SHAPE Society

1. Editorial Slides
VP Watch - May 22, 2002 - Volume 2, Issue 20
K-ras Polymorphism in Cancer,
….for Atherosclerosis?

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

4.  Epidemiologic studies show
variant distribution of coronary
artery disease within and
between populations:
Diet and environmental factors
Genetic factors

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.  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.  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.  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.  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.  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.  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.  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.  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. 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. 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. 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. 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