Genetic and Environmental Factors in Cardiovascular Disease

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Genetic and Environmental Factors in
Cardiovascular Disease

• PHC 6921
• Fall 2006

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Cardiovascular Disease

• Cardiovascular disease (CVD) refers to a variety
  of diseases and conditions affecting the heart
  and blood vessels including
• Stroke
• Atherosclerosis
• Hypertension
• Arteriosclerosis
• Coronary heart disease (CHD)

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Cardiovascular Disease

• Cardiovascular disease is the leading cause of
  morbidity and mortality in adults in Western
  societies.
• African Americans have a disproportionate burden
  of CVD. The age-adjusted death rates from CHD
  currently greater than 35 higher in
  African-American men and almost 70 higher in
  African-American women compared to Caucasians.
• In 2002, an estimated 329 billion in health care
  cost were directly attributable to CVD which
  included both direct cost associated with medical
  care and indirect cost resulting from lost
  productivity from both CVD morbidity and
  mortality.

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Cardiovascular Disease

• No other chronic disease is influenced by the
  contribution of both genes and environments as
  cardiovascular disease.
• Sir Winston Churchill (leader of Great Britain
  during World War II) died at the age of 91 years
  despite a daily regimen of alcohol drinking,
  cigar smoking, and heavy eating through his adult
  life.
• Jim Fixx (Americas first running health guru)
  died from a massive heart attack at the age of
  52.

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Cardiovascular Disease

• CVD is multifactorial etiology involving both
  genetic and environmental factors.
• An individuals susceptibility to CVD is
  determined in large part by variation in levels
  of quantitative intermediate traits that
  influence the onset, development and severity of
  disease.
• This trait variation can result from both genomic
  and environmental variation and/or interaction
  between the two.

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Model of gene-environment interaction
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Cardiovascular DiseaseRisk Factors

• Age
• Smoking
• Elevated Blood Pressure
• Cerebrovascular Disease
• Renal Disease
• Obesity
• Increased intra-abdominal fat
• Type 2 diabetes
• Dyslipidemia
• Insulin Resistance

• PLASMA LIPIDS
• Elevated total and low density lipoprotein (LDL)
  cholesterol levels and
• Low levels of high density lipoprotein (HDL)
  cholesterol

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The New Genetics

• Genomics research will dramatically accelerate
  the development of new strategies for the
  diagnosis, prevention and treatment of disease,
  not just for single-gene disorders but for the
  host of more common complex diseases, e.g.
  cardiovascular disease

Collins FS, NEJM 199934128-37.
Duke Center for Human Genetics
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Cardiovascular DiseaseThe Ultimate Complex
Disorder

• CVD is a polygenic trait
• Rare single-gene exceptions (i.e. FH)

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Single Gene Cardiovascular Disorder

• Familial hypercholesterolemia (FH)
• Familial Hypercholesterolemia is a genetic
  disorder in the production OR function of LDL
  receptors which results in poor LDL clearing.

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Familial hypercholesterolemia (FH)

• Individuals with this disorder commonly develop
  premature atherosclerosis and are prone to die at
  the early age of a heart attack.
• Three possibilities of disorder
• 1. The LDL receptor is not produced
• 2. The receptor is produced but it has a lower
  than normal affinity for LDL
• 3. The receptor binds to LDL but the receptor-LDL
  complex is not taken into the cell by endocytosis
  (bulk uptake of material through the cell
  membrane).

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Familial hypercholesterolemia (FH)

• Familial hypercholesterolemia (FH) results
  primarily from mutations in the receptor for
  low-density lipoprotein (LDLR).
• Goldstein and Brown, showed that genetic
  variation in the LDLR gene can produce
• receptor binding defects
• receptor internalization defects and/or
• a nonfunctional receptor that results in the
  severe atherosclerotic plaque accumulation and
  premature mortality associated with FH.

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Familial Hypercholesterolemia(FH)
Corneal Arcus
Tendinous Xanthomas
Duke Center for Human Genetics
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Candidate Genes for Cardiovascular Disease

• No single gene has been shown or is expected to
  be responsible for the majority of the variation
  in CVD risk.
• The combined effects of multiple genes, each
  with polymorphic alleles having moderate trait
  effects, and multiple environments produce most
  of the genetic variation in CVD risk.

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CVD Candidate Genes
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CVD Candidate Genes

• The two genes that have been associated with both
  risk factor and disease state include
• cholesteryl ester transfer protein (CETP)
• guanine nucleotide binding protein beta 3
  subunit (GNB3)

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CETP Coronary Heart Disease

• Coronary Heart Disease
• -reduces the amount of blood that the coronary
  arteries are able to deliver to the myocardium
  causing damage
• - the degree of damage depends on the size of the
  arteries involved, whether occlusion is gradual
  or sudden.

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CETP Coronary Heart Disease

• As mentioned before, high levels of LDL
  cholesterol and low levels of HDL cholesterol are
  associated wit the development of
  atherosclerosis.
• Deposits of cholesterol in arterial plaques may
  be reduced by reverse cholesterol transport.
• Mechanism- The excess cellular cholesterol is
  carried by HDL, transferred to trigylcerides and
  then removed by the liver in secretion in bile.
• (Triglycerides- Also called triacylglycerol and
  consist of three fatty acids and one glycerol
  molecule covalently bound together).

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CETP Coronary Heart Disease

• The reverse cholesterol transport rate depends on
  the activity of a plasma protein, cholesteryl
  ester transfer protein (CETP), which facilitates
  transport of cholesteryl ester from HDL
  cholesterol to triglyceride-rich lipoproteins.
• The protein CETP regulates the rate of
  cholesterol transport toward the liver for
  excretion.
• The genetic variation that results in decreased
  activity of CETP has been associated with
  increases in HDL cholesterol.

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CETP Coronary Heart Disease

• The CETP gene has been localized to chromosome
  16q21 and encompasses 16 exons.
• Various mutations in the CETP gene have been
  identified that result in
• the absence of detectable CETP mass or activity
• reduction in the rate of reverse cholesterol
  transport
• elevated levels of HDL cholesterol in affected
  individuals

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CETP-TaqIB

• One specific polymorphism in the CETP gene,
  referred to as TaqIB and located in intron 1 of
  gene
• It has been associated with altered
  lipid-transfer activity and HDL cholesterol
  levels.
• The TaqIB variant influences CETP plasma
  concentrations, which modify the reverse
  cholesterol transport process and HDL cholesterol
  levels.

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CETP Case Study

• The CETP -TaqIB variant and its relation to
  incident CHD and HDL cholesterol in a sample of
  white men and women from the Atherosclerosis Risk
  in Communities (ARIC) study was investigated.
• The genotype distribution study sample consisted
  of B1/B1, B1/B2 and B2/B2.
• The sample of 375 incident CHD cases and 611
  controls reported that B2 allele was lower in the
  incident CHD cases than in the noncases.
• Cardiovascular risk factors such as body mass
  index, smoking status, hypertension, total
  cholesterol, diabetes, alcohol drinking status
  and leisure time physical activity, age and
  gender were included in a Cox proportional
  hazards model. It was found that the CETP variant
  remained significantly associated with incident
  CHD and the risk was reduced by almost by half
  for B2 homozygotes, compared with those with one
  or two B1 alleles.
• (Cox proportional-hazards regression allows
  analyzing the effect of several risk factors on
  survival)

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GNB3-Hypertension

• Hypertension
• -abnormally high systemic blood pressure
• -does not produce obvious symptoms
• The GNB3 gene is located on chromosome 12p13

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GNB3-Hypertension

• The GNB3 gene plays a critical role in sodium
  processing and total body fluid homeostasis by
  directing the trafficking of sodium/potassium
  channel in and out of the cell membrane.
• Intracellular signaling by G proteins is an
  essential step in the formation of mature
  adipocytes (fat cells).
• GNB3 has been proposed as a candidate gene for
  both essential hypertension and obseity.
• This gene was first identified as a potential
  important gene for human hypertension. The cell
  lines derived from hypertensive subjects showed
  an increase in G-protein signal transduction and
  activity of the sodium proton exchanger compared
  with cells from nonhypertensive patients.

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GNB3- C825T

• The discovery of polymorphism in the GNB3 gene-
  C825T, which results in a base pair deletion in
  exon 9 of the heterotrimeric G protein.
• The variant was located outside of the known
  census splice site regions and suggested that
  much of variation in DNA sequence might have the
  potential to be functional.
• The allele frequencies differs in the GNB3 gene
  and can partly represent the underpinnings of
  hypertension prevalence differences between
  populations.

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GNB3- C825T

• The GNB3- C825T allele has been associated with
  left ventriclular hypertrohpy, enhanced coronary
  vasoconstriction and imparied left ventricular
  diastolic filling in the Australian, German and
  Canadian OjiCree population.
• The 825T allele was associated with serum
  potassium, total cholesterol and hypertension in
  the Japanese population

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Gene-Environment Interaction and CVD Candidate
Genes

• Detection of gene-environment interactions that
  influence the development of CVD-related
  morbidities may be difficult for a number of
  reasons.
• First
• the disease state are highly heterogeneous and
  can develop via multiple mechanisms (ex chronic
  inflammation or high salt diet).
• Second
• several to many genes are likely to influence the
  development of CVD, each with small to moderate
  effects.

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Gene-Environment Interaction and CVD Candidate
Genes conti

• Third
• expression of the genetic defect producing CVD
  may be context dependent (ex defect in estrogen
  signaling that contributes to alternations in
  lipid levels may be evident in females and not in
  males).
• Fourth
• complex physiologic functions such as the
  regulation of blood pressure or vasoconstriction
  will have multiple pathways and redundancy to
  ensure survival of the organism.

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Gene-Environment Interaction and CVD Candidate
Genes

• CETP
• The interaction between physical activity
  alcohol consumption and gene variant was
  evaluated to investigate how environment
  influence HDL cholesterol and modify variation in
  CETP.
• Physical activity and moderate alcohol
  consumption have both been linked to higher HDL
  cholesterol levels and physical activity is
  considered protective against CVD.
• The CETP variant by activity level interaction
  was not significant however , physically active
  individuals had HDL levels higher than those of
  inactive individuals, which equate to the
  decrease in CVD risk of 10 for active men and
  15 for active women.

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Gene-Environment Interaction and CVD Candidate
Genes

• HDL cholesterol levels are also influenced by
  alcohol intake, with a moderate alcohol intake
  associated with a slight increase in HDL
  cholesterol levels.
• Hata et al., studied Japanese men and women and
  reported that drinking approximately 23 g of
  alcohol increased HDL cholesterol.
• Fumeron et al., reported that alcohol intake
  influences the CETP polymorphism effects and
  increases HDL cholesterol resulting from the B2
  allele evident in moderate drinkers.

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Gene-Environment Interaction and CVD Candidate
Genes

• GNB3
• An analysis of the interaction between variation
  in the GNB3 gene and both obesity and physical
  activity in predicting hypertension.
• A significant interaction between obesity status
  and the GNB3- C825T polymorphism in predicting
  hypertension was found.
• The sample was stratified by obesity status.
  Nonobese individuals who were homozygous for the
  825T allele had significantly lower risk for
  hypertension while obese 825T homozygotes
  experienced higher risk of hypertension compared
  to 825C/825C homozygotes.

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Gene-Environment Interaction and CVD Candidate
Genes

• The relationship between GNB3 variation and
  physical activity in predicting obesity status
  was evaluated.
• Subjects in the highest tertile of physical
  actvity and homozygous for the 825T allele had
  significantly lower risk for obesity while low
  active 825T/825T subjects had higher risk for
  obesity than their respective counterparts who
  were homozygous for the 825C allele.

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Gene-Environment Interaction and CVD Candidate
Genes

• When the sample was stratified by GNB3 genotype,
  subjects with two copies of the 825C allele
  experienced essentially no increase in disease
  risk, while those with one or two copies of the
  825T allele had dramatically increased risk for
  hypertension as they became more obese and
  inactive.
• The finding suggests that 825C (least frequent
  AAs) may confer some level of protection from
  hypertension, even in the fact of obesity and
  sedentary lifestyle.

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Environmental Cardiology

• Environmental factors are considered key
  determinants of cardiovascular disease. Although
  lifestyle choices such as smoking, diet, and
  exercise are viewed as major environmental
  influences, the contribution of pollutants and
  environmental chemicals is less clear.
  Accumulating evidence suggests that exposure to
  pollutants and chemicals could elevate the risk
  of cardiovascular disease. Many epidemiological
  studies report that exposure to fine particles
  present in ambient air is associated with an
  increase in cardiovascular mortality.
  Statistically significant relationships between
  particulate air pollution and ischemic heart
  disease, arrhythmias, and heart failure have been
  reported. Animal studies show that exposure to
  ambient air particles increases peripheral
  thrombosis and atherosclerotic lesion formation.
  Exposures to arsenic, lead, cadmium, pollutant
  gases, solvents, and pesticides have also been
  linked to increased incidence of cardiovascular
  disease. Mechanistically, these effects have been
  attributed to changes in the synthesis or
  reactivity of nitric oxide that may be caused by
  environmental oxidants or increased endogenous
  production of reactive oxygen species. Additional
  studies are urgently needed to identify the
  contribution of individual pollutants to specific
  aspects of cardiovascular disease establish
  causality elucidate the underlying physiological
  and molecular mechanisms estimate the relative
  susceptibility of diseased and healthy
  individuals and that of specific population
  groups and determine whether pollutant exposure
  are risk correlates, that is, whether they
  influence major risk factors, such as
  hypertension, cholesterol, or diabetes, or
  whether they contribute to the absolute risk of
  heart disease. Collectively, these investigations
  could contribute to the emergent field of
  environmental cardiology.
• Environmental Cardiology Study Mechanistic Links
  Between Pollution and Heart Disease
• Aruni Bhatnagar

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Gene-Gene Interactions and CVD Risk

• With regards to gene-gene interactions that may
  contribute to CVD it is difficult due to the
  multitude of putative factors involved both in
  the development of disease and the determination
  of underlying quantitative traits that contribute
  to CVD.
• The investigation of the role of gene-gene
  interaction in determining HDL cholesterol
  levels, genetic variants within three genes known
  to be associated with HDL cholesterol levels were
  viewed.
• The three gene include CETP (TaqIB variant),
  paraoxonase (PONI, Gln192 Arg) and hepatic lipase
  (HL, -514gtT variant).

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Gene-Gene Interactions and CVD Risk

• STUDY
• The genotype in a sample of an estimated 800
  individuals were used.
• Each variant genotype was collapsed into two
  categories indicatingpresence or absence of the
  less common allele within each gene and combined
  to formulate a multilocus genotype consisting of
  presence/absence of the less common allele at
  each of the three loci.
• The HDL cholesterol levels were not significantly
  different from the referent for other multilocus
  genotypes that included the B2 allele at CETP.
• Mean values for HDL cholesterol were lower in the
  presence of of the B1 allele within CETP.

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Gene-Gene Interactions and CVD Riskstudy conti

• HDL cholesterol was lower for all multilocus
  genotypes that included the CETP B1 allele,
  regardless of genotype at the other two loci,
  except in the case when the alternate alleles
  were present on both HL and PON.
• The B1 allele in CETP has been associated with
  lower HDL cholesterol and increased risk for CHD
  (58-64).
• The results suggest that the risk-raising effect
  of the CETP B1 allele may be compensated for by
  the combined effect of the risk-lowering alleles
  at both HL and PONI but that alternations in
  either HL or PONI alone are not sufficient to
  counteract the effect of the CETP B1 allele.

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Thank You?
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References

• Gene Polymorphisms and Susceptibility to Coronary
  Artery Disease
• Svati H. Shah, MD MS MHS
• Human Genome Epidemiology- A Scientific
  Foundation for Using Genetic Information to
  Improve Health and Prevent Disease
• Chapter 29- Molly S. Bray
• Environmental cardiology studying mechanistic
  links between pollution and heart disease.
• Author   Bhatnagar, Aruni
• Affiliation   Institute of Molecular Cardiology,
  Division of Cardiology, Department of Medicine,
  University of Louisville, Louisville, KY 40202,
  USA.
•   Circulation research, 2006 Sep 29,
  99(7)692-705 ISSN   1524-4571