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03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
03 rencontres biomédicale LIR Xavier Jeunemaitre
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03 rencontres biomédicale LIR Xavier Jeunemaitre

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2ND INTERNATIONAL RESEARCH MEETING …

2ND INTERNATIONAL RESEARCH MEETING
4 JUNE 2010- HÔTEL DE MARIGNY PARIS

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  • Presentation of the CV centers in Paris PARCC - genetics
  • As a proof of concept, a demonstration of the interest of the identification of genes involved in rare forms of disease, familial Hypercholesterolemia and the LDL receptor
  • A French group opened a new avenue in the field by the discovery of a new target, PCSK9, a protein proconvertase regulating LDL cholesterol metabolism Mutations in families with FH Interestingly, 2 types of mutations exist – gain of function mutations increased LDL, loss-of-function mutation decreased LDL (2% Black population protection against early CHD Clearly, inhibition or repression of PCSK0 expression is a new and important target for the pharmaceutical industry
  • Simarly to blood cholesterol, regulation of blood pressure is complex 2 examples one from rare disease, one from experimental model
  • Transcript

    • 1. H E G P Epidemiology, Genetics, Pathophysiology, Experimental Models, Imaging, Human Investigation, Therapeutics Genetics of cardiovascular diseases from rare families to common diseases Xavier Jeunemaitre
    • 2. Rare and common variants in CV diseases MacCarthy , Nature Review Gentetics 2006
    • 3. From rare diseases to the general population Heterozygous FH : 1/500 Homozygous FH : 1/10 6 1964 Rare families with autosomal familial hypercholesterolemia (Khachadurian AK, Am J Med 1964) 1973-1980 The LDL receptor pathway (Brown and Goldstein)
    • 4. From rare diseases to the general population Soutar AK and Naoumova RP (2007) Nat Clin Pract Cardiovasc Med 1985-2000 Discovery of mutations in the LDLR gene 1985 NIH : lowering blood cholesterol as a major national health goal. STATINS
    • 5. From rare diseases to the general population Statin therapy reduce the 5-year incidence of CV events by about 1/5th per mmol/L reduction in LDL cholesterol, irrespective of the initial lipid profile 10 fold increase in the use of statins for prevention of CV diseases 1994-2010
    • 6. From rare diseases to the general population PCSK9 : a new target in the LDL-R pathway
    • 7. environment Blood Pressure GENES ARTERIAL HYPERTENSION
    • 8. Arterial Hypertension : the search for new targets through rare diseases Rare forms of hypertension : Gordon syndrome ? 1q32-q42 WNK4 17q21.31 WNK1 12p13.3 ? Chr. ? Chr. 1 Chr. 17 Chr. 12 The WNK ( W ith N o lysine ( K )) family Mansfield Nat Genet 1997, Disse-Nicodeme Am J Hum Genet 2000, Wilson Science 2001
      • Hyperkaliemia
      • Hyperchloremia
      • Metabolic acidosis
      • Normal renal function
      • Reduced plasma renin activity
      • High sensitivity to thiazide diuretics
    • 9. Long and Kidney-Specific WNK1 L-WNK1 KS-WNK1 L- and KS-WNK1: Role on Na, K, Cl balance through renal transporters Cl - Na + Cl - NCC WNK4 L-WNK1 KS-WNK1 K + ROMK WNK4 P ENaC Na + L-WNK1 APICAL BASOLATERAL P KS-WNK1 WNK3
    • 10. Long WNK1 Kinase and the arterial wall L-WNK1 E9.5 E17.5 Embryo -/- Adult +/- L-WNK1 : role in vascular development, in arterial myogenic tone 0 2 4 * -8 -6 -4 L-WNK1+/+ L-WNK1+/- LOG PHENYLEPHRINE CONTRACTION (mN) L-WNK1+/+ L-WNK1-/- Tg (WNK1 IL-LacZ) v a aorta Superficial vessels Delaloy C et al., Am J Path 2006
    • 11. RENIN ANGIOTENSIN SYSTEM Angiotensin II Angiotensinogen Angiotensin I Renin Converting enzyme ARB (sartan) ACE Inhibitors AT 2 R Ca ++ PKC  Phospholipase C DAG G  q  IP3 AT2 agonists Anti AT 1 effects Renin Inhibitors Vasoconstriction Aldosterone secretion Proliferation Cardiovascular remodeling AT 1 R
    • 12.  
    • 13. ARGHEF 1 AS A NEW TARGET FOR ANTIHYPERTENSIVE THERAPIES
    • 14. Genetics of CV diseases : from rare families to common diseases Rare forms of cardiovascular diseases can help to identify pathways important for the general physiology In France, a special access to rare families through a unique network of Centres for Rare Diseases and to Clinical Investigation Centres Strong teams working on basic mechanisms underlying cardiovascular diseases

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