H  E  G  P Epidemiology, Genetics, Pathophysiology, Experimental Models, Imaging, Human Investigation, Therapeutics Geneti...
Rare and common variants in CV diseases MacCarthy , Nature Review Gentetics 2006
From rare diseases to the general population Heterozygous FH : 1/500 Homozygous FH : 1/10 6 1964 Rare families with autoso...
From rare diseases to the general population Soutar AK and Naoumova RP  (2007) Nat Clin Pract Cardiovasc Med 1985-2000 Dis...
From rare diseases to the general population Statin therapy reduce the 5-year incidence of CV events by about 1/5th per mm...
From rare diseases to the general population PCSK9 : a new target  in the LDL-R pathway
environment Blood Pressure GENES ARTERIAL HYPERTENSION
Arterial Hypertension : the search for new targets through rare diseases Rare forms of hypertension : Gordon syndrome ? 1q...
Long and Kidney-Specific WNK1 L-WNK1 KS-WNK1 L- and KS-WNK1: Role on Na, K, Cl balance through renal transporters Cl - Na ...
Long WNK1 Kinase and the arterial wall L-WNK1 E9.5 E17.5 Embryo -/- Adult +/- L-WNK1 : role in vascular development, in ar...
RENIN ANGIOTENSIN SYSTEM Angiotensin II Angiotensinogen Angiotensin I  Renin Converting enzyme ARB (sartan) ACE Inhibitors...
 
ARGHEF 1 AS A NEW TARGET FOR ANTIHYPERTENSIVE THERAPIES
Genetics of CV diseases : from rare families to common diseases Rare forms of cardiovascular diseases can help to identify...
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03 rencontres biomédicale LIR Xavier Jeunemaitre

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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
  • 03 rencontres biomédicale LIR Xavier Jeunemaitre

    1. 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. 2. Rare and common variants in CV diseases MacCarthy , Nature Review Gentetics 2006
    3. 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. 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. 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. 6. From rare diseases to the general population PCSK9 : a new target in the LDL-R pathway
    7. 7. environment Blood Pressure GENES ARTERIAL HYPERTENSION
    8. 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 <ul><li>Hyperkaliemia </li></ul><ul><li>Hyperchloremia </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Normal renal function </li></ul><ul><li>Reduced plasma renin activity </li></ul><ul><li>High sensitivity to thiazide diuretics </li></ul>
    9. 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. 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. 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
    13. 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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