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*Genomics and Pathophysiology of Cardiovascular Diseases

Principal investigators :
David Trégouët, Ph.D. & François Cambien, M.D., Ph.D.

Research team :

Olivier Barthelemy, François Cambien, Philippe Charron, Jean-Philippe Collet, Isabelle Denjoy, Véronique Fressard, Estelle Gandjbakhch, Sophie Garnier, Pascale Guicheney, Francoise Hidden-Lucet, Michel Komajda, Gilles Montalescot, Nathalie Neyroud, Ewa Ninio, Pascale Richard, Laurence Tiret, David-Alexandre Trégouët, Eric Villard.

*In 2019, this team left the IHU-ICAN and joined the Bordeaux Population Research Center.

It relies on 5 major components: 1. large-scale epidemiological and families studies coupled with bioresources; 2. the facilitated access to up-to-date high-throughput genomic technologies; 3. a platform of methodological research in statistics and bioinformatics; 4. a group of experts in molecular and cellular biology focusing on the functional characterization of identified molecular variants and their associated pathways; and 5. clinical scientists having access to patients and clinical trials in order to translate genomic discoveries into clinical applications.

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Relying on the micro-array technology, genome-wide association studies (GWAS) testing the association of a phenotype with hundreds of thousands of single nucleotide polymorphisms (SNPs) covering the whole genome have been a powerful approach to
localize regions harbouring susceptibility genes to human diseases and our team members have strongly contributed to such discoveries in the field of common and rare CVDs. New micro-array DNA chips have recently been released which now focus on an in-depth characterization of coding and putative functional regions with an enrichment for SNPs with minor allele frequencies < 5%. Such DNA chips will be processed in some of the cohorts we have access to in order to identify novel CVD variants.

A remarkable advantage of Next-Generation Sequencing (NGS) approaches in comparison to micro-arrays is that they do not require a priori knowledge of the targeted sequence. In addition NGS may not only identify SNPs but also insertion/deletions (InDels) or more complex variations that may be functionally important. DNA
sequencing can be applied to the whole genome but more often, exons or specific regions of interest in the genome are captured and sequenced. This has become a method of choice for identifying the molecular defect responsible for Mendelian forms of a disease and the variant(s) at the origin of association signals derived from GWAS. Our group has already acquired solid expertise in the experimental works and bioinformatics analysis associated to such approach and will pursue its application to CVDs whose molecular variants remain to be identified. We will also investigate the feasibility of using whole
exome sequencing to identify unsuspected susceptibility loci in relatively large samples of unrelated CVD patients. Once a CVD-associated gene/variant is identified, our group of molecular and cellular biologists has all required expertise to disentangle by using in vitro and in vivo models, which mechanistic
pathways are perturbed and how they relate to the pathophysiology of the studied disease. Related to this functional characterization, NGS offers novel perspectives in which our group aims to get expertise. Indeed, the comparison of RNA-seq transcriptional profiles following over-expression or down-regulation (e.g. using siRNA or shRNA techniques) of a given gene could provide a precise overview of regulatory pathways modulated by this gene. Another
promising NGS application to characterize the unknown regulatory mechanisms associated with a novel transcription factor is the application of Chromatin-ImmunoPrecipitation followed by DNA sequencing (ChIP-Seq). The specific themes developed within our research program are:
– Cardiomyopathies (E. Villard / P. Charron)
– Arrhythmias (P.Guicheney / N. Neyroud)
– Arterial and venous thrombotic disorders (F. Cambien, E. Ninio, L. Tiret, DA Trégouët)
– Clinical genomics and pathophysiology of arterial/coronary thrombosis (G. Montalescot / JP Collet)
– Genomic epidemiology (F. Cambien, L. Tiret, DA Trégouët)

FOCUS

Our research program is dedicated to the characterization of the variability of gene sequence and expression, the identification of genes or sets of genes involved in the predisposition to common and rare forms of cardiovascular diseases (CVDs), the understanding of their functional role in pathophysiological processes, and ultimately, to improve their clinical utility in terms of risk stratification, diagnosis and therapeutic management.


BIOSKETCH

Born 27/01/1973, David-Alexandre Trégouët was recruited at INSERM as a research associate (“Chargé de Recherches”) in 1999 just after completing his PhD in statistical genetics. Since then, he has been working at INSERM UMR_S 937 (previously labelled UMR_S 525), a research department led by Francois Cambien, and focusing on cardiovascular genomics. In December 2009, he was promoted research director-2nd class (“Directeur de Recherches – classe 2”) and heads the team “Genomics of Venous Thrombosis” within INSERM UMR_S 937. In 2011, he was named co-director of the Genomics department of the Institute for Cardiometabolism and Nutrition (IHU-ICAN) created in the context of the French “Investissement d’Avenir” National Program. Since Autumn 2011, he is also coordinating the bioinformatics group of the Post Genomic Platform of the Pitié-Salpêtrière Hospital (P3S). David-Alexandre Trégouët is an internationally recognized expert in statistical/bioinformatics genomics and its application to cardiovascular diseases (CVDs) with a major focus on venous thrombosis (VT). He is the one who led the first two genome-wide association studies on VT. He is also the one who coordinated the unique genome-wide association study conducted on pulmonary arterial hypertension and the only two genome-wide haplotype analysis conducted so far, on myocardial infarction and Alzeihmer disease. He belongs to the statistical core group of several international projects including MORGAM, EURAGEDIC,
CardioGenics and CARDomics. He is an active member of the Extended CHARGE consortium related to haemostatic traits and has established tight international collaborations on the genomics of thrombotic disorders with Dr Gagnon (Toronto, Canada), Dr Soria (Barcelona, Spain), Pr Rosendaal (Leiden, Netherlands) and Dr Wild (CFH Institute, Mainz, Germany). David-Alexandre Trégouët has published 110 manuscripts in international peer-reviewed journals. His associated Hirsch index is 31. He belongs to the editorial board of the Arteriosclerosis Thrombosis and Vascular Biology, Human Genetics (review editor), Journal of Molecular Medicine and BMC Medical Genetics (editor) journals. Area of expertise: Genetic Epidemiology of Cardiovascular Diseases;
Molecular aspects of gene variability; Biostatistics; Bioinformatics; Statistical Genetics; Human genetic polymorphism; Population genomics.


Publications

1. Germain M, Eyries M, Montani D, Poirier O, Girerd B, Dorfmuller P, Coulet F, Nadaud S, M Svetlana, Guignabert C, Carpentier W, Vonk-Noordegraaf A, Lévy M, Chaout A, Lambert JC, Bertrand M, Dupuy AM, Letenneur L, Lathrop M, Amouyel P, de Ravel TJL, Delcroix M, Austin ED, Robbins IM, Hemnes AR, Loyd JE, Berman-Rosenzweig E, Barst RJ, Chung WK, Simonneau G, Trégouët DA, Humbert M, Soubrier F. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013 doi:10.1038/ng.2581.
2. Villard E, Perret C, Gary F, Proust C, Dilanian G, Hengstenberg C, Ruppert V, Arbustini E, Wichter T, Germain M, Dubourg O, Tavazzi L, Aumont MC, Degroote P, Fauchier L, Trochu JN, Gibelin P, Aupetit JF, Stark K, Erdmann J, Hetzer R, Roberts AM, Barton PJ, Regitz-Zagrosek V, Aslam U, Duboscq-Bidot L, Meyborg M, Maisch B, Madeira H, Waldenstrom A, Galve E,Cleland JG, Dorent R, Roizes G, Zeller T, Blankenberg S, Goodall AH, Cook S, Tregouet DA,Tiret L, Isnard R, Komajda M, Charron P,Cambien F. A genome-wide association study identifies two loci associated with heart failure due to
dilated cardiomyopathy. Eur Heart J 2011; 32: 1065-76.
3. Heinig M, Petretto E, Wallace C, Bottolo L,Rotival M, Lu H, Li Y, Sarwar R, Langley SR, Bauerfeind A, Hummel O, Lee YA, Paskas S, Rintisch C, Saar K, Cooper J, Buchan R, Gray EE, Cyster JG, Cardiogenics Consortium, Erdmann J, Hengstenberg C,Maouche S, Ouwehand WH, Rice CM, Samani NJ, Schunkert H, Goodall AH, Schulz H, Roider H, Vingron M, Blankenberg S, Münzel T, Zeller T, Szymczak S, Ziegler A,Tiret L, Smyth DJ, Pravenec DJ, Aitman TJ,Cambien F, Clayton D, Todd JA, Hubner N, Cook SA A conserved trans-acting regulatory locus underlies a proinflammatory gene expression network and susceptibility to autoimmune type 1 diabetes. Nature 2010; 467: 460-4.
4. Tregouet DA, Konig IR, Erdmann J,Munteanu A, Braund PS, Hall AS, Grosshennig A, Linsel-Nitschke P,Perret C, DeSuremain M, Meitinger T, Wright BJ, Preuss M, Balmforth AJ, Ball SG, Meisinger C, Germain C, Evans A, Arveiler D, Luc G, Ruidavets JB, Morrison C, van der Harst P, Schreiber S, Neureuther K, Schafer A, Bugert P, El Mokhtari NE, Schrezenmeir J, Stark K, Rubin D, Wichmann HE, Hengstenberg C, OuwehandW, Ziegler A,Tiret L, Thompson JR,Cambien F, Schunkert H, Samani NJ. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009; 41: 283-5
5. Cayla G, Hulot JS, O’Connor SA, Pathak A, Scott SA, Gruel Y, Silvain J, Vignalou JB, Huerre Y, de la Briolle A, Allanic F, Beygui F, Barthélémy O, Montalescot G, Collet JP. Clinical, angiographic, and genetic factors associated with early coronary stent thrombosis. JAMA. 2011;306:1765-74; Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009;373:309-1.