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Genetic factors in the background of cardiovascular diseases Oliver Rácz, Eva Sedláková 2010 The Role of Genetic Markers in Assesing CV Risk and Targeting Therapy Davidson M, Foody JM, Chapman JM, Sabatine MS, Sacks F (Medscape, Nov. 2009) Cardiovascular diseases Blaskó G, Blaskó B In: Medical patobiochemistry Medicina Budapest, 2007 The classic concept and the genes Vascular disease – rheumatic fever, endocarditis, degeneration and genes??? Congenital diseases – disruption of nromal gene expression pattern, congenital, not hereditary (Holt Oram?) Coronary disease – diet, smoking, no physical activity and also some genes (LDL receptor, apo E, apo B, also as monogenic – 1/500 vs 1/3) Hypertension – salt, obesity, stress and some genes (and rare monogenic HT) Arrythmias – hypoxia, catecholamines and genes? Myocardiopathies – often monogenic Too high number of genes Vascular disease Congenital diseases Coronary disease – diet, smoking, no physical activity Hypertension Arrythmias Myocardiopathies Molecular basis of CVS diseases – behind any protein is at least one gene - where, which? Candidate gene approach, logical, sometimes disappointing Genom wide association studies (GWAS) „blind chicken finds seed“ stupid but sometimes surprisingly successful Problems with interpretation Epistasis Blind chicken (?) GWAS: SNP association with IM/CAD 2000 patients, 3000 controls Something is on ch 9, locus p21.3 4 SNPs Metaanalysis (10 000) = increase of risk by 29 % The risky haplotype is common ! Is it already useful when combined with classic RFs? – not yet What genes, what explanation? (CDKN2A,B is an inhibitor of cyclin dependent kinase, associated with tumours) KIF6 at least a known gene Gene KIF6 is coding a kinesin, microscopic motor of microtubuli, responsible for different transport processes inside the cells (protein complexes, mRNAs) KIF6 high expression in arterial tissue KIF6 polymorphism Trp719Arg An accidental hit after unsuccessful scan of 900 SNPs in 700 candidate genes of CARE study (Cholesterol and recurrent events) – who responds to statins, who not Second step: 11000 SNPs in 7000 genes Micromotor KIF6 polymorphism consequences Higher risk of CVS events (only in men?) The association was proved in other studies – not in every case, maybe the problem with phenotype) “Arg” carriers have a better response to statin treatment Genetic screening to foresee the effect of treatment or to choise the proper treatment The bottom line: – In discussion some very pointed questions from colleauges – Are these studies really independent? – Is only for rich countries? (Iakoubova et al?) OATP polymorphysm and statin response Statins decrease endogenous cholesterol synthesis in liver Lower VLDL, LDL, ApoB , higher LDL receptors Stable plaques, decrease of events But – block of Q10 synthesis And – big individual differences in response – why? OATP polymorphisms and response to statin treatment Individual differences in response – why? The pharmacokinetics of statins is complicated It depends also on the activity of transporter OATP1B1 Pro155Tre polymorphysm (gene SLCO1B1) Weak response, higher risk of side effects Monogenic diseases of the heart, summary? Hypertrophic and dilated cardiomyopathies (AD, AR, Xr; 1/2000) Familiary hypercholesterolemia (AD, 1/500) Long QT, arytmogenic right ventricle dysplasia, Holt-Oram, Carney, Alagille, Noonan, Char sy. etc/. WPW sy., Brugada and many others – more than 100 genes and diseases? Chromosomal aberrations Down VSD, other congenital malformations, split mitral valve Patau, Edward Turner ASD, VSD. PDA, etc. Coarctation of aorta, VSD Bicuspidal aortal valves Not only genes, new biochemical and other markers Extended lipid status – – – – Total cholesterol is a nonexisting thing - obsolete LDL and HDL cholesterol, OK, subtypes ApoB as a marker of small dense LP Other apoproteins Troponins, homocysteine, natriuretic factors, ischemia modified albumin, etc. C reactive protein (? plaque lability) Calcium in coronary vessels, plaque analysis