Transcript genetic determinants in ischemic heart disease

GENETIC SUSCEPTABILITY OF
ISCHEMIC HEART DISEASE
(IHD)
By
Assad Mohi Eldin
Sara M.Abuel Gassim
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Content:
Introduction
Epidemiology
Pathology
Genetic Analysis
Conclusion
By:
-Sara Abu Algasim
-Asaad Mohi Eldin
DEFINITION
• The common name: Coronary Artery Disease
(CAD).
• Condition that affects the supply of blood to the
heart ( nutrients- oxygen to heart muscles).
• Imbalance between cardiac perfusion and
myocardial oxygen demand ( reduced oxygen
capacity).
• Or reduction in coronary blood flow caused by
obstructive atherosclerosis ( vessels occlusion).
Clinical Manifestations:
• There are 4 defined clinical pictures:
1. Angina pectoris (chest pain)/
stable/variant/unstable
2. Acute myocardial infarction MI
3. Heart failure
4. Sudden cardiac death (SCD)
• All are considered as late manifestations of
coronary atherosclerosis.
Coronary heart disease
Diagnosis
Clinical diagnosis:
• characteristic complaint of chest discomfort or pain
brought on by exertion and relieved by rest.
• Confirmation may be obtained by observing reversible
ischemic changes on ECG during an attack or by giving
a test dose of sublingual nitroglycerin.
• Diagnostic tests may include electrocardiogram ,
echocardiogram (measures sound waves), exercisetolerance test, thallium stress test, blood studies to
measure total fat, cholesterol and lipoproteins, X-rays
of the chest and coronary angiogram.
• In MI announced by sever chest pain that
radiate to the neck, jaw, epigasterium or the
left arm.
• Not relieved by rest or Nitroglycerine.
• Lab assessment by measuring blood level of IC
macromolecules that lack out of the injured
myocardial cells (myoglubin, cardiac troponins
T/I, CK-MB, lactate dehydrogenase).
Epidemiology:
• In the developing countries nearly 500,000 death
incidence USA.(13 million incidence of IHD)
• A huge improvement after 50% death rate.
• Recognition and management of the cardiac risk
factors.
• Diagnostic tools: coronary angiography/ ECG/ lab
….)
• Management: Aspirin/ statins/ angioplasty &
bypass surgery……
PTCA – coronary angioplasty
PTCA stands for
"Percutaneous" — through the skin
"Transluminal" — within the lumen or artery
"Coronary" — the artery which supplies the
heart muscle
"Angioplasty" — remodeling the artery.
Stent
Coronary Bypass Graft
Pathogenesis:
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Inadequate blood supply due to:
pre-existing occlusion
superimposed thrombosis and vasospasm
Multi-factorial type of disease.
Genetic & hereditary factors.
Environmental risk factors:
Smoking
Hypertension
Diabetes mellitus
Sex
Cholesterol level
• Formation of atheromatus plaque in the coronary
vessels lead to narrowing of the V. walls and
obstructing the blood flow to musculature of the
heart.
• Complete blockage would lead to damage, death
and necrosis of the tissue or MI (heart attack).
• Plaque change : rupture/ fissuring/ hemorrhage
• inflammation(leukocytes)
• Vasoconstriction (lumen diameter)
GENETIC SUSCEPTABILITY
Risk factors genes associated with IM:
 Lipid metabolism (apolipoproteins, lipolytic enzymes, receptors for
lipoproteins)
 Coagulation system and fibrinolysis (fibrinogen, thrombosis factors,
plasminogen activator
 inhibitor type 1)
 Platelet glycoproteins (GPIIb/IIIa, GPIa/IIa)
 Renin- angiotensin-aldosterone system (angiotensinogen,
angiotensin converting
 enzyme, AT1 receptor, aldosterone synthetase)
 Vasoactive factors (ANP, BNP, CNP)
 Factors of adhesion and migration for monocytes and macrophages
 Inflammation factors (cytokines, tumor necrosis factor)
 Proliferation factors of smooth muscle cells of vessels
Genome wide association analysis of
coronary artery disease:
(Case control/ German - Family based Studies)
• By Samani et al..July-2007- UK
• Analysis of two genomewide association studies for
CAD were performed using modern genotyping tools,
for systematic search for inherited components of
complex disease.
Method:
• Identification of chromosomal loci strongly associated
with CAD in the Wellcome Trust Case Control
Consortium (WTCCC) study (which involved 1926 case
subjects with coronary artery disease and 2938
controls)
• Looked for replication in the German MI
[Myocardial Infarction] Family Study (which
involved 875 case subjects with myocardial
infarction and 1644 controls).
• SNPs that were significantly associated with
coronary artery disease in either study
(P<0.001) were then combined to identify
additional loci with a high probability of true
association.
• Genotyping in both studies was performed with the use
of the GeneChip Human Mapping 500K Array Set
(Affymetrix).
Results:
• Of thousands of chromosomal loci studied, the same
locus had the strongest association with CAD in both the
WTCCC and the German studies: chromosome 9p21.3
(SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6),
respectively).
• WTCCC study revealed nine loci that were strongly
associated with coronary artery disease P<1.2x10(-5)
• two of these loci were successfully replicated (adjusted
P<0.05) in the German study: chromosome 6q25.1
(rs6922269) and chromosome 2q36.3 (rs2943634)
• The combined analysis identified four
additional loci significantly associated with
coronary artery disease (P<1.3x10(-6)) and a
high probability (>80%) of a true association:
chromosomes 1p13.3 (rs599839), 1q41
(rs17465637), 10q11.21 (rs501120), and
15q22.33 (rs17228212)
• Several genetic loci that, individually and in
aggregate, substantially affect the risk of
development of coronary artery disease.
L/S association analysis for identification of genes underlying
premature coronary heart disease: cumulative perspective from
analysis of 111 candidate genes:
• J J McCarthy…et al..2004 – case control..USA
• Aimed to extend the no. of 62 gene to 111 genes with 210
polymorphism.
• 352/ white, familial, premature CHD and random sample of
418/ whites control. From 15 sites around the USA.
• Multivariate logistic regression analysis was used to
compare the distributions of genotypes between cases and
the comparison group while controlling for age, sex, body
mass, diabetes, and hypertension.
• Evaluation of 40 genes associated with coronary heart
disease and found significant (p≤0.05) associations with 10:
ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and
THPO.
• Many of the classic risk factors are themselves
under genetic control (blood pressure, lipids,
obesity).
Candidate gene choice, polymorphism selection,
and genotyping
• 243 candidate genes were chosen based on
previously reported genetic associations or
knowledge of their involvement in CHD pathways
of endothelial cell biology, thrombosis, lipid
metabolism, coagulation cascade, and other risk
factors (diabetes, obesity).
• Focused on 1–3 common polymorphisms, the
majority single nucleotide polymorphisms in the
coding region per gene.
• Analyses were performed using the SAS
statistical package.
• 10 genes ACE, CD14,IL1A, IL1RN, F13A1, LIPC,
PON2, TGFBI, THBD, THPO, VWF excreted
different polymorphisms than previously
examined.
• Polymorphisms in other 10 genes were
significantly associated with CHD or MI. Five
were of exact same variant: APOE, F7, FGB,
GP1BA, MTHFR.
• ACE, IL1RN, THPO, LRP1, SELP association was
enrolled with diff. polymorphism.
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Linkage disequilibrium established B/W:
SELP_3 & SELP_1.
Strong LD b/w LRP1_3 & LRP1_5
APOE, F7, GP1BA and MTHFR express recessive
mode of inheritance.
• FGB has a dominant mode of inheritance.
• ECE1, HRG, PAI2, PLCG1, SDC4, THBS1, THBS2,
and THBS4 were for the first time, with
established association with CHD or MI.
• The THBS4 variant conferred a greater than
twofold increased odds of myocardial infarction
in both heterozygote and homozygote.
• Some genes cluster in the same chromosome do express
LD. IL1 gene cluster including IL1RN, IL1B, and IL1A on
2q12-q22, linkage disequilibrium is strong (between IL1A /
IL1B) and within IL1RN polymorphism.
• Three fibrinogen genes FGA, FGB and FGG are clustered in a
region of <50 kb on chromosome 4q31 have strong LD b/w
the four polymorphism typed but not single nucleotide
polymorphism.
• Selectin genes, SELP and SELL, and Factor V gene (F5) are
clustered in an <220 kb region on 1q22-q25, with significant
association b/w single nucleotide polymorphism.
• (THBS4) A387P polymorphism was associated with (gain of
function) mutation that interferes with endothelial cell
adhesion and proliferation,51 which may account for
predisposition to myocardial infarction.
• Screening of the coding region of candidate
genes identified novel genetic associations
between single nucleotide polymorphisms in
the Endothelial Converting Enzyme(ECE1),
Histidine Rich Glycoprotein (HRG),
Phospholipase C Gamma 1 (PLCG1), Syndecan
(SDC4) and Plasminogen Activator Inhibitor-2
(PAI2) genes and CHD & MI.
• Due to the small sample size, more
confirmation research are required.
Lipid metabolism genes:
Lipoprotein(A) and increased risk of
myocardial infarction
• Kamstrup PR..et al…. Denmark..2007
• 3 studies of CCHS(1991-2007)+CGPS(20032006)+CIHDS
• Lipoprotein(a) kringle IV type 2 (KIV-2)
polymorphism genotype is associated with
increased MI.
• No. of the KIV-2 repeats ranged from 6- 99
• P value ≤0.05-0.001- significant.`
Genetic determinant in IHD
• Anna Wojtczak..et al.. Poland / 2008
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Genes regulating lipids metabolism, mainly
ApoB and Apo E, CETP LPL and HL.
ApoB: Apolipoprotein B protein component
of membrane of LDL.
CETP :Cholesterol Ester Transfer Protien
Important regulator of HDL.
LPL: Lipoprotien Lipase, responsible for hydrolysis
of triglyceride & VLDL →HDL.
HL: Hepatic Lipase, causes lipolysis of VLDL &
Conv. Of HDL2 → HDL3
Gene
ApoB
Polymorphism Association /IHD
C516T
Significant
Effect
- Increase LDL
Apo E
E4
Significant
- Increase MI in young
CETP
B1
Ile405Val
Ser474Ter
Significant
-↑Atherosclerosis
Significant
T107C
Q192R
L55M
-480C
480T
N/C
-↓ Atherosclerosis
- ↓ IHD
-Anti Oxidant
properties
Of HDL
-↑HDL
LPL
PON1
HL
Significant
Genes connected with thrombocytes:
-Glycoproteins (GP) of platelet cell membrane
responsible for their aggregation.
-Significant association was found in terms of
increasing the risk of MI.
Gene
GPIIIa
GPIIb
Polymorphism/
or Genotype
P1A
P1A2
Association /IHD
Effect
-Significant
- N/C
807T/873A
Significant
-Increase MI /
Aggregation/Atherosclerosis
-Inc
-↑risk of MI
Genes of the coagulation system and
fibrinolysis:
• Thrombotic effect is very important factor in
IHD, mainly in acute coronary incidences.
• FB gene does affect the level of fibrinogen.
- Polymorphism G455A has been found to
correlate with advancement of coronary
arteries atherosclerosis.
• PAI- 1 is another candidate gene
- Polymorphism 4G/5G determines the level of
PAI-1. Some studies connect 4G with past MI.
Genes regulating inflammation
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They include :
Tumor Necrosis factor ( TNF α/β)
Transforming Growth Factor ( TGF- β)
Interluekin , CD 14.
Selectin ( SELP- SELE)
Platelet Endothelial Cell Adhesion (PECAM-1)
• Selectine E variants– Arg128, T98, Ph554- do
increase atheroscloresis
• PECAM-1 polymorphism- LeulVal, Ser563Asnshowed the same effect
• Interleukin- 6(Il-6) polymorphism C174G
affects the synthesis of the gene.
• Allele G is more detected in cerebral stroke,
but allele C is associated with higher risk of
coronary disease.
Myocardiac Infarction associate with Sequence
variants affecting eosinophil numbers:
Daniel F Gudbjartsson..et al. 2009
• Eosinophils are pleiotropic multifunctional leukocytes
involved in initiation and propagation of inflammatory
responses and thus have important roles in the pathogenesis
of inflammation.
• The most significant SNPs were studied in ( case control study)
in 12,118 Europeans and 5,212 East Asians.
• In the study 5 SNPs were evaluated in chromosome 2,3,5 1nd
12.
• In 6 different population SNP at 12q24 in SH2B3 singnifecantly
associated with MI p value= 8.6 * 10(-8)
• rs3184504 (T allele) is a nonsynonymous SNP (R262W) in exon 3 of
SH2B3 along with G allele of rs653178 are associated with MI.
• SH2B3 is a member of the APS family of adaptor proteins and acts
as a broad inhibitor of growth factor and cytokine signaling
pathways.
• SH2B3 is expressed in human vascular endothelial cells, where it
promotes inflammation.
• rs3184504[T] could contribute to the progression of plaques in
coronary arteries leading to myocardial infarction through reduced
anti-inflammatory activity of SH2B3.
• No association was observed between rs3184504 and other
traditional risk factors for myocardial infarction such as high-density
lipoprotein (P = 0.63,), low-density lipoprotein (P = 0.70,), type 2
diabetes (P = 0.85)
CD14 C-260T gene polymorphism
• CD14 is a membrane- associated glycosylphosphatidylinositol expressed on macrophage
surface.
• Acts as a co- receptor along with TLR4
• Monocyte differentiate into dendretic cell, encouraged
by cytokines (IL- 4/ GM-CSF )
• Comprehensive studies to declare the association of
the CD14 C-260T polymorphism & IHD were
performed. The genotypes (CC, CT, TT) distributions
were involved in European, East Asian and Indian
studies in patients with ACS, Prior MI and stable
Angina.
• 11,813 cases and 6,196 controls in 9 studies.
• OR under the recessive model was 1.53 (95%
confidence interval: 1.20-1.96) for East Asian
studies.
• OR =1.70 (95% confidence interval: 1.26-2.29)
for Chinese studies
• No significant association was found in
European population or Indian population.
• It seems that T allele and TT genotype are
associated with IHD in the East Asian
population but not in the European or Indian
populations.
Genome-wide scan for HDL3-C in the Framingham
Study
•High density lipoprotein cholesterol (HDL-C) is inversely associated with
coronary heart disease and has a genetic component Subfractions of
HDL, such as HDL 3 -C, is a better phenotypes for linkage studies.
genome-wide variance components linkage analysis with 401
microsatellite markers spaced 10 centimorgan (cM) apart
•The highest multipoint log-of-the-odds (LOD) score from
the initial linkage analysis was 3.7 at 133 cM on chromosome 6.
•SNP rs2257104 in PLAGL1 at_ 143 cM was associated with multivariable
adjusted HDL 3 (P=0.03)
Yang et al.2005
Genetic Variation associated with Ischemic Heart Failure
Meta-Analysis
•Seven polymorphisms (angiotensin-converting enzyme insertion/deletion (ACE I/D),
angiotensinogen (AGT) M235T, α2C subtype-adrenergic receptor (ADRA2C) Del322325, ß2-adrenergic receptor (ADRB2) Arg16Gly, ADRB2 Gln27Glu, endothelin-1 (EDN1)
Lys198Asn, and vascular endothelial growth factor (VEGF) G-405C) showed significant
association
•Five polymorphisms (ACE I/D, ADRB1 Arg389Gly, ADRB2 Arg16Gly, ADRB2 Gln27Glu,
TNF G308A) were examined by more than one study.
•No significant association, except for polymorphism ADRB2 Arg16Gly under a
recessive model
(odds ratio = 1.32, 95% confidence interval: 1.05, 1.65)
•Case-control studies that investigate gene-gene and gene-environment interactions
might further elucidate the genetics of ischemic heart
Georgios Kitsios1 and Elias Zintzaras-2007
Coronary Heart Disease and Periodontitis
•Candidategene association study confirm the known association
of two neighboring linkage disequilibrium with CHD and show the
additional strong association of these loci with the risk of
aggressive periodontitis associated linkage disequilibrium region,
rs1333048
•The two associated linkage disequilibrium regions map to the
sequence of the large antisense noncoding RNA ANRIL
which partly overlaps regulatory and coding sequences of
CDKN2A/CDKN2B
•Both diseases are associated with similar risk factors such as smoking,
diabetes, and gender, and both diseases are further characterized by a
chronic inflammatory process.
•A region of the human genome near the CDKN2A and CDKN2B genes as
having
an influence on CHD.
•This genetic region, being the most important susceptibility locus for CHD to
date, is also associated with a substantial risk increase of aggressive
periodontitis.
•The interplay between these common inflammatory complex diseases could
be partially due to the shared genetic risk variants of this antisense RNA.
•Three SNPs of this LD region (rs2891168, rs1333042 and rs1333048)
•All SNPs gave evidence for association with CHD with SNP rs2891168
being the marginally most significant P=,00000011
Arne S. Schaefer et.al 2009
GENETIC DETERMINANTS IN ISCHEMIC HEART
DISEASE
•Ischemic heart disease (IHD) is a complex
of clinical symptoms of various
pathogenesis
•Common genetic variations of polymorphic
candidate genes contributing to ischemic
heart disease
Genes regulating lipid metabolism
•The most important genes connected with lipid
metabolism are apolipoprotein B (ApoB) and E
(ApoE) genes, cholesterol esters transporting protein (cholesterol
ester transfer protein - CETP ) genes and genes of lipoprotein
lipase (lipoproteidipase -LPL ).
Genes regulating inflammation
•Other important genes in the ischemic heart
disease pathogenesis are genes regulating inflammation
and influencing adhesion molecules.
•Polymorphisms of the following genes have been
investigated genes of: the tumor necrosis factor
(TNF alpha and beta) transforming growth factor
beta (TGF-beta 1), interleukin, CD14, selectine P
and E, and platelet endothelial cell adhesion molecule
(PECAM-1)
Genes of the renin - angiotensin ñ-aldosterone
System
•Other investigated genes concern the renin- angiotensin - aldosterone
system (RAA) which is considered an important factor in the etiopathogenesis
of circulatory system diseases.
Genes of the coagulation system and fibrinolysis
•The thrombotic process is a very important factor
in ischemic heart disease, particularly in acute coronary events
Genes connected with thrombocytes
•Genes regulating the function of thrombocytes constitute another group of
genes significant for the development of ischemic heart disease. In the centre
of interest are glycoproteins (GP) of platelet cell membrane responsible for their
aggregation
ANNA WOJTCZAK* and JADWIGA SKR TKOWICZ 2008
Some candidate genes associated with ischemic heart disease.
Alle or polymorphismss
ATP-bindingcassette
transporter A1 (ABCA1)
mutations.
ABCA A1
V771M,
I883M
E1172D
R1587K
V825I
R219K
D allele
of the ACE gene
MTTP polymorphisms 493G>T and -164T>C
Lipoprotein lipase gene
S447X
phenotype
Tangier disease
association
Increase risk of IHD
p = 0.005
IHD
Study
Copenhagen City
Heart study
2005
predict risk of IHD
Ruth Frikke et.al
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2008
-Myocardial
infarction
-IHD
P =0.56
P=0.24
IHD
P= < 0.05
Myocardial
infarction
p<0.01
LTA
CHD
rs909253 and rs1041981
p.value
-
No association with
ischemic heart
disease or
myocardial
infarction.
associated with
increased risk of IHD
confer protection from
Myocardial infarction
not strongly
associated with
susceptibility to CAD
Klaus.L Indpain
et. al 1995
Anna Aminoff
2009
Costa Rica
2004
Robert Clarke et.al
2006
ABCA1
Cassette transporter A1 -ATP-binding (ABCA1)
•Type of study:cohort study/24 years
•Tangier disease, a rare high-density lipoprotein cholesterol
(HDL-C) deficiency syndrome with IHD, is caused by
homozygous ABCA1 mutations
•The cumulative incidence of IHD as a function of age was increased
in K776N heterozygotes compared with non-carriers (p =0.005)
•Results :Heterozygosity for an ABCA1 mutation (K776N)
conferred two- to three-fold risk of IHD
Ruth Frikke-Schmidt et.al
2005
LTA
Lymphotoxin-a and Risk of Myocardial Infarction
Type of study:case-control study
•(LTA) is a pro-inflammatory cytokine that plays an important role in the immune
system and local inflammatory response known also as (TNF-β).
•LTA is expressed in atherosclerotic plaques and has been implicated in the
pathogenesis of atherosclerosis and coronary heart disease (CHD).
•Polymorphisms in the gene encoding lymphotoxin-a (LTA) on Chromosome
6p21 have been associated with susceptibility to CHD.
•seven SNPs (including the rs909253 and rs1041981 SNPs previously
implicated in the risk of CHD
•Results: polymorphisms for the LTA gene are not strongly associated with
susceptibility to coronary disease.
Robert Clarke et.al 2006
lipoprotein lipase gene
To assess common variants of the LPL gene that could influence susceptibility to
myocardial infarction (MI)
Type of study: case -control study
The carriers of the X447 allele, known to decrease triglyceride levels
in plasma, had a decreased risk of MI
Results:
the X447 mutant allele is associated with a modest decrease of MI risk among
residents of the Central Valley of Costa Rica.
Yang et al.2004
ANGIOTENSIN-CONVERTING–ENZYME GENE POLYMORPHISM
•Homozygosity for the deletional allele (D) of the angiotensin-converting–enzyme (ACE )
•Type of study:case-control study
•Results. The ACE genotype was not associated with the occurrence of either ischemic
heart disease or Myocardial infarction. The adjusted relative risk associated with the D
allele was 1.07 (95 percent confidence interval, 0.96 to 1.19; P =0.24) for ischemic heart
disease and 1.05 (95 percent confidence interval, 0.89 to 1.25; P =0.56) for myocardial
infarction.
KLAUS L INDPAINTNER et.al 1995
MTTP
•Promoter polymorphisms in (microsomal triglyceride transfer protein (MTTP) have been
associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD)
•presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in
lower transcription of MTTP in vivo in the heart, liver and macrophages.
•Type of study: case-control study
•Results: ( -493G>T )single nucleotide polymorphism (rs1800591) has been associated with
metabolic traits and ischemic heart disease, IHD
•Minor MTTP -164C variant resulted in lower expression of MTTP in the heart, liver and
macrophages, most likely due to a reduced binding of C/EBPs. CCAAT/enhancer binding protein
•The -164C allele was associated with increased risk for IHD and we postulate that lower
concentration of MTTP results in increased lipid accumulation in the myocardium and thus
increased susceptibility to IHD.
Anna Aminoff et.al 2009
Combined Effects of Thrombosis Pathway Gene Variants
Prospectively followed population cohorts
•The role of four thrombosis genes: coagulation factor V (F5), intercellular
adhesion molecule 1 (ICAM1), protein C (PROC),and thrombomodulin
(THBD) in cardiovascular diseases CVD risk.variants were identified:
•In women combination of F5 rs75422813THBD rs1042580,
together with three single F5 SNPs, was associated with CVD events
•Among men, PROC rs1041296, when combined with either ICAM1
rs5030341 or F5 rs2269648, was associated with total mortality
•As a single variant, PROC rs1401296, together with theF5 Leiden mutation,
was associated with ischemic stroke events.
•Results: variants in these four thrombosis genes contribute to arterial
Cardiovascular events at population level
Kirsi Auro et.al 2007
C-reactive protein
•CRP is a marker for ischemic vascular disease
•Method:general population cohort ,cross-sectional general population study.
• Results:The risk of ischemic heart disease and ischemic cerebrovascular
disease was increased by a factor of 1.6 and 1.3, respectively, in persons
who had CRP levels above 3 mg per liter Genotype combinations of the four
CRP polymorphisms were associated with an increase in CRP levels
Jeppe Zacho, M.D 2008
GATA2 and Coronary Artery Disease
•Family-based sample
•The transcription factor GATA2 plays an essential role in the
establishment and maintenance of adult hematopoiesis
expressed in hematopoietic stem cells, as well as the cells that
make up the aortic vasculature, namely aortic endothelial cells
and smooth muscle cells..
• Five SNPs significantly associated with early-onset CAD
• Results: polymorphisms in the 3` end of GATA2 may increase
susceptibility to developing CAD.
Jessica J. Connelly et.al 2006
Prevention
Risk factors like a fatty diet, smoking, sedentary lifestyle
and stress should be avoided, as they are the main areas
of focus in prevention. Avoiding foods rich in saturated fats
is vital to reduce lipid levels in the blood and to prevent
arteriosclerosis. Adequate regular exercise is also
essential. Diabetes Mellitus and hypertension should be
kept under good control with proper treatment.
Conclusion
•Research concerning the impact of particular
genes variants upon ischemic heart disease is difficult
and complex because of the multifactorial character
of this disease as well as of the interaction of genetic
and environmental factors
•Studies of genetic etiopathogenesis of ischemic
heart disease will certainly result in more effective
prevention and therapy of particular patients.
Recommendations for Future Practice and Research
•Continue to use family history as a tool to identify susceptible individuals and families.
•Develop a research infrastructure.
•Prioritize gentic studies.
• Prepare proactively for effective genetic screening programs
•Educate researchers, clinicians, public health professionals, and the general public.
Thank You