SHAPE Society

1. Editorial Slides
VP Watch - May 29, 2002 - Volume 2, Issue 21
K-ras Polymorphism in Cancer,
….for Atherosclerosis? (PART II)

2.  Coronary artery disease is a
complex genetic disease with
many genes involved,
environmental influences, and
important gene-environment
interactions.

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. 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.  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.  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.  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.  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.  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.  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.  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.  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.  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.  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. 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. 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. 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. 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. 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