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  1. 1. Editorial Slides VP Watch - May 22, 2002 - Volume 2, Issue 20 K-ras Polymorphism in Cancer, ….for Atherosclerosis?
  2. 2.  K-ras is one of the best characterized tumor-related genes, which somatically mutates in several types of sporadic human cancers.  K-ras polymorphism is used for early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers.
  3. 3.  Coronary artery disease is a complex genetic disease with many genes involved, environmental influences, and important gene-environment interactions.
  4. 4.  Epidemiologic studies show variant distribution of coronary artery disease within and between populations: Diet and environmental factors Genetic factors
  5. 5.  Polymorphisms of the following routes may affect atherosclerosis: Lipid metabolism (e.g. ApoA-I Milano, ApoE) Inflammation and immune response (e.g. IL-1- beta, IL-10) Endothelial function (e.g. eNOS, NADP(H)- oxidase)
  6. 6.  A common genetic variation that influences LDL in the population is in the ApoE gene.  Hixson et al. have shown that LDL cholesterol levels are approximately 10 to 20 mg/dl higher in E4/3 subjects and 10 to 20 mg/dl lower in E3/2s compared with E3/3s. 4 Polymorphism in Lipid Metabolism
  7. 7.  Boerwinkle et al. found that Apo E genotype ε 2/3 was related to carotid atherosclerotic disease. 7  Hooft et al. showed that Apo-AII -265C allele is associated with decreased plasma apoA-II concentration, enhanced postprandial metabolism of large VLDL, and decreased waist circumference in healthy 50-year-old men. 1 Polymorphism in Lipid Metabolism
  8. 8.  Frequency of the 192R allele of the human paraoxonase 1 gene may be an independent risk factor for CAD. 10  Human paraoxonase (PON)1 has two genetic polymorphisms. Studies show no significant association between PON1 L55M polymorphism and CAD risk. Polymorphism in Lipid Metabolism
  9. 9.  Keso et al. found no significant association between TNF-α –308A polymorphism and either frequency of healed myocardial infarction and coronary thrombosis or number and severity of coronary stenoses.  E selectin polymorphism increases the risk of atherosclerosis (but not necessarily of infarction), especially in younger patients.  PECAM 1 polymorphism may increase the risk of atherosclerosis (but not necessarily of infarction), especially in patients with a low atherosclerotic risk profile. Polymorphism in Inflammation and Immune Response
  10. 10.  The IL 1 gene variants are not significantly associated with the presence or extent of disease, whereas homozygosity for IL 1ra is significantly associated with single vessel disease. 9  IL-1ra may act as a "disease modifying" rather than a causative polymorphism. Polymorphism in Inflammation and Immune Response
  11. 11.  One of the most important endothelial cell products is nitric oxide (NO), which is synthesised from L-arginine by the endothelial nitric oxide synthase (eNOS).  NO plays a key role in the relaxation of vascular smooth muscle, inhibits platelet and leucocyte adhesion to the endothelium, reduces vascular SMC migration and proliferation, and limits the oxidation of atherogenic LDL. 5 Polymorphism in Endothelial Function
  12. 12.  Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. Accumulation of this endogenous inhibitor of NO synthase is an important risk factor for cardiovascular disease in chronic renal failure and suggest a possible link between ADMA and inflammation.  The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of coronary heart disease. Polymorphism in Endothelial Function
  13. 13.  As reported in VP Watch of this week, Colombo and colleagues showed the association between the common Glu298 Asp polymorphism of the eNOS gene.  They found an excess of homozygosity for the Asp298 variant among CAD cases compared with controls, and the risk of developing CAD was about 3-fold higher for Asp298 homozygotes than in persons with a Glu298 allele in the eNOS gene.
  14. 14. Conclusion  eNOS Glu298 Asp polymorphism is associated with the presence, extent, and severity of angiographically assessed coronary artery disease.  In the process of atherosclerotic remodeling of human vessels, alterations in NO production resulting from the substitution of Glu298 with Asp298 could have a major impact on SMC migration and proliferation. .
  15. 15. Questions: • What are the major gene polymorphism studies to be done in order to explain variations found in atherosclerosis within and between population? • Knowing atherosclerosis as an inflammatory disease with a major metabolic component, polymorphism of which of these 2 components (immune response and lipid metabolism) is more important?
  16. 16. Questions: • Since atherosclerosis is largely affected by “modifiers”, the question is whether polymorphism in modifier genes can explain variations in atherosclerosis and its outcome? • Do you expect discovery of a gene (a group of genes) like K-ras in cancer, for atherosclerosis?
  17. 17. 1) Van’t Hooft F, Ruotolo, G, Boquist S, et al. Human evidence that the apolipoprotein A-II gene is implicated in visceral fat accumulation and metabolism of triglyceride-rich lipoproteins. Circulation. 2001; 104: 1223–1228 2) Hopkins PN, Williams RR. A survey of 246 suggested coronary risk factors. Atherosclerosis 1981;40:1–52. 3) Breslow, J. L. (2000). GENETICS OF LIPOPROTEIN ABNORMALITIES ASSOCIATED WITH CORONARY HEART DISEASE SUSCEPTIBILITY. Annu. Rev. Genet. 34: 233-254 4) Hixson JE. 1991. Apolipoprotein E polymorphisms affect atherosclerosis in young males. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler. Thromb. 11:1237–44 5) vSchmidt HHHW, Walter U. NO at work. Cell 1994;78:919–25 6) Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM.; LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res. 2000 Jul 21;87(2):99-105. 7) de Andrade M, Thandi I, Brown S, Gotto A Jr, Patsch W, Boerwinkle E.; Relationship of the apolipoprotein E polymorphism with carotid artery atherosclerosis.; Am J Hum Genet. 1995 Jun;56(6):1379-90. 8) Keso T, Perola M, Laippala P, et al. Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men. Atherosclerosis 2001;154:691–7 9) Francis SE, Camp NJ, Dewberry RM, et al. Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease. Circulation 1999;99:861–6 10) Osei-Hyiaman D, Hou L, Mengbai F, Zhiyin R, Zhiming Z, Kano K. Coronary artery disease risk in Chinese type 2 diabetics: is there a role for paraxonase 1 gene (Q192R) polymorphism?; Eur J Endocrinol. 2001 Jun;144(6):639-44. References