The main research areas of the team

For many years, the Gene-Environment Interactions in Cardiovascular Physiopathology (IGE-PCV) Unit has been focused on the epidemiological study of cardiovascular diseases which, after cancer, is the second major cause of death in France. Various risk factors underlie the development of cardiovascular disorders; some of these are clearly identified: for example, environmental factors (smoking, diet, physical inactivity); while others, genetic factors in particular, are unknown. UMR U1122; thus, the IGE-PCV unit is not only focused on highlighting these unknown factors, but also on the study of the complex mechanisms that combine environment and genetics in leading to the development of the pathology.
To this end, the team was able to support the scientific and technical developments in the field by implementing family-based designs based on the recruitment of the Stanislas Cohort, also by integrating advanced technologies and various approaches such as genome-wide association studies and did this immediately these were introduced.
Thus, the scientific project of the unit aims to elucidate, using a genetic epidemiology approach, the complex physiopathological mechanisms involved in the development of the cardiovascular pathologies that the unit's researchers propose to study, drawing on their experience in the field, with an integrated approach combining genetics, proteomics and transcriptomics of intermediate phenotypes of these pathologies.
The unit focuses on inflammation, a central mechanism with regard to the risk factors that are classical, but also suspected in cardiovascular disorders such as blood pressure, lipid metabolism, obesity and cell adhesion.
The strategy of the study is to integrate the specific methodologies of two complementary scientific approaches, specifically, the candidate gene approach and the genome-wide approach. The approach requires very broad biological collections on which confirmatory replication studies are carried out and, it is in this context that the unit has established collaborative networks by incorporating MAGIC (Meta-Analyses of glucose and insulin-related traits Consortium) in particular, and other national and international networks corresponding to the unit's researchers areas of expertise. These communities allow the replications studies required for a "translational" approach to be conducted, by bringing together the various disciplines and skills that the unit has at its disposal.

The following steps are taken for a given phenotype (or cluster of phenotypes):

  1. The determination of the genetic component influencing the inter-individual variability of the intermediary phenotype concerned.
  2. The research and characterisation of the biomarkers involved in the genetic heritability observed in the "candidate gene" (prior hypothesis) and "genome-wide association" (hypothesis-free) approaches.
  3. The determination of the influence of epistasis phenomena and gene-environment interactions.
  4. The research of functional genetic variants identified by transcriptomic-epigenetic approaches.
  5. The practical applications of the results in pharmacogenomics

This multidisciplinary approach is innovative since it allows the integration both of the family-based and multifactorial component of the cardiovascular disease and of the preventive and predictive character of the biomarkers identified.

This research program involves close collaboration between epidemiologists, biochemists, molecular biologists, geneticists, biostatisticians and clinicians as part of the structure of the unit and its network of collaborations



IGE-PCV «Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire»

Director Dr. Sophie VISVIKIS-SIEST, Director of INSERM Research
Université de Lorraine - Faculté de Pharmacie
30, rue Lionnois - 54000 NANCY

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  1. Debette S*, Visvikis-Siest S*, Chen MH, Ndiaye NC, Song C, DeStefano AL, Safa R, Azimi-Nezhad M, Sawyer D, Marteau JB, Xanthakis V, Siest G, Sullivan L, Pfister M, Smith H, Choi SH, Lamont J, Lind L, Yang Q, Fitzgerald P, Ingelsson E, Vasan RS, Seshadri S. Identification of cis and trans acting genetic variants explaining up to half the variation in circulating VEGF levels. Circ Res. 2011; 109(5): 554-63. *co-first authors
  2. Jacquemont S, Reymond A, Zufferey F,…, Ndiaye NC, Nordgren A, Pasquier L, Petit F, …, Van Binsbergen E, Van Der Aa N, Vincent-Delorme C, Visvikis-Siest S, …, Metspalu A, Scherer Sw, Stefansson K, Blakemore Ai, Beckmann Js, Froguel P. Reciprocal extreme BMI phenotypes associated with gene dosage at the 16p11.2 locus. Nature. 2011 Aug 31; 478(7367): 97-102.    
  3. El Shamieh S, Ndiaye NC, Stathopoulou M, Murray H, Masson C, Lamont J, FitzGerald PS, Benetos A, Visvikis-Siest S. Functional epistatic interaction between rs6046G>A in F7 and rs5355C>T in SELE modifies systolic blood pressure levels. PLoS ONE 2012;7(7):e40777.
  4. Froguel P*, Ndiaye NC*, Bonnefond A, Bouatia-Naji N, Dechaume A, Siest G, Herbeth     B, Falchi M, Bottolo L, Guéant-Rodriguez RM, Lecoeur C, Langlois MR, Labrune Y,     Ruokonen A, El Shamieh S, Stathopoulou MG, Morandi A, Maffeis C, Meyre D,     Delanghe JR, Jacobson P, Sjöström L, Carlsson LM, Walley A, Elliott P, Jarvelin MR, Dedoussis GV, Visvikis-Siest S. A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels. PLoS One. 2012; 7(3): e32327. *co-first authors.
  5. Bonnefond A*, Saulnier PJ*, Stathopoulou MG*, Grarup N**, Ndiaye NC**, Dechaume A, Roussel R, Lantieri O, Hercberg S, Balkau B, Hansen T, Pedersen O, Froguel P, Charpentier G, Marre M, Hadjadj S, Visvikis-Siest S. What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications? PLoS One 2013;8(2):e55921. *co-first authors, **co-second authors
  6. Stathopoulou MG*, Bonnefond A*, Ndiaye NC*, Azimi-Nezhad M, El Shamieh S, Saleh A, Rancier M, Siest G, Lamont J, Fitzgerald P, Visvikis-Siest S. A common     variant     highly associated with plasma VEGFA levels also contributes to the variation     of both     LDL-C and HDL-C. J Lipid Res. 2013;54(2):535-41. *co-first authors.
  7. Azimi-Nezhad M*, Stathopoulou MG*, Bonnefond A, Rancier M, Saleh A, Lamont J,Fitzgerald P, Ndiaye NC, Visvikis-Siest S. Associations of vascular endothelial growth factor (VEGF) with adhesion and inflammation molecules in a healthy population. Cytokine 61 (2013) 602-607. *co-first authors.
  8. Stathopoulou MG, Monteiro P, Shahabi P, Penas-Lledo E, El Shamieh S, Silva Santos L, Thilly N, Siest G, Llerena A, Visvikis-Siest S. Newly identified synergy     between Clopidogrel and calcium-channel blockers for blood pressure regulation possibly involves CYP2C19 rs4244285. Int J Cardiol. 2013 Oct 3; 168(3): 3057-8.
  9. Falchi M, El-Sayed Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-Assarsson JC, Sudmant PH, Dorajoo R, Al-Shafai Mashael Nedham, Bottolo L, Ozdemir E, So HC, Davies RW, Patrice A, Dent R, Mangino M, Hysi PG, Dechaume A, Huyvaert M, Skinner J, Pigeyre M, Caiazzo R, Raverdy , Vaillant E, Field S, Balkau B, Marre M, Visvikis-Siest S, Weill J, Poulain-Godefroy O, Jacobson P, Sjostrom L, Hammond CJ, Deloukas P, Sham PC, McPherson R, Lee JJ, Shyong TE, Sladek R, Carlsson LMS, Walley A, Eichler EE, Pattou F, Spector TD, Froguel P. Low number of copies of the salivary amylase gene predisposes to obesity. Nat. Genet. 2014 May;46(5):492-7 doi:10.1038/ng.2939.
  10. Shahabi P, Siest G, Meyer U and Visvikis-Siest S. Human Cytochrome Epoxygenases: Variability in Expression and Role in inflammation-related Disorders. Pharmacol Ther. 2014 Nov, 144(2): 134-161.



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