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GENETIC SUSCEPTABILITY OF ISCHEMIC HEART DISEASE (IHD )

GENETIC SUSCEPTABILITY OF ISCHEMIC HEART DISEASE (IHD ). By Assad Mohi Eldin Sara M.Abuel Gassim. Content: - Introduction Epidemiology Pathology Genetic Analysis Conclusion By: -Sara Abu Algasim - Asaad Mohi Eldin. DEFINITION. The common name: Coronary Artery Disease (CAD).

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GENETIC SUSCEPTABILITY OF ISCHEMIC HEART DISEASE (IHD )

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  1. GENETIC SUSCEPTABILITY OF ISCHEMIC HEART DISEASE(IHD) By Assad MohiEldin Sara M.AbuelGassim

  2. Content: - Introduction • Epidemiology • Pathology • Genetic Analysis • Conclusion By: -Sara Abu Algasim -AsaadMohiEldin

  3. 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).

  4. Clinical Manifestations: • There are 4 defined clinical pictures: • Angina pectoris (chest pain)/ stable/variant/unstable • Acute myocardial infarction MI • Heart failure • Sudden cardiac death (SCD) • All are considered as late manifestations of coronary atherosclerosis.

  5. Coronary heart disease

  6. 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), exercise-tolerance test, thallium stress test, blood studies to measure total fat, cholesterol and lipoproteins, X-rays of the chest and coronary angiogram.

  7. 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).

  8. 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……

  9. 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.

  10. Stent

  11. Coronary Bypass Graft

  12. 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

  13. 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)

  14. GENETIC SUSCEPTABILITY

  15. 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, aldosteronesynthetase) • 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

  16. 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)

  17. 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.

  18. 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)

  19. 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.

  20. 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.

  21. 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.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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.`

  27. 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

  28. 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.

  29. 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.

  30. 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)

  31. 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.

  32. 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.

  33. 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)

  34. 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.

  35. 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.

  36. Genome-wide scan for HDL3-C in the Framingham Study • High density lipoprotein cholesterol (HDL-C) isinversely associated with coronary heart disease and has agenetic componentSubfractions of HDL, such as HDL 3 -C, is a betterphenotypes for linkage studies. genome-wide variance components linkage analysis with 401microsatellite 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

  37. 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) 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

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