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  1. 1. Editorial Slides VP Watch - May 29, 2002 - Volume 2, Issue 21 K-ras Polymorphism in Cancer, ….for Atherosclerosis? (PART II)
  2. 2.  Coronary artery disease is a complex genetic disease with many genes involved, environmental influences, and important gene-environment interactions.
  3. 3.  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)
  4. 4. Inflammation and Immune Response Endothelial Function Lipid Metabolism TNF-α eNOS Paraxonase TNF-β ACE APO-E TGF-ß NADP(H) APO-A I IL-1 E-selectin APO-A II IL-6 PCAM-1 IL-10 MMP-7
  5. 5.  Tumor Necrosis Factor  ECTIM study: no association between TNF-α polymorphisms and MI or CAD.2  In an autopsy series and Padovani et al. also found no association between -308A TNF-α polymorphism and infarction.3,4  Braun et al. showed no association between TNF-β and presence or extent of coronary disease.5 Polymorphism of Inflammatory Molecules
  6. 6.  Transforming Growth Factor  Cambien et al. in ECTIM study showed that TGF-ß1 polymorphisms were not associated with the degree of angiographically assessed coronary artery disease in patients.6  They also found that Pro25 allele of TGF- ß1 was more frequent in patients than in control subjects in specific regions. Polymorphism of Inflammatory Molecules
  7. 7.  Interleukins  Momiyama et al. found that IL-1 gene polymorphisms influence the susceptibility to the atherogenic effect of Chlamydia pneumoniae infection.7  They showed that patients with such variants are more likely to develop CAD associated with Chlamydia pneumoniae infection. Polymorphism of Inflammatory Molecules
  8. 8.  Interleukins  Francis et al. in 1998 showed that carriage of *2 of IL- 1RN is significantly associated with the presence of single-vessel coronary disease .8  Recently Koch et al. found that allele frequencies, genotype distributions, and frequencies of allele combinations for three IL-10 promoter polymorphisms were similar between CAD, MI, and matched controls.9  Donger et al. also showed that IL-10 polymorphisms are not associated with increased risk of MI.10 Polymorphism of Inflammatory Molecules
  9. 9.  Interleukins  Carotid intima media thickness is higher among subjects homozygous for functional variants in gene related to IL6 -174G.20  Brull et al. showed that IL6-174G > C promoter polymorphism influences endothelial function in healthy male subjects.21 Polymorphism of Inflammatory Molecules
  10. 10.  Shimada et al. showed that CD14 monocyte receptor gene polymorphism is associated with acute MI rather than with coronary atherosclerosis. This polymorphism may be linked to plaque vulnerability and it may be one of the genetic risk factors for acute MI in Japanese men.11  Sasaoka and colleagues showed that PECAM-1 polymorphisms are significantly associated with MI in Japanese.12 Polymorphism in Inflammation and Immune Response
  11. 11.  In 1992 Cambien et al. found that DD variant of angiotensin converting enzyme (ACE) gene, which is associated with higher circulating ACE than other genotypes, is more frequent in MI patients, especially in those with low plasma levels of ApoB.13  Prasad et al. showed that patients with the D allele and higher ACE levels had greater improvement in endothelial dysfunction after treatment with ACE inhibitor. 14 Polymorphism in Endothelial Function
  12. 12.  Jormsjö et al. found functional polymorphisms influencing the transcriptional activity of the MMP-7 gene and its relation with CAD.17  Colombo and colleagues showed the association between the common Glu298 Asp polymorphism of the eNOS gene. 19 Polymorphism in Endothelial Function
  13. 13.  Study showed significant associations between -514 C/T hepatic lipase polymorphism and HDL, LDL and apo A-I were observed before and/or after 3 months of HRT.15  Boerwinkle et al. found that Apo E genotype ε 2/3 was related to carotid atherosclerotic disease. 18 Polymorphism in Lipid Metabolism
  14. 14.  As reported in VP Watch of this week, Ridker and Zee in Physicians' Health Study showed that plasma CRP significantly reduces among carriers of a 1059G/C polymorphism in the human CRP gene (GC or CC) as compared with non-carriers (GG).16  They showed that this polymorphism is not significantly associated with risk of arterial thrombosis despite the fact that CRP concentration is a potent independent predictor of future vascular events in this cohort study.
  15. 15. Conclusion  There is no evidence of a univariate association between the 1059G/C polymorphism of CRP gene and subsequent risk of arterial thrombosis.  Genetic and environmental determinants each importantly contribute to the vascular risk associated with inflammation.
  16. 16. 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?
  17. 17. 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?
  18. 18. 1) Tai ES, Demissie S, Cupples LA, Corella D, Wilson PW, Schaefer EJ, Ordovas JM.; Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):805-10. 2) Herrmann SM, Ricard S, Nicaud V, et al. Polymorphisms of the tumour necrosis factor-alpha gene, coronary heart disease and obesity. Eur J Clin Invest 1998;28:59–66 3) Padovani JC, Pazin-Filho A, Simoes MV, et al. Gene polymorphisms in the TNF locus and the risk of myocardial infarction. Thromb Res 2000;100:263–9 4) 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. 5) Braun J, Marz W, Winkelmann BR, et al. Tumour necrosis factor ß alleles and hyperinsulinaemia in coronary artery disease. Eur J Clin Invest 1998;28:538–42 6) Ricard S, Troesch A, et al. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The étude cas-temoin de l'infarctus du myocarde (ECTIM) study. Hypertension 1996;28:881–7. 7) Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F.; Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection. J Am Coll Cardiol. 2001 Sep;38(3):712-7. 8) Sheila E. Francis, Nicola J. Camp, Rachael M. Dewberry, Julian Gunn, Petros Syrris, Nicholas D. Carter, Stephen Jeffery, Juan Carlos Kaski, David C. Cumberland, Gordon W. Duff, and David C. Crossman ; Interleukin-1 Receptor Antagonist Gene Polymorphism and Coronary Artery Disease Circulation 99: 861-866 9) Koch W, Kastrati A, Bottiger C, Mehilli J, von Beckerath N, Schomig A.; Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction.; Atherosclerosis. 2001 Nov;159(1):137-44. 10) Donger C, Georges JL, Nicaud V, Morrison C, Evans A, Kee F, Arveiler D, Tiret L, Cambien F.; New polymorphisms in the interleukin- 10 gene--relationships to myocardial infarction.; Eur J Clin Invest. 2001 Jan;31(1):9-14. 11) Shimada K, Watanabe Y, Mokuno H, Iwama Y, Daida H, Yamaguchi H.; Common polymorphism in the promoter of the CD14 monocyte receptor gene is associated with acute myocardial infarction in Japanese men.; Am J Cardiol. 2000 Sep 15;86(6):682-4. 12) Sasaoka T, Kimura A, Hohta SA, Fukuda N, Kurosawa T, Izumi T.; Polymorphisms in the platelet-endothelial cell adhesion molecule-1 (PECAM-1) gene, Asn563Ser and Gly670Arg, associated with myocardial infarction in the Japanese.; Ann N Y Acad Sci. 2001 Dec;947:259-69; discussion 269-70. 13) F. Cambien, O. Poirier, L. Lecerf, A. Evans, J.P. Cambou, D. Arveiler, G. Luc, J.M. Bard, L. Bara, S. Ricard, L. Tiret, P. Amouyel, F. Alhenc-Gelas and F. Soubrier, Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 359 (1992), pp. 641¯644. 14) Prasad A, Narayanan S, Husain S, Padder F, Waclawiw M, Epstein N, Quyyumi AA.; Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition.; Circulation. 2000 Jul 4;102(1):35-41. 15) Kimiko Yamakawa-Kobayashi, Yoshiaki Somekawa, Mitsuko Fujimura, Shigeo Tomura, Tadao Arinami and Hideo Hamaguchi; Relation of the -514C/T polymorphism in the hepatic lipase gene to serum HDL and LDL cholesterol levels in postmenopausal women under hormone replacement therapy, Pages 17-21 References
  19. 19. 16) Robert Y. L. Zee and Paul M. Ridker; Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis, Pages 217-219 17) Jormsjo S, Whatling C, Walter DH, Zeiher AM, Hamsten A, Eriksson P.; Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients.; Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1834-9. 18) 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. 19) M G Colombo, M G Andreassi, U Paradossi, N Botto, S Manfredi, S Masetti, G Rossi, A Clerico, and A Biagin ; Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298 Asp polymorphism) to the presence, extent, and severity of coronary artery disease; Heart 2002; 87: 525-528 20) Carotid intima-media thickness is associated with allelic variants of stromelysin-1, interleukin-6, and hepatic lipase genes: the Northern Manhattan Prospective Cohort Study. Stroke. 2002 May;33(5):1420-3. 21) Brull DJ, Lesson CP, Montgomery HE, Mullen M, deDivitiis M, Humphries SE, Deanfield JE. The effect of the Interleukin-6-174G > C promoter gene polymorphism on endothelial function in healthy volunteers. Eur J Clin Invest. 2002 Mar;32(3):153-7. References