5yr MM18 Genetics of Cardiovascular Disease 2012

7/31/2019 5yr MM18 Genetics of Cardiovascular Disease 2012

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Learning Outcomes

1. Appreciate the concept of a genetic basis for complexcommon diseases.

2. Appreciate cardiovascular disease (CVD) as a prototypical

3. Become familiar with the genetic and non-genetic risk

factors associated with CVD.4. Become familiar with aspects of human population genetics

and the Common Disease / Common Variant (CD/CV)hypothesis.

5. Become familiar with the most common gene variantsassociated with increased risk for venous thrombosis

including factor V Leiden and the prothrombin variant.6. Understand the molecular mechanism through which FVL

R506Q may lead to increased risk of venous thrombosis.

7. Appreciate the potential advantages and disadvantages ofgenetic testing for FVL.


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Many common diseases cluster in

Breast cancer

Diabetes

Neurodegenerative disorders

Heart attack

Stroke

High blood pressure

Prostate cancer

Arthritis

Obesity


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Gene 1

Gene 2

Gene 3

Gene N

Cardiovascular Disease

Genes

Environment

Diet

Exercise

.

.

.

Lifestyle

inheritance

Polygenic

Multifactorial


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Causation Spectrum of Human Disease

Genetics Environmental

Rare

Genetics simple

(Unifactorial)

Higher recurrence risk

Common

Genetics complex

(Multifactorial)

Lower recurrence risk

Tuberculosis

Scurvy

Diabetes

Peptic ulcer

Dislocation of hip

Spina bifida

Ischemic heart disease

Duchenne

muscular

dystrophy

Haemophilia

Phenylketonuria


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Complex Traits

Controlled by multiple genes

Inheritance does not follow simple rules of Mendelian genetics

Influence of environmental factors

Relationship between genetic variation & phenotypic variation is

non-linear, and the relevant genes do not interact additively


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Cardiovascular Disease (CVD)

Includes dysfunctional conditions of the: heart

arteries, veins, capillaries, lymphatics

supplying oxygen to vital life-sustaining areasof the body


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Cardiovascular disease includes:

Atherosclerosis

Coronary heart disease (or coronary arterydisease)

Angina

Stroke

High blood pressure (or hypertension)

Heart failure Venous thrombosis

Infection of the heart, carditis,endocarditis,pericarditus


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Cardiovascular Disease as a Common,Complex Disease

Common disease 2 implications Disease is prevalent (frequency)

That it is widespread (distribution)

Genetic Susceptibility to Cardiovascular Disease

Result of an inherited predisposition orgenetic susceptibility

Polygenic inheritance Multifactorial

Lack of penetrance age dependence


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Model for gene-environment interaction

Risk

CHD

Environmental

challengesGenetic

susceptibility

High Low

Low High

Genes of small effect: ranging from few to many

Different lifestyles: ranging from unhealthy

to healthy


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Search for markers in populations (association), notfamilies (linkage)

Where effects are probabilistic, must compare

frequencies in cases and controls

Affecteds Controls

Association Studies in Complex Disease

In a population, a

certain % will

have one allele,the rest the

other.

A higher than

expected

incidence in adisease group

suggests

polymorphism is

associated with a

disease (or the

common

sequence isprotective)


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Age Diabetes mellitus

Hypercholesterolemia (elevated cholesterol levels)and lipoprotein profile (cholesterol subtypes)

Tobacco smoking

Higher fibrinogen and PAI-1 blood concentrations Elevated homocysteine

High blood pressure

Obesity, especially central or male-type obesity

Genetic factors/family history of CVD Physical inactivity

Male sex

Risk factors for CVD


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Ten-year risk of fatal cardiovascular disease in populations at high cardiovascular diseaserisk

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CVD is Extraordinarily Complex

Risk Factor Number of GenesHDL cholesterol >20LDL cholesterol >10

Lipoprotein a [Lp(a)]levels 1Triglyceride levels >10

Hypertension >20Insulin resistance >10

Obesity >30

Male gender 1

Homocysteine levels >3

The number of significant genetic factors in CVD is likely tobe in the hundreds

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But most of the genes underlying common forms

of CVD have a small number of common alleles

Trait Gene No. of alleles

HDL Hepatic lipase 2

Homocysteine MTHFR* 2

Type 2 diabetes PPAR gamma** 2

LDL/VLDL ApoE 2MI 5-Lipoxygenase 3

*methylenetetrahydrofolate reductase

**peroxisome proliferator-activated receptor gamma

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The Common Disease / CommonVariant (CD/CV) hypothesis

Proposes that the gene variationunderlying susceptibility to common

heritable diseases existed within thefounding population of contemporaryhumans

As population expanded outwards, theancient gene variation of these foundershas been distributed globally

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Recent African Origin or Replacement

Model

Anatomically modern humans emerged as acompletely new species in Africa just ~100,000 years

ago (Recent) Out of Africa model: recent expansion from a

small population

Began to migrate into the rest of the world. Instead ofinterbreeding with locals, modern human replaced

them, driving all other humans (e.g. Neanderthals andHomo erectus on Earth to extinction

http://www.action

bioscience.org/evo

lution/johanson.ht

ml

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http://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.htmlhttp://www.actionbioscience.org/evolution/johanson.html


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Most variation is due to common alleles dating backto this small population, not to rare, newer mutations

Disease susceptibility alleles included among this

variation have persisted at moderate frequency(selectively neutral) until the recent emergence ofenvironment required for disease manifestation

CD/CV Hypothesis - Precedents

CKR5D32 and resistance to HIV

(chemokine receptor 5, 32bp deletion mutation)

CD/CV Hypothesis - Population Genetics

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Why have alleles that cause CVD notbeen removed from the gene pool?(Why is CVD so common?)

1. Most forms are late-onset and thus do

not affect reproduction2. Most forms are only lethal given our

high energy consuming, low energy

expending lifestyle3. Some CVD alleles may be underpositive selection for unknown reasons

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Venous Thrombosis

Inherited Causes Common

Factor V Leiden (R506Q)

Prothrombin variant (G20210A)

Homozygous C677T mutation in the methylene-tetrahydrofolatereductase gene (MTHFR)

Rare Antithrombin deficiency

Protein C deficiency

Protein S deficiency

Acquired Causes Surgery & trauma Prolonged immobilization

Previous thrombosis

Pregnancy

Oral contraceptives or HRT

Older Age

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Idiopathic Cerebral Venous Thrombosis

Catastrophic occlusion of cerebral veins

Rare, affects young adults, high mortality rate(5-30%)

Predisposition to disease caused by Predisposing genetic factors

factor V

prothrombin

Environmental, use of contraceptives Each known to individually

3 factors lead to abnormal blood coagulability

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Is a mutant allele of factor V

Arginine replaced by glutamine at position 506(Arg506Gln = R506Q)

Renders the factor V protein resistant tocleavage by activated protein C (APC)[APC is a natural anticoagulant that acts to limit the

extent of clotting by cleaving and degrading factorV]

Thus increasing generation of thrombin

Factor V Leiden (FVL)

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The coagulation cascade

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Factor V Leiden(activated protein C resistance (APCR))

Normal factor VFactor V Leiden

Arg506Gln

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25

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Prothrombin variant G20210A

Prothrombin (factor II) is a protein

essential for the clotting of blood

Prothrombin variant: mutation causing Gto A at position 20210 (G20210A)

Frequency of 2.4% in Caucasians

Variant (G20210A) associated with

increased risk of blood clots

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Frequency of FVL and prothrombin G20210A

variant in UK population and corresponding risk

of venous thrombosisRisk Factor Status Population

frequencyApproxincreasedrisk*

Factor VLeiden

HeterozygousHomozygous

4% (1 in 25)0.15% (1 in 625)

4.910-80

Prothrombin Heterozygous

Homozygous

2% (1 in 50)

0.04% (1 in 2500)

3.8

Not known

FVL andprothrombin

Heterozygous

for both

0.08% (1 in 1250) 20

* Figures increased in presence of antithrombin, protein C orprotein S deficiency, use of OCP, HRT, etc

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Factor V Leiden can be associated withthe following complications:

Venous Thrombosis, blood clots in veins, such as: Deep vein thrombosis (DVT), veins in arms and legs

Superficial thrombophlebitis (veins in the legs)

Sinus vein thrombosis, veins around the brain Mesenteric vein thrombosis, intestinal veins

Pulmonary Embolism (PE), blood clots in the lungs

Arterial clots (stroke, heart attack) in selectedpatients

Possibly link with stillbirth or recurrent unexplainedmiscarriage

Preeclampsia and/or eclampsia

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Venous Thrombosis Treatment:Anticoagulation therapy using heparin orwarfarin

Monitor international normalized ratio (INR)

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Genetic Testing for FVL

>50% of venous thromboembolisms can be explainedby factor V Leiden and prothrombin variant

acute case management

Advantages of FVL testing:Pharmacogenetics: Identification of high risk patients who could

benefit from:

Long-term anticoagulant therapy

Aggressive prophylaxis in temporary periods of high

thrombotic risk e.g. surgery

Choice of oral contraceptives, decisions regarding HRT orpregnancy complications

Asymptomatic family member screening not generallyrecommended


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Case Report

Sequence of clinical events and testing referrals:II-1 had pulmonary embolism several years ago and standard tests forhypercoagulability (including protein C, protein S and antithrombin III deficiency)showed no abnormalities.I-1 had deep vein thrombosis (DVT) after breaking a leg. Factor V mutation

testing revealed he is a heterozygote.Subsequent testing showed that II-1 is homozygous for the factor V mutation, I-2and II-3 are heterozygotes, (have no personal history of DVT) and II-2 has anormal genotype.II-3 became pregnant shortly after learning she was a heterozygote. She wastreated with heparin throughout her pregnancy as a preventive measure againstDVT.

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Understanding genetic basis ofcomplex traits & common diseases is

an important goal Information on risk to patients

Aid in prediction, prognosis

Prospects for personalized cardiovascularmedicine

Potentially good drug targets Designing optimal therapies and intervention

Relating genotype to phenotype is thus thechallenge for genetic medicine over the nextcentury

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Further Reading

GENETICS IN MEDICINE (6th Edition)

Thompson & Thompson

WB Saunders Company

Nature Education:

http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919

Genetests.org:Case 39. Two Patients Presenting to a Walk-In Clinic withSymptoms of a Blood Clot
http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.genetests.org/servlet/access?id=8888891&key=DxnJDkGIOkX4X&fcn=y&fw=ovNR&filename=/tools/cases/thrombophilia-39/index.htmlhttp://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919http://www.nature.com/scitable/topicpage/multifactorial-inheritance-and-genetic-disease-919

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5yr MM18 Genetics of Cardiovascular Disease 2012

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