Transcript Document

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