adult, Male, Disability Evaluation, Multiple Sclerosis, HLA Antigens, Humans, Female, Age of Onset
Abstract

Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease.To determine the contribution of familial factors to the clinical expression of MS.The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features).The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03).This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

Published
1999

26. Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis

Author

M N Bonnard, Y. Pawlotsky, Pascal Guggenbuhl, J Yaouanq, Gilbert Semana, Aleth Perdriger, E Quelvennec, Gérard Chalès, Centre Hospitalier Universitaire [Rennes], Service de Neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Microenvironnement et cancer (MiCa), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
medicine.medical_specialty, Linkage disequilibrium, Genotype, HLA-DM, Human leukocyte antigen, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Rheumatology, Internal medicine, medicine, Humans, Pharmacology (medical), Allele, Allele frequency, Alleles, ComputingMilieux_MISCELLANEOUS, DNA Primers, 030304 developmental biology, HLA-D Antigens, 0303 health sciences, business.industry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Histocompatibility Testing, Histocompatibility Antigens Class II, HLA-DR Antigens, 3. Good health, Genotype frequency, Endocrinology, HLA-DMB, Immunology, Disease Susceptibility, business, 030215 immunology
Abstract

Objective. HLA DM is a non-classical major histocompatibility complex (MHC) class II molecule that has been shown to facilitate peptide loading with classical class II molecules. Methods. In this study, we analysed the polymorphism in exon 3 of HLA DMA and DMB genes by a polymerase chain reaction-sequence-specific oligonucleotide probe method in 163 rheumatoid arthritis (RA) patients and 146 ethnically matched controls. The HLA-DRBI genotype was also analysed by a reverse-dot blot method. Results. Our results show in RA patients a significant increase in the HLA DMB * 0101 allele frequency (83% vs 72.3% of the controls, P < 1.6 x 10 -3 , significance at P < 0.0125) and in the HLA DMB * 0101-0101 homozygote genotype frequency [70.8% vs 50% of the controls, P < 4.2 x 10 -4 , significance at P < 0.00625, odds ratio (OR) = 2.4, 95% confidence interval (CI): 1.43-4]. The increase in DMB * 0101 allele and homozygote genotype frequencies was independent of a linkage disequilibrium between DMB and DRB1 alleles. The analysis of non-random associations between the HLA-DM and DRB1 alleles only revealed a significant association in controls between DMB * 0104 and DRB1 * 07 alleles (Δ = 0.01, P < 7 x 10 -4 , significance at P < 9.6 x 10 -4 ). On the other hand, the DMB * 0101-0102 genotype frequency was increased in DRB1 * 0401-negative RA patients as compared to controls (11% vs 2%, P < 0.011, significance at P < 0.015, OR = 6.2, 95% CI: 1.2-30). Conclusion. Our data suggest that HLA-DM alleles could play a role in the genetic susceptibility to RA.

Published
1999
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27. [Should we screen for hemochromatosis? Critical analysis of the literature]

Author

S, Charvet-Protat, J, Yaouanq, and F, Fleurette

Subjects
Male, Cost-Benefit Analysis, Incidence, Middle Aged, Sensitivity and Specificity, Community Health Planning, Population Surveillance, Prevalence, Humans, Mass Screening, Female, Hemochromatosis, Public Health, Morbidity
Abstract

This paper focus on the main issues to evaluate before planning public health interventions which may optimise the prevention of hemochromatosis. The main indicators are considered: prevalence, morbidity and mortality of the disease, efficacy of the available treatment, sensitivity, specificity and predictive values of the screening tests; potential benefit of a national screening program in a public health perspective. These are evaluated through a critical appraisal of the clinical, epidemiologic and economic literature on hemochromatosis. The paper emphasizes how individual behavior and preferences become crucial to take into account when well-being subjects will face a population-based screening program. We conclude that further arguments are required before the implementation of a national screening program for hemochromatosis.

Published
1998

28. Significance of interleukin-1beta and interleukin-1 receptor antagonist genetic polymorphism in inflammatory bowel diseases

Author

D, Heresbach, M, Alizadeh, A, Dabadie, N, Le Berre, J F, Colombel, J, Yaouanq, J F, Bretagne, and G, Semana

Subjects
Adult, Male, Polymorphism, Genetic, Crohn Disease, Humans, Colitis, Ulcerative, Female, Receptors, Interleukin, Inflammatory Bowel Diseases, Severity of Illness Index, Alleles, Interleukin-1
Abstract

Genetic susceptibility to inflammatory bowel disease is well recognized. There is also increasing evidence for the activation of the mucosal immune system and the production of inflammatory cytokines, i.e., interleukin (IL)-1ra and IL-1beta in the inflammatory bowel disease. The aim of this study was to analyze the IL-1beta and IL-1ra gene polymorphism and linkage disequilibrium coefficient between the different alleles of these genes in patients with Crohn's disease (CD) or ulcerative colitis (UC), according to the severity of the disease.Two hundred twenty-eight inflammatory bowel disease patients (87 UC and 141 CD) were included in this study and compared with 113 unrelated controls. The IL-1beta and IL-1ra gene polymorphism was studied after specific amplification of variable regions by PCR. A penta-allelic polymorphism, corresponding to a VNTR region located in intron 2 of the IL-1ra gene, was analyzed, whereas bi-allelic RFLPs displayed by two restriction enzymes (TaqI and AvaI) at position -511 of the IL-1beta gene were analyzed.There was no significant difference of genotype distribution between controls and CD or UC patients. However, surgically treated UC patients were characterized by a higher frequency of genotype IL-1ra 1-2 (39 vs 16%, pc0.01) compared with nonoperated UC patients. Moreover, nonoperated UC patients displayed a lower frequency of IL-1ra allele 2 than surgically treated UC patients (14 vs 34%, pc0.002) or controls (14 vs 30%, pc0.005). Furthermore, simultaneous analysis of the IL-1beta and IL-1ra genes that are located in the same region of chromosome 2 revealed that CD patients carrying the IL-1beta allele 2 were more often noncarriers of IL-1ra allele 2 (p0.005). Moreover, UC and CD patients were, characterized by a lower frequency of the association of IL-1ra allele 2 and IL-1beta allele 2 compared with controls (8.3 vs 20.3% and 10.6 vs 20.3%, p0.03).IL-1ra and IL-1beta gene polymorphism analysis from a clinical standpoint might help in defining UC prognosis. However, functional studies at both the circulating and mucosal level with stratification on allele associations, especially IL-1ra allele 2-IL-1beta allele 2 subgroups must be realized before therapeutic implications.

Published
1997

29. Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE)

Author

Véronique David, V. Mauvieux, Anne-Marie Jouanolle, J. Le Gall, G. Gandon, Bruno Chauvel, A. Le Treut, Josué Feingold, and J. Yaouanq

Subjects
Genetic Markers, Male, Linkage disequilibrium, Positional cloning, Population, Molecular Sequence Data, Genes, MHC Class I, Biology, Polymerase Chain Reaction, Linkage Disequilibrium, Gene mapping, Genetic linkage, Genetics, Humans, Family, education, Genetics (clinical), DNA Primers, education.field_of_study, Polymorphism, Genetic, Base Sequence, HLA-A Antigens, Haplotype, Chromosome Mapping, Pedigree, Haplotypes, HLA-B Antigens, Microsatellite, Chromosomes, Human, Pair 6, Female, Hemochromatosis, Restriction fragment length polymorphism
Abstract

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with the HLA Class I genes. Linkage disequilibrium (LD) studies were designed to narrow down the most likely candidate region for HFE, as an alternative to traditional linkage analysis. However, both the HLA-A and D6S105 subregions, which are situated 2-3 cM and approximately 3 Mb apart, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and normal chromosomes from 66 families of Breton ancestry. In addition to the previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our combined data not only confirm a peak of LD at D6S105, but also reveal a complex pattern of LD over the i82 to D6S105 interval. Within our ethnically well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers display a lower LD. Fine haplotype analysis enabled us to identify two categories of haplotypes segregating with HFE. In contrast to the vast majority of normal haplotypes, 50% of HFE haplotypes are completely conserved over the HLA-A to D6S105 interval. These haplotypes could have been conserved through recombination suppression, selective forces and/or other evolutionary factors. This particular haplotypic configuration might account for the apparent inconsistencies between genetic linkage and LD data, and additionally greatly complicates positional cloning of HFE through disequilibrium mapping.

Published
1996

30. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging

Author

Pierre Brissot, Yves Deugnier, J. Yaouanq, Yves Gandon, M. Carsin, J. F. Heautot, M I Reda, T. Buhe, and Dominique Guyader

Subjects
Male, Liver Iron Concentration, medicine.diagnostic_test, business.industry, Iron, Magnetic resonance imaging, Middle Aged, medicine.disease, Mr imaging, Magnetic Resonance Imaging, Sensitivity and Specificity, Liver, Liver biopsy, Liver tissue, medicine, Liver iron, Humans, Radiology, Nuclear Medicine and imaging, Female, Hemochromatosis, Prospective Studies, Nuclear medicine, business, Gradient echo
Abstract

To assess the role of magnetic resonance (MR) imaging in detection and quantification of liver iron overload.MR imaging at 0.5 T was prospectively performed on 77 patients (67 with liver iron overload and 10 without) who underwent a liver biopsy with biochemical determination of the liver iron concentration (LIC) (normal,36 mumol per gram of liver tissue [dry weight]). Ratios of signal intensities and liver T2 relaxation time were calculated from images obtained with spin-echo and breath-hold gradient-echo (GRE) sequences.Liver-to-tissue signal intensity ratios were better correlated with LIC than T2 relaxation time. Long-echo-time GRE sequences were the most sensitive for detection of slight overload. Thus, high sensitivity (94%) and specificity (90%) were obtained with a liver-to-fat ratio threshold of 1. The quantification of iron with MR imaging was accurate when the LIC was 80-300 mumol/g. For heavy overload, above 300 mumol/g, quantification was impossible owing to complete signal loss. Pancreatic and splenic signal intensity were unchanged in most cases.This method, which can be improved by using more sensitive sequences with a high-field-strength system, should be competitive with biopsy for the diagnosis of substantial liver iron overload.

Published
1994

31. [Molecular genetics of hemochromatosis]

Author

J Y, Le Gall, V, David, J, Yaouanq, M, Périchon, M, Blayau, A M, Jouanolle, V, Mauvieux, A, el Kahloun, B, Chauvel, and I, Dorval

Subjects
Polymorphism, Genetic, Genetic Carrier Screening, Histocompatibility Antigens Class I, Chromosome Mapping, Polymerase Chain Reaction, Linkage Disequilibrium, Gene Frequency, HLA Antigens, Chromosome Inversion, Humans, Hemochromatosis, Cloning, Molecular, Molecular Biology, HLA-A1 Antigen
Abstract

Haemochromatosis is an inherited disorder of iron metabolism characterized by a general iron over loading. Without diagnosis and early treatment, it is a serious and potentially fatal disease by cardiac failure or hepatocellular carcinoma in particular. Gene prevalence was estimated at 0.06 in Brittany, so that haemochromatosis may be the most common genetic disease in this area. The biochemical defect of the disease is unknown; only one fact is well established: the iron absorption through duodenal mucosa is excessive. However we don't know if it is a primary event. The gene is also unknown but in 1975 it was located on the short arm of chromosome 6, closely linked to the HLA class I region, less than 1 cM from HLA-A. None of the genes coding for the known iron proteins could be the haemochromatosis gene because of their chromosomal localization. In order to locate this gene with precision, we have used a reverse genetic approach now called positional cloning. Characterization of new polymorphic markers and linkage disequilibrium analysis, have led us to locate the gene within a 350 kb region around HLA-A. We have then searched for all the structural genes in this region. Seven new genes have been so identified and located with precision. A structural analysis of these genes was undertaken to find an eventual abnormality in patients.

Published
1993

32. Percent transferrin saturation in segregating hemochromatosis

Author

J. M. Lalouel, Ingrid B. Borecki, D. C. Rao, and J. Yaouanq

Subjects
Genetics, chemistry.chemical_classification, Adult, Male, Transferrin saturation, Genetic Carrier Screening, Homozygote, Transferrin, Heterozygote advantage, Disease, Genetic hemochromatosis, Biology, medicine.disease, Phenotype, Pedigree, chemistry, medicine, Humans, Female, Hemochromatosis, Genetics (clinical)
Abstract

The segregation of genetic hemochromatosis was analyzed by using percent transferrin saturation (TS) as a phenotypic marker of the disease. Homozygotes for the disease were readily discernable with the added information provided by the quantitative indicator. However, there was no evidence of partial expression of TS abnormalities in heterozygotes, contrary to previous studies.

Published
1990

33. Serum ferritin as a marker of affection for genetic hemochromatosis

Author

Ingrid B. Borecki, J. M. Lalouel, D. C. Rao, and J. Yaouanq

Subjects
Adult, Genetic Markers, Male, Population, Physiology, Locus (genetics), Disease, Biology, Genotype, Genetics, medicine, Humans, education, Allele frequency, Genetics (clinical), Hemochromatosis, Aged, Aged, 80 and over, education.field_of_study, Middle Aged, medicine.disease, Ferritin, Phenotype, Genetic marker, Ferritins, biology.protein, Female
Abstract

A bivariate segregation analysis of genetic hemochromatosis with serum ferritin concentration was undertaken to examine the pleiotropic effect of the hemochromatosis locus on each of the two phenotypes, in an ascertained sample of families from Brittany, France. The gene was recessive with respect to both phenotypes, and the estimated gene frequency in the general population was 0.054. Although the ferritin concentration was corrected for the linear relationship with age among controls, there was a residual correlation with age among male family members, consistent with the progressive increase in body iron stores among hemochromatosis homozygotes. This genotype-specific relationship with age illustrates the importance of incorporating interaction effects into analytic models, and suggests that even as a better indicator of progress of disease, rather than liability to disease, serum ferritin concentration serves well to distinguish hemochromatosis homozygotes from alternate genotypes in a family study.

Published
1990

35. Haemochromatosis and HLA–H

Author

Gwenaelle Carn, Nancy Andrieux, Blayau M, David, Le Gall Jy, Campion Ml, Bruno Chauvel, Isabelle Gicquel, Patricia Fergelot, J. Yaouanq, G. Gandon, Pascal Jézéquel, Pascale Bouric, Jean Mosser, and Anne-Marie Jouanolle

Subjects
Text mining, business.industry, Genetics, Computational biology, Human leukocyte antigen, Biology, business, C282y mutation
Published
1996
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37. Familial factors influence disability in MS multiplex families

Author

B. Fontaine, C. Mertens, M. Clanet, J. Yaouanq, Olivier Lyon-Caen, J. Reboul, Gilles Edan, C. Azais-Vuillemin, David Brassat, Gilbert Semana, and I. Cournu

Subjects
medicine.medical_specialty, Pathology, Expanded Disability Status Scale, business.industry, Multiple sclerosis, Concordance, Human leukocyte antigen, Disease, medicine.disease, Central nervous system disease, Internal medicine, Epidemiology, medicine, Neurology (clinical), Sibling, business
Abstract

Background: Both genetic and environmental factors play a role in the pathophysiology of MS and may influence the clinical expression of the disease.Objective: To determine the contribution of familial factors to the clinical expression of MS.Methods: The French Multiple Sclerosis Genetics Group identified 87 sibling pairs. For each patient, sex, age at onset, duration of the disease, and disease course from onset were recorded. Disability was determined by the progression index (PI), defined as the ratio of the Expanded Disability Status Scale (EDSS) score disease duration when the latter exceeded 5 years. Statistical analyses were performed either with a group of patients (clinical features, relation between human leukocyte antigen and clinical features) or with a group of sibpairs (concordance for clinical features).Results: The mean age at onset was 29.6 years, the ratio of women to men was 59:28, and the mean PI was 0.27. There was no correlation for disease course and age at onset between sibs with MS. In contrast, we observed a weak but significant correlation of the PI in MS sibpairs (r = 0.234, p = 0.03).Conclusion: This study revealed a concordance in MS sibling pairs for the disease severity, supporting the hypothesis that the degree of disability might be partly influenced by familial factors (environmental or genetic).

Published
1999
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38. Interleukin-1 receptor antagonist gene in multiple sclerosis

Author

Mehdi Alizadeh, G. Semana, M. Clanet, J Yaouanq, and Gilles Edan

Subjects
Genetics, Proband, Candidate gene, Genetic linkage, Polymorphism (computer science), Immunology, Genetic predisposition, General Medicine, Odds ratio, Allele, Biology, Nuclear family
Abstract

1 reported a positive association between allele 2 of the interleukin-1 receptor antagonist (IL- 1ra) gene which maps to 2q13-14 and multiple sclerosis (MS). Our data, based on a larger set of cases and controls and on French MS families, lessen the strength of their argument favouring the IL-1ra gene as functionally important in the susceptibility to MS. In the course of a French collaborative research project on MS genetic susceptibility, our team also listed IL-1ra among candidate genes. We first investigated the penta-allelic polymorphism of the IL-1ra gene in 77 sporadic MS patients who originated from Brittany and 168 unrelated ethnically matched controls. Although homozygosity for allele 2 was two-fold higher in MS patients than in controls, the relative excess of patients carrying allele 2 yielded an odds ratio of only 1·18 (95% CI 0·77-2·13). Moreover, the frequency of allele 2 among MS patients was not significantly different from that observed in controls (38·9% vs 30·9%, χ 2 -test), leading to the conclusion that IL-1ra alleles and the disease were randomly associated. The discordant results reported by Crusius et al 1 prompted us to extend our work on IL-1ra by use of alternative methods based on family data rather than randomly ascertained cases and controls. Our second study focused on 92 unrelated nuclear families (47 from Brittany, and 45 from south-west France) ascertained for the presence of only one affected child who did not belong to the first group of 77 patients studied, and each consisting of the proband and his/her parents. The ascertainment scheme of the families allowed parental alleles not transmitted to the proband to be used as unbiased control alleles, whereas those inherited by the proband were considered as diseased alleles. 2

Published
1997
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39. Survie dans l'hémochromatose génétique: détermination des facteurs pronostiques indépendants chez 217 hommes bretons

Author

L. Campion, J. Chaperon, and J. Yaouanq

Subjects
Pathology, medicine.medical_specialty, Cirrhosis, Proportional hazards model, business.industry, Gastroenterology, Non alcoholic, Genetic hemochromatosis, medicine.disease, Fibrosis, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Alcohol intake, business
Abstract

Survival in genetic hemochromatosis was studied in 217 unrelated men from Brittanny (follow-up = 1 to 358 months). Not only cirrhosis but also fibrosis at diagnosis were significantly related to survival. Independent prognostic factors, determined by means of Cox model, were different with alcohol intake: in non alcoholic men, liver histological failure, myocardiopathy and age remained significant; in alcoholic men, only age and diabetes.

Published
1992
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40. Ferritin H gene polymorphism in idiopathic hemochromatosis

Author

M. Simon, Véronique David, Martine Blayau, J. Yaouanq, Panos Papadopoulos, J. Le Gall, J.W. Drysdale, E. Zappone, M. Perichon, and Laurent Abel

Subjects
Genetic Markers, Male, TaqI, EcoRI, Deoxyribonuclease HindIII, HindIII, chemistry.chemical_compound, HLA Antigens, Genetics, medicine, Humans, Genetics (clinical), Hemochromatosis, Polymorphism, Genetic, biology, Chromosome Mapping, Nucleic Acid Hybridization, DNA, medicine.disease, Molecular biology, Pedigree, Ferritin, Restriction enzyme, chemistry, Ferritins, biology.protein, Chromosomes, Human, Pair 6, Female, Restriction fragment length polymorphism, DNA Probes, Polymorphism, Restriction Fragment Length
Abstract

The authors studied the H ferritin restriction polymorphism in 83 hemochromatosis patients and 84 controls as well as in 19 nuclear families. No significant difference was found with the ten restriction enzymes used (HindIII, EcoRI, EcoRV, PvuII, BamHI, PstI, Bg/I, Bg/II, HincII, and TaqI). Hence, the genomic abnormality responsible for idiopathic hemochromatosis is not a major deletion of an H ferritin gene. A higher frequency of one HindIII fragment, although nonsignificant when the number of comparisons made is taken into account, was observed in the patients. This HindIII fragment hybridizes with the H ferritin probe and with a 28 S ribosomal probe, and its segregation with HLA haplotypes (hence its assignment to chromosome 6) is uncertain. Its possible meaning in the expression of the disease is discussed.

Published
1989
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41. Genetic hemochromatosis: Distribution analysis of six laboratory measures of iron metabolism

Author

Ingrid B. Borecki, D. C. Rao, L. le Mignon, M. Simon, J. M. Lalouel, and J. Yaouanq

Subjects
Male, Proband, Genetic Linkage, Iron, Locus (genetics), Deferoxamine, Biology, Sex Factors, HLA Antigens, Genetic linkage, Homoscedasticity, medicine, Humans, Genetics (clinical), Hemochromatosis, Genetics, chemistry.chemical_classification, medicine.diagnostic_test, Transferrin, medicine.disease, Ferritin, chemistry, Ferritins, Serum iron, biology.protein, Female, Software
Abstract

Six laboratory measures of iron metabolism were studied in a control sample, and a family sample was ascertained on the basis of probands with clinically diagnosed genetic hemochromatosis. The respective distribution of each variable evidenced a mixture of components, presumably arising from the segregation of an HLA-linked locus for hemochromatosis. There were significant differences in the distributional characteristics with respect to sex and genotype-specific variances. These aspects of the data have important implications for subsequent segregation and linkage analyses, which traditionally assume homoscedasticity and homogeneity of the genetic effect.

Published
1989
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42. [Heredity and genetics of hemochromatosis]

Author

J, Yaouanq

Subjects
Male, HLA-B7 Antigen, Heterozygote, Haplotypes, Genetic Linkage, HLA Antigens, Homozygote, Humans, Female, Hemochromatosis, HLA-A3 Antigen, Alleles, Pedigree
Published
1989

43. DNA polymorphism related to the idiopathic hemochromatosis gene: evidence in a recombinant family

Author

Daniel Cohen, M. Simon, Pascale Paul, Véronique David, Isabelle Gicquel, Renée Fauchet, Loïc Le Mignon, J. Le Gall, J. Yaouanq, Isabelle Dugast, and Michel Bourel

Subjects
Proband, Adult, Genetic Markers, Male, Genetic Linkage, EcoRI, Locus (genetics), HindIII, HLA Antigens, MHC class I, Genetics, medicine, Humans, Gene, Genetics (clinical), Hemochromatosis, Polymorphism, Genetic, biology, HLA-A Antigens, Chromosome Mapping, DNA, Middle Aged, medicine.disease, Molecular biology, Pedigree, EcoRV, biology.protein, Female, Polymorphism, Restriction Fragment Length
Abstract

The metabolic error involved in idiopathic hemochromatosis, as well as the underlying genetic defect remain unknown. It has, however, been recently shown that this genetic lesion occurs at a locus linked to the major histocompatibility complex, probably close to the HLA-A locus, and that the disease is recessively transmitted. Therefore, in a family where one subject has idiopathic hemochromatosis his HLA-identical siblings should also be affected. We present here the restriction polymorphism with two MHC class I probes and one DR beta probe in an exceptional family with three HLA-identical siblings: one (the proband) has a major form of idiopathic hemochromatosis, while the other two are free of any clinical or biochemical signs of the disease. The restriction patterns observed after DNA digestion by enzymes EcoRI, EcoRV, BglII, BamHI, PvuII, TaqI, HincII, and HindIII led to the conclusion that one of the proband's chromosome 6 had undergone two alterations: one, a deletion in the DR region, was revealed by missing fragments all correlated with DR5; the other was an unbalanced cross-over or a genetic conversion in the MHC class I region. This latter alteration was revealed by modifications in the patterns of high molecular weight HindIII bands which hybridize with probe pHLA2 and also by the absence of a HindIII fragment of 7.4 kb hybridized by another class I probe. This latter alteration most likely involved the hemochromatosis gene and could be the first step toward a molecular approach to this gene.

Published
1986

44. Genetics of hemochromatosis: HLA association and mode of inheritance

Author

Pierre Brissot, Michel Bourel, Renée Fauchet, J. Yaouanq, Marcel Simon, and Jean-Yves Le Gall

Subjects
Genetics, Genetic Markers, business.industry, Genetic Linkage, General Neuroscience, Chromosome Mapping, Genes, Recessive, Hla association, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Pedigree, Inheritance (object-oriented programming), History and Philosophy of Science, HLA Antigens, medicine, Humans, Disease Susceptibility, Hemochromatosis, business
Published
1988

45. Segregation of genetic hemochromatosis indexed by latent capacity of transferrin

Author

I B, Borecki, D C, Rao, J, Yaouanq, and J M, Lalouel

Subjects
Adult, Aged, 80 and over, Male, Models, Genetic, Transferrin, Middle Aged, Pedigree, Sex Factors, Humans, Female, France, Hemochromatosis, Aged, Probability, Research Article
Abstract

A genetic analysis of the segregation of hereditary hemochromatosis, indexed by the measurement of latent capacity of transferrin (LCAP), was undertaken in an ascertained sample of 147 pedigrees from Brittany, France. There were no mean differences by sex in the distribution of LCAP in the control sample, although in the family data there was a higher representation of males with low values than of females with low values, consistent with the higher proportion of affected males. The results of bivariate segregation analysis revealed no systematic evidence for heterozygous expression either in the biochemical domain of LCAP abnormalities or in increased liability to overt symptomatic disease. Joint consideration of the quantitative variable with hemochromatosis affection status allowed clear resolution of a recessive single-gene inheritance pattern in these families.

Published
1989

47. Hérédité et génétique de l'hémochromatose

Author

J. Yaouanq

Subjects
Genetics, medicine.medical_specialty, Genetic marker, Molecular genetics, Genotype, Gastroenterology, Internal Medicine, medicine, Biology, Phenotype
Abstract

A la lumiere du marquage HLA, le determinisme genetique de l'hemochromatose idiopathique a ete solidement precise conduisant a definir le concept d'hemochromatose genetique (HG), determinee par un gene recessif etroitement lie au locus HLA-A

Published
1989
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48. Small-area distribution of multiple sclerosis incidence in western France: in search of environmental triggers.

Author

Hammas K, Yaouanq J, Lannes M, Edan G, and Viel JF

Subjects
Adult, Female, Follow-Up Studies, France epidemiology, Humans, Incidence, Male, Middle Aged, Multiple Sclerosis diagnosis, Registries, Environmental Exposure adverse effects, Geographic Mapping, Multiple Sclerosis epidemiology
Abstract

Background: Despite intensive research over several decades, the etiology of multiple sclerosis (MS) remains poorly understood, although environmental factors are supposedly implicated. Our goal was to identify spatial clusters of MS incident cases at the small-area level to provide clues to local environmental risk factors that might cause or trigger the disease., Methods: A population-based and multi-stage study was performed in the French Brittany region to accurately ascertain the clinical onset of disease during the 2000-2004 period. The municipality of residence at the time of clinical onset was geocoded. To test for the presence of MS incidence clusters and to identify their approximate locations, we used a spatial scan statistic. We adjusted for socioeconomic deprivation, known to be strongly associated with increased MS incident rates, and scanned simultaneously for areas with either high or low rates. Sensitivity analyses (focusing on relapsing-remitting forms and/or places of residence available within the year following clinical onset) were performed., Results: A total of 848 incident cases of MS were registered in Brittany, corresponding to a crude annual incidence rate of 5.8 per 100,000 inhabitants. The spatial scan statistic did not find a significant cluster of MS incidence in either the primary analysis (p value ≥ 0.56) or in the sensitivity analyses (p value ≥ 0.16)., Conclusion: The findings of this study indicate that MS incidence is not markedly affected across space, suggesting that in the years preceding the first clinical expression of the disease, no environmental trigger is operative at the small-area population level in the French Brittany region.

Published
2017
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49. Register-based incidence of multiple sclerosis in Brittany (north-western France), 2000-2001.

Author

Yaouanq J, Tron I, Kerbrat A, Leray E, Hamonic S, Merienne M, Hinault P, and Edan G

Subjects
Adult, Age Distribution, Female, France epidemiology, Humans, Incidence, Male, Middle Aged, Registries, Sex Distribution, Multiple Sclerosis epidemiology
Abstract

Objectives: To report on multiple sclerosis (MS) incidence in Brittany, north-western France., Materials & Methods: From 2000, we set up a population-based register for patients presenting a putative incident MS (PIMS), that is first symptoms compatible with MS onset. We used 3 medical sources of case ascertainment (neurologists, CSF, regional MS-Clinic). Eligibility criteria required both clinical onset and being permanent resident of Brittany in 2000 or 2001. From 2010, all medical records were tracked, the 10-year follow-up allowing previously reported data to be updated., Results: Of 313 eligible PIMS, there were 208 definite MS (both McDonald and Poser criteria), 41 CIS-probable MS (Poser criteria), 32 CIS-possible MS and 32 non-MS. Our incident cohort of 249 MS cases with definite/probable MS (sex ratio 2.95) gave a crude annual incidence of 4.28 per 100,000 inhabitants (6.22 for women, 2.23 for men), and age-standardized rates (adjustment to the European population) of 4.41 [3.32-5.51], 6.68 [4.75-8.60], and 2.21 [1.12-3.31], respectively. Age-specific rates by gender and initial course showed that attack onset MS peaked at 25-29 years and progressive onset MS at 40-44 years in women (20-24 years and 45-49 years in men, respectively)., Conclusions: Brittany is confirmed a high-risk region for MS. Our data show marked differences in sex-specific pattern of MS incidence by clinical course and point out 25- to 29-year-old women as having the highest MS risk. While temporal variations cannot be excluded, comparison with overall French data suggests that other factors rather than latitude may influence the MS risk in France., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2015
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50. Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients.

Author

Kerbrat A, Hamonic S, Leray E, Tron I, Edan G, and Yaouanq J

Subjects
Adolescent, Adult, Aged, Child, Female, Follow-Up Studies, Humans, Male, Middle Aged, Prognosis, Recurrence, Time Factors, Young Adult, Disease Progression, Multiple Sclerosis, Chronic Progressive diagnosis, Multiple Sclerosis, Relapsing-Remitting diagnosis
Abstract

Background and Purpose: Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort., Methods: A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected., Results: In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6., Conclusion(s): Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive-onset MS group. This finding impacts the prognosis given to patients in clinical practice., (© 2014 EAN.)

Published
2015
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