This document summarizes research on the genetic factors influencing the development of carotid atherosclerosis and plaque. Several studies have found heritability of carotid plaque and genetic influences on atherosclerosis risk factors like hypertension and diabetes. While some genes like ACE, CX37, and mitochondrial DNA variants have been linked to plaque development, results have been inconsistent. Further research is needed to better understand genetic and environmental interactions, and identify both risk and protective genetic factors, in order to improve prevention and treatment of atherosclerosis.

1. Can You Inherit A Carotid
Plaque?!
Genetic Influence on Carotid Atherosclerosis
Xiaohong Wu, PhD
Mehran Haidari, PhD
Gene Array Laboratory
Center of Vulnerable Plaque Research
Texas Heart Institute

2. • Atherosclerosis is a common, but
complex, multifactorial disorder that
accounts for much of morbidity and
mortality in adult life.
• Several complex mechanisms have
been hypothesized to play a key role in
the development of atherosclerosis,
including metabolic and inflammatory
processes.

3. • The new developments in molecular
biology have directed research of
human disease etiology towards its
genetic basis.
• The understanding of the genetic basis
of a disorder and the insight into the
way genetic information is expressed or
modulated by the environment will have
a major impact on treatment and
prevention of disease.

4. Genetic Mechanisms of
Diseases
• Gene-Gene Interaction
• Gene-Environment Interaction
• Monogenic Cause
• Multigenic Cause

5.  The change in the gene must cause a relevant
alteration in the function or level of the gene
product.
 The beneficial and harmful phenotypes must have
apparent clinical differences.
 The hypothesis linking the genotype to disease
must be convincing.
 The number of cases linking a genotype to disease
must be sufficient.
Criteria in establishing medically useful linksCriteria in establishing medically useful links
between genetic variations and diseasebetween genetic variations and disease11
::

6. • It is estimated that more than 400 genes
fairly involved in the regulation of the
atherosclerotic plaque such as endothelial
function, coagulation, Inflammation,
carbohydrate and amino acid
metabolism2
.
• The role of only a minority of genes
involved in the atherosclerotic process is
known.

7. Which Chromosome?
• Several investigators have reported
atherosclerosis susceptibility loci on
different chromosomes.
• Breslow and colleagues discovered
atherosclerosis susceptibility loci on
chromosomes 10, 14, and 19 in mice.13

8. • A genetic polymorphism in connexin 37 was
reported as a prognostic marker for
atherosclerotic plaque development.3
• Connexin 37 (cx37) is a gap junctiuonal protein
uniquely expressed in endothelial cells.
• Recently, Richard and co-workers detailed a
variant form of cx37 with a C to T shift at
codon 1019. This causes a shift from proline
to serine at amino acid 303 in the original
published protein sequence4
.

9. • The study on the allelic distribution in well defined
human populations demonstrates that one allelic form
of the cx37 gene ( base-pair 1019 C of the coding
region, cx37 *1) is significantly over-represented in
human populations exhibiting well-defined thickening
of the carotid intima, irrespective of a history of
hypertension.
• It suggest that the C1019-T polymorphism in cx37
may provide a “single gene marker”, which could be
useful in assessing atherosclerotic plaque
development, particularly in cardiovascular risks
groups such as those with borderline hypertension.

10. • The gene coding for the angiotensin I-converting
enzyme is of potential importance for the risk of
hypertension.
• An insertion/deletion polymorphism of the ACE gene
first intron has been reported to correlate with plasma
levels of ACE enzyme, and homozygosity of the
deletion allele is associated with increased ACE
concentrations, increased blood pressure, and has
also been reported to influence the risk for
cardiovascular disease.
• This Indicates that the ACE gene polymorphism may
be a risk factor for the development of Carotid
stenosis5
.

11. • Neuropeptide Y (NPY) is a member of the
pancreatic polypeptide family and
neuromodulator. It is the most abundant peptide
in the brain and heart.
• A rather common leucine to proline substitution
in codon 7 of the NPY gene (Leu6
Pro) was found
to be associated with common carotid intima
media thickness suggesting that leucine 7 to
Proline 7 Polymorphism in the Neuropeptide Y
Gene is Associated with Enhanced Carotid
Atherosclerosis in Elderly Patients with Type 2
Diabetes and Control Subjects6
.

12. • The mitochondrial genotype, Mt5178, derived
from the c->A transversion at nucleotide 5178
of mtDNA that causes a Leu-to-Met
substitution within the NADH dehydrogenase
subunit 2 (ND2) gene, was related to longevity
in the Japanese population.
• Further study7
in Japanese subjects with type 2
diabetes indicated that the Longevity-
associated mitochondrial genotype (Mt5178)
was significantly associated with carotid IMT
and carotid plaque, so this genotype may be
related to early atherosclerosis, at least in type
2 diabetic individuals.

13. • Polymorphism of stromyelysin-1, a key
regulator of matrix remodeling, is
involved in development of
atherosclerosis4
.
• Individuals who produce less MMP3
would have a lower ability to remodel
and degrade the matrix components,
leading to faster arterial wall thickening
and plaque growth8
.

14. • Genetic polymorphism in the
promoter region of the HL gene plays
a major role in the control of HDL2
cholesterol.
• High HL (Hepatic Lipase) activity is
associated with an increase in small
dense LDL particles and increased
risk of vascular events8
.

15. • A polymorphism of the interleukin-6
(IL-6) gene (inflammation ) with a
G>C change at position –174 has
been recently identified. 8
• It has been reported that individuals
homozygous for the G allele have
greater intima-media wall thickness
(IMT) than other subjects8
.

16. Genetic Diagram in Atherosclerosis

17. • It deserves merit consideration that several
studies have shown contrasting results
concerning the relation between different
genes polymorphism and carotid
atherosclerosis.
• For instance genetic polymorphism of
apolipoprotein E (apoE) is an important factor
in the development of coronary artery disease
but the results concerning apoE genotype
and carotid artery atherosclerosis remain
controversial.

18. • Erkki Ilveskoski9
et al investigated a random sample of
189 Finnish middle aged men (mean age 54 years,
range 50–59) to assess the role of apoE polymorphism
in the process of carotid atherosclerosis.
• The carriers of E3/2 (n=20) genotype had significantly
lower (P<0.01) total cholesterol and LDL cholesterol
concentrations than carriers of E3/3 genotype (n=109)
or the E4 allele (n=60). The overall mean IMT varied
significantly with apoE genotype and it was also lowest
in the carriers of E3/2 genotype.
• This suggests that apoE E3/2 genotype is a protective
factor in the development of carotid artery
atherosclerosis in randomly selected middle-aged men.
The favorable effect might be mediated at least partly by
the lowering effect of E3/2 genotype on serum
cholesterol.

19. • In a large Japanese population (Mannami10
) of
4031 subjects and an Australian study(Hung11
)
based on a population of 1111 subjects ,in
contrast to others, ACE Inhibitor gene
polymorphism was not found a potentially useful
predictive marker for carotid atherosclerosis.
• These inconsistency in the investigations cab be
attributable to ethnic difference, gene to gene
interaction, gene to environmental interaction
or simply because of methodological problems.

20. As reported in VP watch this week:
• Dr. Kelly J. Hunt and his colleague investigated
that the presence or absence of CAP (Carotid
Artery Plaque) was under genetic control in the
San Antonio Family Heart Study ( SAFHS ).
• SAFHS consists of 750 individuals distributed
across 27 families who participated in this
study.
• B-mode ultrasound evaluations of
atherosclerosis were completed on bilateral
segments of the extracranial carotid arteries.

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Phenotypic, Genetic, and Environmental Correlations Between Carotid
Artery Plaque, Selected Cardiovascular Risk Factors, and Clinical
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25. • Their results showed that liability to focal
CAP is heritable even after accounting
for the established cardiovascular
factors, which suggested that focal CAP,
diabetes, and self-reported clinical
cardiovascular disease have a common
genetic background.
• Increased age, male sex, smoking,
hypertension, diabetes, and in creased
waist circumference were associated
with the presence of focal CAP.

26. Conclusion:
• Atherosclerosis is a complex disorder
with environmental causes and strong
genetic basis.
• Studies in twins have revealed a greater
genetic risk in monozygotic than
dizygotic twins, and adoption studies
have shown that most of the excess risk
is genetic rather than environmental.

27. Conclusion:
• In many cases the outcome of the
atherosclerotic process is the result of the
interaction between the environment and
the genetic make-up of each individual.
• Intervention should be directed towards
both environmental and genetic risk
factors.

28. Questions:
• If carotid plaques can be inherited
and predicted independent of
traditional risk factors, what is the
take home message?
• Does it mean that we yet to discover
unknown risk factors that are
controlled by certain genes?

29. Questions:
• Which one is more likely to be influenced
by genetic factors, plaque development
(atherosclerosis) or plaque complications
(link to thrombosis)?
• In search for the genetic causes of
atherosclerosis, besides risk factors, do
we also need to look for protective factors
specially?

30. Questions:
• What is the role of “Genetic
Modifiers” in atherosclerosis?
• What is the role of “Genetic
Modifiers” in develoment of
vulnerable plaque?

31. ReferencesReferences
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• Funke H, Assmann G. Strategies for the assessment of genetic coronary artery disease risk.Funke H, Assmann G. Strategies for the assessment of genetic coronary artery disease risk. Curr OpinCurr Opin
LipidolLipidol 1999;10: 285-291.1999;10: 285-291.
• Boerma M, forsberg L, and et al. Agenetic polymorphism in connexin 37 as a prognostic marker forBoerma M, forsberg L, and et al. Agenetic polymorphism in connexin 37 as a prognostic marker for
atherosclerotic plaque development.atherosclerotic plaque development. European Journal of clinical investigationEuropean Journal of clinical investigation (1999) 29, 478-483.(1999) 29, 478-483.
• Richard G, Lin JP, Smith L et al. Linkage studies in erythrokeratodermias: fine mapping, geneticRichard G, Lin JP, Smith L et al. Linkage studies in erythrokeratodermias: fine mapping, genetic
heterogeneity, and analysis of candidate genes.heterogeneity, and analysis of candidate genes. J Invest DermatolJ Invest Dermatol 1997: 109:666-711997: 109:666-71
• Kostulas K, Huang W-X, and et al. An angiotensin-converting enzyme gene polymorphism suggests aKostulas K, Huang W-X, and et al. An angiotensin-converting enzyme gene polymorphism suggests a
genetic distinction between ischaemic stroke and carotid stenosis.genetic distinction between ischaemic stroke and carotid stenosis. European Journal of clinicalEuropean Journal of clinical
investigationinvestigation (1999) 29, 478-483.(1999) 29, 478-483.
• Niskanen L, karvonen MK, and et al. leucine 7 to Proline 7 Polymorphism in the neuropeptide Y gene isNiskanen L, karvonen MK, and et al. leucine 7 to Proline 7 Polymorphism in the neuropeptide Y gene is
Associated with Enhanced carotid atherosclerosis in Elderly Patients with Type 2 Diabetes and ControlAssociated with Enhanced carotid atherosclerosis in Elderly Patients with Type 2 Diabetes and Control
Subjects.Subjects. The Journal of Clinical Endocrinology MetabolismThe Journal of Clinical Endocrinology Metabolism 85(6): 2266-226985(6): 2266-2269
• Matsunaga, Hajime et al. Antitherogenic Mitochondrial Genotype in Patients with Type 2 Diabetes.Matsunaga, Hajime et al. Antitherogenic Mitochondrial Genotype in Patients with Type 2 Diabetes.
Diabetes CareDiabetes Care 24(3): 500-503, 200124(3): 500-503, 2001
• Rundek T, Elkind MS, and et al. Carotid Intima-Media Thickness is Associated with Allelic Variants ofRundek T, Elkind MS, and et al. Carotid Intima-Media Thickness is Associated with Allelic Variants of
Stromelysin-1, Interleukin-6, and Hepatic Lipase Genes.Stromelysin-1, Interleukin-6, and Hepatic Lipase Genes. StrokeStroke 2002;33:1420-1423.2002;33:1420-1423.
• Erkki IlveskoskiErkki Ilveskoski et al. Apolipoprotein E polymorphism and carotid artery intima-media thickness in a
random sample of middle-aged men Atherosclerosis 2000: 153(1): 147-153
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polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a
Japanese city: the Suita study. Stroke 2001 Jun:32 (6):1250-6
• Hung J et al . Angiotensin-converting enzyme gene polymorphism and carotid wall thickening in a
community population. ATVB 1999 aUG:19(8):1969-74
• Hunt KJ, Duggirala R and et al. Genetic Basis of Variation in Carotid Artery Plaque in the San Antonio Family Heart Study.Hunt KJ, Duggirala R and et al. Genetic Basis of Variation in Carotid Artery Plaque in the San Antonio Family Heart Study.
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• Smith JD, Dansky HM, Breslow JLSmith JD, Dansky HM, Breslow JL Ann N Y Acad Sci 2001 Dec;947:247-52; discussion 252-3Ann N Y Acad Sci 2001 Dec;947:247-52; discussion 252-3