Genetic factors in the background of cardiovascular diseases

Oliver Rácz, Eva Sedláková2010

The Role of Genetic Markers in Assesing CV Risk and Targeting TherapyDavidson M, Foody JM, Chapman JM, Sabatine MS, Sacks F(Medscape, Nov. 2009)

Cardiovascular diseases

Blaskó G, Blaskó BIn: Medical patobiochemistryMedicina 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 genesVascular diseaseCongenital diseasesCoronary disease – diet, smoking, no physical activity HypertensionArrythmiasMyocardiopathies

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/CAD2000 patients, 3000 controlsSomething is on ch 9, locus p21.34 SNPsMetaanalysis (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 tissueKIF6 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 notSecond 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 treatmentGenetic screening to foresee the effect of treatment or to choise the proper treatmentThe 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 liverLower VLDL, LDL, ApoB , higher LDL receptorsStable plaques, decrease of eventsBut – 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 complicatedIt depends also on the activity of transporter OATP1B1Pro155Tre 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

Patau, EdwardTurner

VSD, other congenital malformations, split mitral valve

ASD, VSD. PDA, etc.Coarctation of aorta, VSDBicuspidal 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