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Public health and molecular epidemiology of aging-related diseases

The research objective of our unit is to improve the knowledge on the impact of environmental and genetic factors, as well as their interactions, on the occurrence, the evolution and management of age-related diseases in humans. Two large pathologies are studied: the cardiovascular and neurodegenerative diseases. Those research topics are approached thanks to the existing know-how in epidemiology and molecular biology inside our unit, integrating recent advances in high-throughput genomic, transcriptomic, proteomic and bioinformatic areas. ..

Our project has three tight topics :

  • 1.Public health and epidemiology of cardiovascular diseases,
  • 2.Identification of the molecular determinants of cardiovascular diseases with proteomic analysis and candidate gene approaches,
  • 3.Identification of the molecular determinants of neurodegenerative diseases using transcriptomics analysis and candidate gene approaches.


Our work should allow the discovery of new concepts in age-related diseases. The analysis of trends of cardiovascular diseases will allow to estimate their impact in public health. The identification of proteic markers will favour the development of better targeted prevention policies. The study of original candidate genes and gene-environment interactions will initiate the discovery of new physiopathological mechanisms and will supply targets for new treatments. The close links existing, at the molecular level, between the vascular risk and neurodegenerative risk should lead to the design of new concepts to classify diseases. The knowledge generated by this molecular epidemiology approach will provide new interpretation of the determinism of multi-factorial chronic diseases.


Our research project is structured around three topics corresponding each to a team working in close and permanent cooperation with one another, both in terms of concepts and techniques :

Topic 1 : Public health and epidemiology of cardiovascular diseases


altThe objectives of this team are to assess vascular risks in the population and analyse their impacts on the occurrence of cardiovascular diseases. The methods are descriptive and analytical epidemiology. The morbidity register of ischemic heart diseases in the Urban Community of Lille is at the heart of this activity. This register works, in close cooperation with the two other French registers (Bas-Rhin & Haute-Garonne) and with other registers from the MONICA programme (Belfast, Augsbourg, Barcelona…) allowing to draw a European picture of coronary heart disease. In the past years, the developments of new treatments and medications radically changed the prognosis of cardiovascular diseases, including coronary affections. The increased life expectancy of coronary patients eventually will favour an increase prevalence of heart failure in Western populations. These trends require enhanced monitoring so as to guarantee continuity and homogeneity in the production of epidemiological indicators. A new population-based study using a representative sample has been planned. Care practices and treatments given in the acute stage of myocardial infarction are being collected for detailed analyses. In terms of analytical epidemiology, we are working on various case control and cohort studies, including, in particular, the PRIME cohort study which reached 10-year monitoring. The certification of cases is underway and will significantly enhance the statistical power of this study. A thorough analysis of the traditional risk factors of cardiovascular diseases will be developed through the study of overweight, obesity and diabetes, as well as nutritionnal factors, both on a descriptive and analytical level and genetic and molecular level. A number of regional and European research programmes in genetic epidemiology on obesity in adults and children are underway. A special approach to the concentration of such risk factors around the metabolic syndrome in particular will be pursued. Logistic resources provided by the Centre of Biological Resources and the high throughput genomics platform of the Genopole will provide the opportunity of analysing the impact of new genetic susceptibility factors derived from the work of the 2 other teams, and of checking the impact of those derived from physiopathological knowledge in each study.


Topic 2 : Identification of the molecular determinants of cardiovascular diseases with proteomic analysis and candidate gene approaches


altThe opportunities offered by the high technology platforms have led us to develop an original candidate gene research strategy on the basis of differential proteomics analysis. Research projects are performed in close cooperation with cardiologists enabled us to build clinical studies to collect biological samples adjusted to such approaches. Three pathological cardiovascular fields were selected - abdominal aorta aneurysms, myocardial infaction in young subjects and heart failure. The strategy consists in comparing the proteome of cells and/or plasma from patients suffering from such affections to that of cells in unaffected subjects. The cells used for such comparisons are macrophages and smooth muscle cells. Bi-dimensional analysis and protein chip technologies are used associated with bioinformatic analysis and mass spectrometry to identify proteins selected. This approach has already been validated and the first maps of the proteome of human macrophages and smooth muscle cells have been published. This team also makes adjustments to proteomics techniques so as to increase their sensitivity and be able to analyse proteome on reduced quantities of tissues (2D-DIGE), or even directly on plasma or serum. Several clinical protocols have been dedicated to these projects (LILAS, CORONA for abdominal aorta aneuryms, YAMIP for myocardial infarction in young subjects, PTHF for chronic heart failure and REVE1 and REVE 2 for left ventricular remodeling after myocardial infarction). This work should allow to set up an early screening of patients predisposed to the different cardiovascular pathologies studied.


Topic 3 : Identification of molecular determinants of neurodegenerative diseases using transcriptomics analysis and candidate gene approaches


The study of the common determinants of cardiovascular diseases and dementias enabled us to gather original hypothesis on both these affections. However, the discovery of new candidate genes for dementias, despite the identification of chromosomal regions of interest by positional cloning, progresses rather slowly. Indeed, these regions are still large and the number of genes within these areas is very important. This is why we have devised a strategy to couple information derived from such screenings with functional data. A DNA chip was designed on the basis of the prediction of all genes present in targeted chromosomal regions. A differential transcriptomics analysis was made on banks of brains taken from patients affected by definite Alzheimer's disease compared with healthy brains from control subjects. At the same time, Affymetrix pangenomic chips were used on the same tissues. Heavy work consisting in the utilisation of such data using bioinformatics before and after such experiments is being carried out in our unit. The comparison of these data should enable us to evidence a number of candidate genes in chromosomal regions of interest and focus more rapidly on new candidate genes. After these genes have been selected, a systematic search for polymorphisms will be made. The impact of targets so identified will be assessed in other types of neurodegenerative diseases : fronto-temporal dementia, Lewy body diseases, Sporadic Parkinson disease. Finally, we will also explore the impact of these factors in subjects suffering from slightly impaired cognitive functions. These studies should enable us to predict what genetic factors favour a conversion to dementia. Collaborative work with an American team (through a request for a NIH grant) and European teams are pending, in order to ensure independent international analyses in large samples of population. The impact of candidate genes so identified will be examined in epidemiological studies defined in team 1 and team 2 on vascular risk. Under such circumstances, the DNA chip bringing together genes involved in remodelling will also be used on brains.

Tasks performed by all three teams are closely connected and new knowledge generated by them will provide new interpretation of the determinism of multi-factorial chronic diseases. Expected results fall in line with three major directions, which were integrated to provide new concepts in the approach to the prevention and treatment of diseases related to aging, and therefore meet INSERM objectives in terms of Public Health, Physiopathology and Therapeutics :

1. The analysis of trends in cardiovascular diseases, the development of vascular imaging and the finding of proteic markers will make it possible to apprehend the impact of these affections and implement better targeted prevention policies.

2. Evidencing gene-environment interactions and original candidate genes will make it possible to discover new physiopathological mechanisms and put forward targets for new treatments.

3. The close links which exist between the vascular risk and neurodegenerative risk on a molecular level should lead to the design of new concepts to classify diseases.

 

Laboratory’s name
Public health and molecular epidemiology of aging-related diseases
Head of the lab
Philippe Amouyel, Jean-Charles Lambert
Contact DN2M
Jean-Charles Lambert
Email
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Telephone
+33 3 20 87 77 10
Address
UMR744 - Institut Pasteur de Lille, 1 rue du Professeur Calmette - BP 245 59019 Lille cedex
Website

http://www.pasteur-lille.fr/fr/recherche/u744