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GENETIC SUSCEPTABILITY OF ISCHEMIC HEART DISEASE
(IHD) By
Assad Mohi EldinSara M.Abuel Gassim
• Content:- Introduction- Epidemiology- Pathology - Genetic Analysis- ConclusionBy:-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/unstable2. Acute myocardial infarction MI3. Heart failure 4. Sudden cardiac death (SCD) • All are considered as late manifestations of
coronary atherosclerosis.
Coronary heart disease
DiagnosisClinical 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), exercise-tolerance 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:• 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.
• 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(2003-
2006)+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
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 Polymorphism Association /IHD EffectApoB C516T Significant - Increase LDL
Apo E E4 Significant - Increase MI in young
CETP B1Ile405Val
Significant -↑Atherosclerosis
LPL Ser474Ter Significant -↓ Atherosclerosis- ↓ IHD
PON1 T107CQ192RL55M
N/C -Anti Oxidant properties Of HDL
HL -480C480T
Significant -↑HDL
Gene Polymorphism/ or Genotype
Association /IHD Effect
GPIIIa P1AP1A2
-Significant- N/C
-Increase MI / Aggregation/Atherosclerosis-Inc
GPIIb 807T/873A Significant -↑risk of MI
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.
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
• 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, Ser563Asn- showed 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 glycosyl- phosphatidylinositol 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 fromthe initial linkage analysis was 3.7 at 133 cM on chromosome 6.•SNP rs2257104 in PLAGL1 at_ 143 cM was associated with multivariableadjusted HDL 3 (P=0.03) Yang et al.2005
Genetic Variation associated with Ischemic Heart FailureMeta-Analysis• Seven polymorphisms (angiotensin-converting enzyme insertion/deletion (ACE I/D),
angiotensinogen (AGT) M235T, α2C subtype-adrenergic receptor (ADRA2C) Del322-325, 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 thesequence of the large antisense noncoding RNA ANRILwhich 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 rs2891168being 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 lipidmetabolism 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 heartdisease pathogenesis are genes regulating inflammationand influencing adhesion molecules.•Polymorphisms of the following genes have beeninvestigated genes of: the tumor necrosis factor(TNF alpha and beta) transforming growth factorbeta (TGF-beta 1), interleukin, CD14, selectine Pand E, and platelet endothelial cell adhesion molecule (PECAM-1)
Genes of the renin - angiotensin ñ-aldosteroneSystem•Other investigated genes concern the renin- angiotensin - aldosterone system (RAA) which is considered an important factor in the etiopathogenesisof circulatory system diseases.
Genes of the coagulation system and fibrinolysis•The thrombotic process is a very important factorin 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 centreof interest are glycoproteins (GP) of platelet cell membrane responsible for their aggregation ANNA WOJTCZAK* and JADWIGA SKR TKOWICZ 2008
Alle or polymorphismss phenotype p.value association Study ATP-bindingcassette transporter A1 (ABCA1) mutations.
Tangier diseasep = 0.005
Increase risk of IHD
Copenhagen City Heart study2005
ABCA A1V771M, I883M E1172D R1587K V825I R219K
IHD -
predict risk of IHD
Ruth Frikke et.al2008
D alleleof the ACE gene
-Myocardial infarction-IHD
P =0.56
P=0.24
No association with ischemic heart disease or myocardialinfarction.
Klaus.L Indpainet. al 1995
MTTP polymorphisms -493G>T and -164T>C IHD P= < 0.05
associated with increased risk of IHD
Anna Aminoff 2009
Lipoprotein lipase geneS447X Myocardial
infarctionp<0.01
confer protection from Myocardial infarction Costa Rica
2004
LTA rs909253 and rs1041981
CHD -not strongly associated with susceptibility to CAD
Robert Clarke et.al 2006
Some candidate genes associated with ischemic heart disease.
ABCA1 Cassette transporter A1 -ATP-binding (ABCA1)
• Type of study:cohort study/24 years
• 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
• Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations
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
To assess common variants of the LPL gene that could influence susceptibility to myocardial infarction (MI)
Type of study: case -control study
lipoprotein lipase gene
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 ICAM1rs5030341 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 arterialCardiovascular 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 particulargenes variants upon ischemic heart disease is difficultand complex because of the multifactorial characterof this disease as well as of the interaction of geneticand environmental factors•Studies of genetic etiopathogenesis of ischemicheart disease will certainly result in more effectiveprevention 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
