Institut Pasteur de Lille

The Institut Pasteur de Lille (IPL) is a state-approved private foundation created in 1898 with a mission to improve public health through better knowledge of human diseases mechanisms and risk factors.

The research team participating in this proposal has been operating at the Institut Pasteur de Lille for 15 years and was formally established in 2006 as Inserm UMR 1167, entitled “Risk factors and molecular determinants of aging-related diseases”. Its accreditation was renewed in 2010 and 2014. The research unit is dedicated to the identification and analysis of the impact of the main aging-related vascular and neurodegenerative diseases using epidemiological, molecular and cellular biology-based methods.

The unit’s work is focused on two major disease areas related to aging; cardiovascular disease and neurodegenerative disease, with a focus on coronary heart disease, cerebrovascular disease and Alzheimer's disease. The overall goal is to identify the environmental determinants and individual susceptibility factors by taking account demographic variables and the main clinical and biological confounding factors, and to dissect, for some of them, their molecular impacts. The unit’s scientific objectives are: (1) identify environmental and genetic susceptibility factors for age-related diseases and characterize their impact on the occurrence and progression of these conditions, (2) improve our knowledge of the underlying disease mechanisms by developing molecular and cellular explorations of these determinants and (3) design and develop, based on this knowledge, new strategies for the diagnosis, prognosis, prevention and management of these diseases.

Role in CoSTREAM

In this project, IPL will be involved the work package on clinical prediction (Work Package 5). Data from a French prospective cohort study will be used to replicate main results from the other work packages using data from genomics, metabolomics, brain MRI and cognitive tests. Risk prediction tools will then be derived from those results. To that end, IPL will also coordinate efforts to measure data used by the other work packages that are not currently available in IPL’s study.

Inserm UMR 1167 specializes in the conduct and analysis of epidemiological and genetic studies and has acquired the expertise necessary to analyze and interpret large volumes of data in the field of Alzheimer's disease and cerebrovascular diseases thanks to the involvement in genome-wide association studies (GWAS). This experience has led a major global collaboration (the International Genomics Alzheimer’s Project (I-GAP)) allowing to perform the largest ever GWAS meta-analysis in this field on 74,046 individuals.

Given the large number of epidemiological studies that IPL is developing, a Biological Resource Center (BRC) was created that has developed expertise in the management of very large biological databases. The biological and genetic features of these resources are either characterized within the unit itself or out-sourced to high-throughput platforms in the region or elsewhere in France or abroad.

As such, IPL is confident that the experience and expertise in setting up epidemiological studies, managing biological samples and analyzing data will match the tasks of the present project.

Key staff

Prof. Philippe Amouyel is the Director of UMR1167 Inserm, Univ Lille, IPL and Director of Excellence Laboratoty Distalz. Trained as hospital medical resident in Neurology, Philippe Amouyel, MD, PhD, is Professor of Epidemiology and Public Health at the University Hospital of Lille. Since 1998, he heads a research unit of 50 persons dedicated to the public health and the molecular epidemiology of age-related diseases . Part of its work is devoted to cardiovascular diseases and to the understanding of their multiple determinants. The other part of his research focuses on the study of the determinants, mainly genetic, of neurodegenerative diseases associated with cognitive decline and Alzheimer's disease in particular. Since 2012 he obtained an excellence laboratory from the government, named Distalz that brings together seven of the very best French research teams whose objective is the development of innovative strategies for transdisciplinary approach to Alzheimer's disease. He published more than 600 articles and participated in the discovery of 20 confirmed genetic locus predisposing to sporadic Alzheimer’s disease. He headed from 2002 to 2011 the Pasteur Institute of Lille, a non-profit foundation dedicated to the improvement of the health of man and his environment. Since 2008, he heads the National Foundation for Scientific Cooperation on Alzheimer's disease and related disorders that participated to the implementation of the research measures of the French Alzheimer Plan 2008-2102. This non-profit foundation dedicated to Alzheimer's disease and related disorders research, thanks to several partnerships, funds and supports research programs from basic research to social and health care research, including clinical and translational research. At the European level, Philippe Amouyel chairs the European Joint Programming Initiative on research on neurodegenerative diseases and Alzheimer’s in particular (JPND) that groups 28 countries including Canada and whose main objective is to combine the strengths of European and global research to tackle more efficiently these diseases.

Dr. Vincent Chouraki PhD is a post-doctoral fellow in the Inserm research unit 1167 “Risk factors and molecular determinants of aging-related diseases” at Institut Pasteur de Lille, France. He has a longstanding interest in classical and genetic epidemiology of Alzheimer's disease and related endophenotypes derived from brain MRI, cognitive tests and plasma samples.

Since 2008, he has been a key collaborator of several international genetic consortia: European Alzheimer's Disease Initiative (EADI), International Genomics of Alzheimer's Project (IGAP) and Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE).

Throughout his career, he has developed skills to analyze large volume of genetic data and evaluate the incremental value of genetic risk scores and plasma biomarkers to improve Alzheimer's disease risk prediction. In this context, he has recently published a study using plasma amyloid β levels to predict risk of Alzheimer's disease and dementia (Chouraki et al. Alzheimers Dement 2014) and presented results on a genetic risk score for Alzheimer's disease risk prediction at the Alzheimer's Association International Conference 2014.

This background puts him in a unique position to meet the goals and deliverables of the work package 5 of this program.

Céline Bellenguez, PhD is a tenured researcher (CR2) at Inserm Unit UMR-1167 (formerly UMR-744), Institute Pasteur of Lille, University Lille 2, with an expertise in statistical genetics and genetic epidemiology. She has a theoretical background in statistics, which she began to apply to genetics during her PhD (2005-2008). Her focus was on developing new tools for linkage analysis of multifactorial traits in large and complex pedigrees from isolated populations. As a post-doctoral researcher at the Wellcome Trust Centre for Human Genetics, a research institute of the University of Oxford, she has then been working within the analysis group for genome-wide association studies (GWAS) being conducted as part of the Wellcome Trust Case Control Consortium 2 (2008-2011). In 2011, she received a post-doctoral funding from FRM (Fondation pour la Recherche Médicale) and joined Inserm UMR-744 to work on the genetic epidemiology of Alzheimer's disease. She has been recruited in October 2012 as a tenured researcher at Inserm UMR-744 and is working on the identification of variants associated with complex traits, focusing more particularly on traits linked to neurodegenerative and cardiovascular diseases, through the study of general and isolated populations.

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University of Bordeaux

The University of Bordeaux (UBx) is a multidisciplinary University counting about 50,000 students and 6,600 permanent staff, and including more than 5,000 international students. UBx is a dynamic university offering innovative educational programs (including 40 international master and doctorate programmes) and high level of research with an international scope (90 FP7 & H2020 projects, 12 joint laboratories). Its cutting-edge research activities are carried out in 80 research departments associated with major research bodies (CNRS, CEA, INSERM and INRA). UB is a top class education and research organisation (#208 in the Shanghai ranking and #3 in France), which has been recently rewarded the label “Campus of Excellence” by the French government.Within this frame, Public Health is one of the key excellent area and the U897 unit has built a strong expertise participating in large research projects funded by the French government (i-share cohort as PI; SYRIC BRIO on Cancer as head of a WP; the Labex Vaccine Research Institute as head of a division) and by the EC (FP6/FP7/H2020 projects: FRAILOMIC, EUROCOORD, CHAIN, NEAT,EYE-RISK and IMI2 EBOVAC) including one ERC Starting Project.

U897 has a unique position in France by its critical mass of researchers, the quality of its teams and researchers, and its backing by a teaching structure and training, the ISPED (Institut de santé publique et développement). The research topics covered by the research centre include Biostatistics, epidemiology of neurological diseases, aging, HIV infection and other infectious diseases, cancer, nutrition, prevention of traumas.

The Research Centre "Epidemiology and Biostatistics" (Unit U897 Inserm-University of Bordeaux, Director: Pr Christophe Tzourio) is structured around 7 labelled research teams, and 4 affiliated or emerging teams. They cover a wide range of domains (infectious diseases including HIV, neurology, oncology, trauma, mental health), determinants (social, environmental, nutritional, genetic), methods (biostatistics, psychology) and populations (youth, adults, seniors, general population, patients). There are close links with the hospital through the participation of several clinicians to research teams.

In 2015, the Centre comprises more than 270 people including 160 engineers and admin staff, 59 researchers and teaching researchers - 35 of which are accredited to direct research (HDR) - and about 40 PhD and master students. The researchers of the centre publish 250-300 articles per year in international journals. They have developed major cohorts (the Paquid and 3C cohorts in the older general population, the MeMento cohort on dementia, the more recent i-Share student cohort, the Aquitaine HIV cohort, etc.) and databases that provide experimental platforms for the study of diseases and their surveillance in populations.

The 3C study is an ongoing cohort study in the elderly that has started in 1999 and comprises more than 9000 community-based participants aged 65 yrs and over at baseline, with prospective surveillance of incident stroke and dementia, as well as extensive repeated cognitive testing. About 2000 brain MRIs have been performed (Dijon center), as well as genome-wide genotyping on an Illumina 610K chip and a biobank for most of the participants. Recently whole exome sequencing was performed in 500 3C-Dijon participants with brain MRI. Additional sequencing efforts are under way.

Role in CoSTREAM

UBx contributes expertise in stroke, dementia, and (genetic) epidemiology as well as MRI image analysis to various tasks of the project in Work Packages 1, 2, 5 and 6.

Key staff

Prof. Stéphanie Debette is professor of epidemiology and neurology (PU-PH) at UBx and INSERM Center UMR897, France, and adjunct associate professor in the department of neurology, Boston University School of Medicine, USA. She is a practicing neurologist and holds a master degree in statistical genetics and a PhD in Epidemiology. She co-authored 90+ peer-reviewed articles (first author papers in Nat Genet, BMJ, Lancet Neurol, Ann Neurol, Circulation; Google Scholar: H–index: 28, 3825 citations). She obtained a Fulbright fellowship, a Chair of Excellence from the French National Research Agency (ANR), and is member of a Leducq Transatlantic Network of Excellence on cerebral small vessel disease. Recently she obtained a European Research Council starting grant to study genetic determinants of early structural brain alterations. She is PI on a grant (ANR) aimed at using genetic markers of vascular risk factors as a tool to better understand their relationship with dementia in the community. Prof. Debette is an active member of the Cohorts of Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, the International Stroke Genetics Consortium (ISGC) of which she hosted the 16^th workshop, and coordinates the CADISP (Cervical Artery Dissection and Ischemic Stroke in young Patients) consortium.

Prof. Christophe Tzourio is professor of epidemiology and public health (PU-PH) at UBx and director of INSERM Center of UMR897. Prof. Tzourio co-authored 253 peer-reviewed articles (Web of Science H–index = 52, >13000citations) and is ranked in the top 1% of highly cited scientists by the ISI Web of Science in 'Neuroscience'. He was initially trained as a vascular neurologist and in 1994 became full time researcher with the INSERM. In 2005 he was appointed Director of a new research lab in neuroepidemiology (Inserm U708) in Paris and in 2013 director of the research center Inserm U897 in Bordeaux. He is currently PI of an ongoing population-based cohort study in >9000 elderly individuals, the 3C study, the main aim of which is to assess the importance of vascular factors in dementia. He is also PI of an ongoing blood pressure lowering trial aiming at reducing the burden of silent cerebral infarcts and therefore lowering the risk of cognitive decline, and PI of the i-Share study, an ongoing large student cohort aiming at studying students’ health as well as early determinants of common diseases occurring later in life. Prof. Tzourio a special interest for the consequences of blood pressure on the brain and particularly through the study of MRI small-vessels related brain lesions.