Can You Inherit A Carotid Plaque?!

Genetic Influence on Carotid Atherosclerosis

Xiaohong Wu, PhDMehran Haidari, PhD

Gene Array LaboratoryCenter of Vulnerable Plaque Research

Texas Heart Institute

• 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.

• 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.

Genetic Mechanisms of Diseases

• Gene-Gene Interaction• Gene-Environment Interaction• Monogenic Cause• Multigenic Cause

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 links Criteria in establishing medically useful links between genetic variations and diseasebetween genetic variations and disease11::

• 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.

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

• 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.

• 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.

• 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.

• 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 (Leu6Pro) 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.

• 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.

• 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.

• 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.

• 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.

Genetic Diagram in Atherosclerosis

• 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.

• 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.

• 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.

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 environmental

Phenotypic, Genetic, and Environmental Correlations Between Carotid Artery Plaque, Selected Cardiovascular Risk Factors, and Clinical

Cardiovascular Disease

WC, mmType-2 DM, %HPT, %Smoker, %Cli CVD, %

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• Adjusted for age, sex and body mass index. PE indicates point estimate; WC indicates waist circumference; DM, diabetes mellitus; HPT, hypertension; Cli CVD, Clinical cardiovascular disease.

Adapted from stroke. 2002;33:2775-2780

PE

• 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.

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.

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.

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?

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?

Questions:

• What is the role of “Genetic Modifiers” in atherosclerosis?

• What is the role of “Genetic Modifiers” in develoment of vulnerable plaque?

ReferencesReferences• RosenthalN and Schwartz RS. In search of perverse polymorphisms. RosenthalN and Schwartz RS. In search of perverse polymorphisms. N Engl J. MedN Engl J. Med 1998; 338:122-4. 1998; 338:122-4.

• 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 Opin Curr Opin Lipidol Lipidol 1999;10: 285-291.1999;10: 285-291.

• Boerma M, forsberg L, and et al. Agenetic polymorphism in connexin 37 as a prognostic marker for Boerma 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 investigation European 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, genetic Richard 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: 109:666-71 1997: 109:666-71

• Kostulas K, Huang W-X, and et al. An angiotensin-converting enzyme gene polymorphism suggests a Kostulas 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 clinical European Journal of clinical investigation investigation (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 is Niskanen 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 Control Associated with Enhanced carotid atherosclerosis in Elderly Patients with Type 2 Diabetes and Control Subjects. Subjects. The Journal of Clinical Endocrinology & Metabolism The 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, 2001 24(3): 500-503, 2001

• Rundek T, Elkind MS, and et al. Carotid Intima-Media Thickness is Associated with Allelic Variants of Rundek 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

• Mannami T et al. Low potentiality of angiotensin-converting enzyme gene insertion/deletion 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. Stroke Stroke 2002;33:2775-27802002;33:2775-2780

• 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