Coronary Heart Disease Genetics:An Overview

Amy Sturm, MS, CGCCertified Genetic CounselorClinical Assistant ProfessorDivision of Human Genetics

Amy Sturm discloses significant financial interests or other relationships with commercial interests in the following areas: Consultant/Speaker Bureau: Berkeley HeartLab. Presentation will not include discussion of commercial products or services and will not include unapproved or off-label usage of a commercial product or device.

The following planning committee members have no significant financial interests or relationships with commercial interests to disclose, their educational unit does not have a financial interest or affiliation with an organization that may receive direct benefit from the subject of the proposed CME activity, and they will not be personally compensated for their role in the planning or execution of this proposed CME activity by an organization other than The Ohio State University: Amy Ehrlich, MA and Henry Zheng, PhD, MBA

Some Facts about CHD • Most common type of cardiovascular disease• Leading cause of death in the US for men and women• Average age of first heart attack

– 64.5 for men– 70.3 for women

• Lifetime risk of developing CHD after age 40– 49% for men and 32% for women (Framingham Heart Study)

• In most cases, no “single gene” as a cause• Usually multifactorial due to interaction of multiple genetic

and environmental risk factors

Heart Disease and Stroke Statistics — 2009 Update, American Heart Association

Established CHD Risk Factors

• Physical inactivity• Smoking• High LDL (“bad

cholesterol”)• Low HDL (“good

cholesterol”)• Overweight and

obesity

• Diabetes mellitus• High blood pressure• Family History

Monogenic versus Polygenic Disease

• Monogenic – Disorders caused by a mutation in a single gene– Also known as Mendelian disorders– Include CHD as one part of the clinical spectrum– Example: familial hypercholesterolemia

• Polygenic– Disorders caused by multiple genetic variants with low

penetrance– Example: common, complex CHD

Mendelian Disorders Featuring CHD and/or MI

• Abdominal obesity-metabolic syndrome• Apolipoprotein(a) elevation• Apolipoprotein A-I deficiency• Arterial calcification, generalized, of

infancy• Atherosclerosis susceptibility/Atherogenic

lipoprotein phenotype• Cerebrotendinous xanthomatosis • Coronary artery disease, autosomal

dominant 1, MEF2A • Coronary artery dissection, spontaneous• Fabry disease• Familial combined hyperlipidemia• Familial defective apolipoprotein B-100• Familial hypercholesterolemia, autosomal

dominant– LDLR and PCSK9 genes

• Familial hypercholesterolemia, autosomal recessive

• Familial hypertriglyceridemia• Familial partial lipodystrophy• Familial pseudohyperkalemia due to red

cell leak• Fibromuscular dysplasia of arteries• Heparin cofactor II deficiency• Homocysteinemia• Homocystinuria• Hutchinson-Gilford Progeria Syndrome• Hyperlipoproteinemia, type III• Niemann-Pick disease, type E• Pseudoxanthoma elasticum, autosomal

dominant and recessive forms• Sitosterolemia• Tangier disease• Werner syndrome• Williams syndrome

Online Mendelian Inheritance in Man

Familial Dyslipidemias• Inherited conditions that cause high levels of

cholesterol and, in some cases, triglycerides– Familial hypercholesterolemia– Familial hypertriglyceridemia– Familial combined hyperlipidemia

• All three are common, autosomal dominant disorders– Polygenic dyslipidemia

• Most common form of elevated serum cholesterol

• Often result in the premature onset of CHD• Typically underdiagnosed

Crouch MA and Gramling R, Prim Care Clin Office Pract 2005

In Most Cases CHD is a Complex, Multifactorial Disease

• Hundreds of modifier genes likely influence the risk for CHD, each with an incremental effect on risk

• These modifier genes have the potential to interact with other traits that are also polygenic (e.g. diabetes, blood pressure)

• Numerous dietary, environmental and lifestyle risk factors and their interactions also impact CHD risk

Most CHD-Associated Gene Variants Have Low Penetrance

• Genome-wide association (GWA) studies of large populations have identified gene variants that contribute to an individual's risk for CHD

• These variants only exert a small influence on the individual's CHD risk (i.e. low penetrance)

9p21 Example

• GWA analyses have revealed strong associations with the 9p21 locus and CHD, as well as other types of cardiovascular disease, such as abdominal aortic aneurysm

• SNP rs1333049– An individual's status for the rs1333049 SNP influences his/her

risk for CHD– Heterozygotes (possess one copy of the rs1333049 risk-

increasing allele [the C allele]) have a relative risk of 1.3 for CHD– Homozygotes have a relative risk of 1.7

Familial Hypercholesterolemia (FH)

• In contrast to polygenic, common, complex CHD, FH is inherited in an autosomal dominant fashion

• FH affects 1 in 500 individuals• In the heterozygous form of FH, elevated plasma levels of LDL-C

and total cholesterol lead to excessive deposition of cholesterol in the arterial walls, accelerated atherosclerosis and premature CHD

• Most commonly caused by germline mutations in the LDL receptor gene, LDLR

• High penetrance• Lifetime penetrance is close to 100% in males and approximately

70% in females

Family History of Coronary Heart Disease

• Important and independent risk factor for both– CHD events – Atherosclerosis in asymptomatic adults

• First Degree Relative (FDR) with CHD: 2-3 fold increase in risk– Risk increases

• As number of affected FDRs increases– 3-6 fold increase in risk if >2 FDRs with CHD

• With younger ages of CHD onset in relatives

Odds Ratios for Various Definitions of a “Positive Family

History of CHD”• First Degree Relatives (FDR)

– > 1 FDR with early-onset CHD (5.0)– > 1 FDR with late-onset CHD (2.5)– 1 FDR with CHD at any age of onset (3.0)– > 2 FDRs with CHD at any age of onset (5.1)– > 1 sibling with CHD at any age of onset (3.1)– > 1 parent with CHD at any age of onset (3.8)– Parent and sibling pair with CHD at any age of onset (5.0)– Both parents with CHD (6.2)

• Second Degree Relatives (SDRs)– > 1 SDR with early-onset CHD (4.6)– > 2 SDRs with CHD at any age of onset (2.8)

• Related conditions– > 1 FDR with early-onset stroke (2.9)– > 1 sibling with stroke at any age of onset (3.2)– FDRs and SDRs with stroke at any age of onset (2.7)– > 1 FDR with diabetes (2.4) (women only)

Scheuner MT et al, Genet Med 2006

Familial Risk Stratification

MI d. 85 MI d. 85

CAD dx. 67 MI dx. 53

MI d. 85

Diabetes dx. 45

Weak Risk Moderate Risk Strong Risk

Published Risk Stratification Guidelines in Scheuner MT. Genet Med 2003

CAD dx. 67

Familial CHD Risk

Three or more

n=376

ORa (95% CI)

Two

n=740

ORa (95% CI)

One

n=1203

ORa (95% CI)

None

n=1716

ORa (95% CI)

Strong (n=1273)62.2

(18.5-209.1)

48.6

(14.8-160.0)

17.9

(5.3-61.0)

4.3

(1.1-17.6)

Moderate (n=471)24.9

(5.2-119.7)

27.8

(7.2-106.8)

2.1

(0.21-20.0)

3.6

(0.6-21.9)

Weak (n=2291)16.5

(4.4-61.2)

12.6

(3.6-44.4)

3.7

(1.0-13.9)

1.0

(referent)

Risk for Early-Onset CHD Given Familial CHD Risk and Number of CVD Risk Factors

CVD risk factors = diabetes, hypercholesterolemia, hypertension and obesity Adjusted for age, gender, ethnicity/race, educational level, income, and marital status.

Adapted from Table 4, Scheuner MT et al. Genet Med 2006

Genetic Susceptibility to CHDBe on the Watch for…

• Early onset CHD (men < 55, women < 65)• Angiographic severity (degree of blockage) • Multi-vessel disease (coronaries, carotids, aorta)• >1 close relative with CHD, especially female

relatives• Absence of risk factors in family members with CHD• Family history of related disorders (diabetes,

hypertension, stroke, peripheral vascular disease)

Genetic Counseling for CHDSame goals as other types of adult genetic counseling,

like cancer genetic counseling…

We just don’t have a genetic test for “CHD1 and CHD2”!

• Pedigree risk assessment• Medical history• Physical examination• Differential diagnosis, including Mendelian disorders featuring CHD• Genetic counseling and education regarding risk level

• Laboratory testing (biochemical testing for traditional and emerging CHD risk factors)• Screening for early detection of atherosclerosis

• Based on results make recommendations for targeted risk factor modification and prevention strategies

• Follow-up on response to therapy• Identify at-risk family members

What about Genetic Testing for CHD?

• Currently available, but is it clinically useful? • Does it add value to current risk prediction tools?• For any gene variant the effect on risk is likely to be relatively small

– Most relative risks in range of 1.2-1.4– Given the low penetrance of these variants, genetic tests will

have limited predictive power and clinical utility• What about reclassification of risk level as more is learned about

additional genetic modifiers of risk ?• What about complex gene-gene and gene-environment

interactions?• Family history remains the “gold standard” in familial risk

assessment for CHD• Genetic testing appropriate if Mendelian disorder(s) in differential

Case Example:Is This Woman at Increased Risk?

d. 47 Heart Attack

P

Breast ca dx 3540 35

61

d. 6 moSIDS

10

Expanding the Pedigree…

d. 47Heart Attack

P

Breast ca dx 3540 35

61

d. 6 moSIDS

10

65CABGx3, 62Non-smoker

67DM dx 55HTN dx 45

d. 61Heart attack

Now what???

Familial Risk for Patient: Strong

d. 47 Heart Attack

P

Breast ca dx 3540 35

61

d. 6 moSIDS

10

65CABGx3, 62Non-smoker

67DM dx 55HTN dx 45

d. 61Heart attack

CardioGenetic Consultation• Proband and sister go through risk assessment

• Proband’s physical exam and bloodwork okay, but…

• Sister diagnosed with borderline HTN; medication started

• CT coronary angiography also ordered

– Shows 50-75% luminal narrowing in the left anterior descending (LAD) coronary artery

– Results reviewed with sister, who is still symptom-free; statin, beta-blocker and aspirin

added to medical therapy

• Invasive cardiac catheterization/coronary angiography

scheduled– Balloon angioplasty and stents placed across LAD lesion

• Cardiac Rehabilitation/Secondary Prevention

Long-term Proband and Family Follow-up

P

Breast ca dx 3540 35

10

Proband’s husband also came in for genetic

risk assessment based on his own strong familial

risk; evaluation did not show increased personal

risk; managing weight and lipid levels with

diet and exercise

Proband’s sister continues follow-up with her cardiologist and stops smoking

half pack of cigarettes per day

Proband joined women’s hockey league and gym and began losing weight; also changed

diet and food she prepares for family

Family History as a Guide forEarly Detection and Prevention

Modified from Scheuner MT. Genet Med 2003

Collect family history every 1-2 years

High Moderate Average

Possible Mendelian disorder?

Assessment of established and emerging CHD risk factors every 1-2 yrs

Consider early detection strategies every 2-3 yrs beginning 10 yrs before earliest CHD onset in family

Provide personalized prevention strategies tailored to CHD risk factors and presence of subclinical disease

Identify at-risk relatives

Assessment of established CHD risk factors every 2-3 yrs

If multiple risk factors identified, assign high risk

Provide personalized prevention strategies tailored to CHD risk factors

Assessment of established CHD risk factors every 5 yrs

Provide public health prevention messages

Useful Online Programs to Estimate CHD Risk

• Framingham Risk Score (http://www.framinghamheartstudy.org/)

– Family history not included in Framingham risk score – Recent study concluded that a third of women classified as low risk by Framingham

had significant subclinical atherosclerosis (Michos et al, Am Heart J, 2005)• CardioSmart Risk Assessment Tool (http://www.cardiosmart.org)

– Patient education site based on findings from the Framingham Heart Study• Reynolds Risk Score (http://www.reynoldsriskscore.org)

– Also incorporates serum C-Reactive Protein level and family history of CHD prior to age 60 in the parents of the user

• Your Disease Risk (http://www.yourdiseaserisk.wustl.edu)

– Assesses CHD risk using medical and smoking history, diet, physical activity measures and family history of affected first-degree relatives

• Family HealthLink (https://familyhealthlink.osumc.edu)– Risk triage tool that assesses risk for CHD based on family history– Stratifies risk into average, moderate and high risk categories