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)
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?
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