Human Genetics and CV Risk AssessmentCV Risk Assessment Nathan Stitziel, MD, PhD Assistant Professor of Medicine and Genetics ... Kiran Musunuru1,2, Eric E Schadt8, Lee Kaplan9, Derrick

Human Genetics and CV Risk Assessment

Nathan Stitziel, MD, PhD

Assistant Professor of Medicine and Genetics

Director, Center for Cardiovascular Genetics

Assistant Director, McDonnell Genome Institute

National Lipid Association Scientific Sessions

May 19, 2016

Disclosures

1. Grant support: AstraZenica

2. Consultant: Aegerion Pharmaceuticals

Genetic risk of CAD

Mendelian (monogenic)

Most notable examples involve disorders of cholesterol metabolism

Minority of CAD in population

Complex (polygenic)

Clustering within families but not due to single gene mutations

Majority of CAD in population

Focus for today

Case presentation• Chief complaint: “I am homozygous for the risk

allele at 9p21”

• 43 yo male• Otherwise healthy

• Family history:• Paternal uncle: MI in 50s

• Paternal aunt: MI in 50s

• No medications

• Physically active without chest discomfort

• BP 112/60, exam unremarkable

• TC 180, LDL 115, normal hsCRP

Patient HandoutPatient Handout 1/1

REQUESTING PHYSICIAN / INSTITUTION:

Jane Doe ID: n/a

Female/ ! " #" $%&

SA&*+! " Sample ID: DGMI/0&*+!

ABC Hospital/Dr. John Smith

! ! Main Street' An(to)n' %!* + I , - S

* * * " 1#" 1#2

NAME:

Gender/DOB:

De.ode ID:

Date Colle.ted: ! " %"1!!$ Date 3e.ei4ed: ! " $"1! !$ Date 3eported: !"1%"1!!$

GENE5IC 5ES5 3ES - ,5S 6 7A5IEN5 HANDO-5

8 O - 3 GENE5IC 3E,A5I9E

3 I S :

2.35e;<als # * = in.reased ris>' o4er

?eneral pop<lation ris> o@ . !

This means that you are, irrespective of age or gender, at 135%

increased risk of having MI (heart attack) relative to the average risk

of the white population. This test measures 8 variants in the DNA

sequence you were born with.

GENETIC RISK SCA E

7O7-,A5ION 3 I S :

DIS53IB-5ION

AAo<t ! . 1 = o@the )hite pop<lation ) i l l ha4e the similar ris> res<lts

as (o< )hereas aAo<t ! . ! = ha4e hi?her ris> and aAo<t $$.&= ha4e

lo)er ris> than (o<.

Note: An indi4id<al ) ho has hi?her ?eneti. ris> is not destined to

ha4e a heart atta.> and a patient at lo)er ?eneti. ris> is not @ree o@

heart atta.> ris>. 5his is a ris> test' not a determinati4e test.

8 O - 3 O9E3A, , 3 I S : A more .omplete ! (ear ris> estimate @or .oronar( heart disease

.an Ae deri4ed A( m<ltipl(in? the ris> deri4ed @rom .ommonl( <sed ris> s.orin? al?orithms ) i th the relati4e ?eneti. ris> res<lts o@the deCODEMI

5M

test. 5he s.orin? al?orithms ta>e into a..o<nt the

indi4id<alBs a?e' seC' Alood press<re' smo>in? histor( and Alood lipids. Cons<lt ) i th (o<r ph(si.ian.

NO5E

MI SAME AS HEA35 A55AC: M(o.ardial [email protected] DMIE is the same as heart atta.> and is one o@the ) a ( s that .oronar( heart

disease presents itsel@.

3EFE3ENCE 7O7-,A5ION T!e"e #e"u$t" on$% a&&$% to ' ! i t e indi(idua$" o) Eu#o&ean an*e"t#%.5M

73OFESSIONA, CO-NSE,ING 7ro@essional .o<nselin? is re.ommended @or interpretation o@the deCODEMI ris> res<lts.

mailto:[email protected]

ASCVD Statin Benefit Groups

CClliinniicacall LLDDLL-C-C TTypypee 22 1100-Y-

Yeeaarr ASCASCVDVD ≥≥ 190190

DDiiaabbeetteessRRiisksk

>>77..55%%

How should we manage this patient?

Can genetics inform our decision?

Why would we want to improve risk stratification?

Asym

xist

by

Effective therapies e

Lower LDL cholesterol

variety of mechanisms

Treatment during long

ptomatic progression over decadesasymptomatic phase

proven to reduce riskLibby P Circ 2001;104:365-372

of MI

Problem is current approach:

Target treatment to highest risk based on

clinical factors (mainly those with

established disease older individuals)

Why might genetics improve risk stratification?

Genetic factors have unique properties:

Represent fixed risk over lifetime

Can be measured early in life before the

development of traditional risk factors

~3500 subjects < 35 years old

15-20 years

Piers et al. BMC Cardiovascular Disorders

2008 8:38

LDL levels and risk of disease

LDL levels and risk of disease

Pletcher et al. Ann Intern Med 2010

153(3)

Pre

vale

nce o

f C

oro

nary

Calc

ific

ati

on

0

0.5

0.4

0.3

0.2

0.1

0.9

0.8

0.7

0.6

1

White Men

228

16*

368

164

P < 0.001

41

<1.81 mmol/L (<70 mg/dL)

1.81–2.56 mmol/L (70–99 mg/dL)

2.59–3.34 mmol/L (100–129 mg/dL)

3.37–4.12 mmol/L (130–160 mg/dL)

≥4.14 mmol/L (≥160 mg/dL)

What genetic factors associate with CAD?

Stratifying CAD risk

Modifying genetic CAD risk

Can genetics inform risk assessment?





ACAATTCTATTAAAGCCAATCCACAATTCTATTAAAGCCAATCC

TGATGA TCTTGGG[G/

T]GTTCTCCAT]GTTCTCCATGCTGCTGCTGC GCTGAGCATTTTGTAGTGAAATTTAGAG ATGTCACCTTTAGG[C/

A]A]GGAGAGGGCCAATT TTACAAAACATTTTTGCATTAG

CTTCTTAA TCAGCCAGGTGTTGAAATTCC[

A/A/GG]] CCCTATCTTATTATCATATGAGTTCCTCCT[A/CC]]GGCCTTAAGAAGTTCCCCTTCCACACCCTTGGAAAGAAAGAGCTTTACCCCAATCCCCATCCT AAAAATAAA ACTGTGTGGTAGA[T/

A]A]GGTTAATTCCACACTTAA TTGTTATTATTGTTAGTGGAGC

TGCTTGCT A[G/

TCTTGGG[G/

GCTGAGCATTTTGTAGTGAAAT

ATGTCACCTTTAGG[C/

TTACAAAACATTTTTGCATTAG

TCAGCCAGGTGTTGAAATTCC[

CCCTATCTTATTATCATATGAGT

[A/

AGCTTTACCCCAATCCCCATCC

ACTGTGTGGTAGA[T/

TTGTTATTATTGTTAGTGGAGC

A[G/

A]A]AGAGGGAAAACAAAACCCAAAATTTTCCCCAATTGGCCTT TCGCCCAACACAGATCCGAATGGCCAAAA TACAAATTTCACTCCATGGTA[T

TCGCCCAACACAGATCCGAAT

TACAAATTTCACTCCATGGTA[T

Human Genome Complexity

Genome: 3 billion basepairs

Encodes instructions for ~20,000 genes

Each individual has ~4 million point changes

Fundamental challenge in human

genetics:T

What genetic changes are related to

health and disease?

Measure genotypes:

= G =A

Genetic association study

Patients with MI Controls free of MI

Genotype → Phenotype association

AA AG GG AA AG GG

Association No association

Ris

kofM

I

Homozygous for risk allele

Heterozygous

Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan*1–5,37,38, Cristen J Willer6,37, Gina M Peloso4,7,37, Serkalem Demissie4,7,37, Kiran Musunuru1,2, Eric E Schadt8, Lee Kaplan9, Derrick Bennett10, Yun Li6, Toshiko Tanaka11, Benjamin F Voight2,3,12,Lori L Bonnycastle13, Anne U Jackson6, Gabriel Crawford3, Aarti Surti3, Candace Guiducci3, Noel P Burtt3,Sarah Parish10, Robert Clarke10, Diana Zelenika14, Kari A Kubalanza13, Mario A Morken13, Laura J Scott6, Heather M Stringham6, Pilar Galan15, Amy J Swift13, Johanna Kuusisto16, Richard N Bergman17,Jouko Sundvall18, Markku Laakso16, Luigi Ferrucci11, Paul Scheet6, Serena Sanna19, Manuela Uda19,

AR T I C L E S

64 genetic loci for CAD (58

published)

Deloukas at al, Nat Genet 2013Deloukas et al, Nat Genet 2013

Common va dyslipidemia riants at 30 loci contribute to polygenic

Cristen J Willer6,37, Gina M Peloso4,7,37, Serkalem Demissie4,7,37, Kiran Musunuru1,2,9, Derrick Bennett10, Yun Li6, Toshiko Tanaka11, Benjamin F Voight2,3,12,

Sekar Kathiresan*1–5,37,38, Eric E Schadt8, Lee KaplanLori L Bonnycastle13, Anne U Jackson6, Gabriel Crawford3, Aarti Surti3, Candace Guiducci3, Noel P Burtt3,Sarah Parish10, Robert Clarke10, Diana Zelenika14, Kari A Kubalanza13, Mario A Morken13, Laura J Scott6, Heather M Stringham6, Pilar Galan15, Amy J Swift13, Johanna Kuusisto16, Richard N Bergman17,Jouko Sundvall18, Markku Laakso16, Luigi Ferrucci11, Paul Scheet6, Serena Sanna19, Manuela Uda19,

AR T I C L E S

1/3 map to known risk factors

(genes for lipids and BP)

2/3 potentially provide

additional information beyond

traditional risk factors

64 genetic loci for CAD (58

published)





Deloukas et al, Nat Genet 2013

9p21 Locus

9p21 and risk for CAD

Lead polymorphism at 9p21: G and T alleles

GG GT TT

Ris

kofM

I

Patient HandoutPatient Handout 1/1

REQUESTING PHYSICIAN / INSTITUTION:

Jane Doe ID: n/a

Female/ ! " #" $%&

SA&*+! " Sample ID: DGMI/0&*+!

ABC Hospital/Dr. John Smith

! ! Main Street' An(to)n' %!* + I , - S

* * * " 1#" 1#2

NAME:

Gender/DOB:

De.ode ID:

Date Colle.ted: ! " %"1!!$ Date 3e.ei4ed: ! " $"1! !$ Date 3eported: !"1%"1!!$

GENE5IC 5ES5 3ES - ,5S 6 7A5IEN5 HANDO-5

8 O - 3 GENE5IC 3E,A5I9E

3 I S :

2.35e;<als # * = in.reased ris>' o4er

?eneral pop<lation ris> o@ . !

This means that you are, irrespective of age or gender, at 135%

increased risk of having MI (heart attack) relative to the average risk

of the white population. This test measures 8 variants in the DNA

sequence you were born with.

GENETIC RISK SCA E

7O7-,A5ION 3 I S :

DIS53IB-5ION

AAo<t ! . 1 = o@the )hite pop<lation ) i l l ha4e the similar ris> res<lts

as (o< )hereas aAo<t ! . ! = ha4e hi?her ris> and aAo<t $$.&= ha4e

lo)er ris> than (o<.

Note: An indi4id<al ) ho has hi?her ?eneti. ris> is not destined to

ha4e a heart atta.> and a patient at lo)er ?eneti. ris> is not @ree o@

heart atta.> ris>. 5his is a ris> test' not a determinati4e test.

8 O - 3 O9E3A, , 3 I S : A more .omplete ! (ear ris> estimate @or .oronar( heart disease

.an Ae deri4ed A( m<ltipl(in? the ris> deri4ed @rom .ommonl( <sed ris> s.orin? al?orithms ) i th the relati4e ?eneti. ris> res<lts o@the deCODEMI

5M

test. 5he s.orin? al?orithms ta>e into a..o<nt the

indi4id<alBs a?e' seC' Alood press<re' smo>in? histor( and Alood lipids. Cons<lt ) i th (o<r ph(si.ian.

NO5E

MI SAME AS HEA35 A55AC: M(o.ardial [email protected] DMIE is the same as heart atta.> and is one o@the ) a ( s that .oronar( heart

disease presents itsel@.

3EFE3ENCE 7O7-,A5ION T!e"e #e"u$t" on$% a&&$% to ' ! i t e indi(idua$" o) Eu#o&ean an*e"t#%.5M

73OFESSIONA, CO-NSE,ING 7ro@essional .o<nselin? is re.ommended @or interpretation o@the deCODEMI ris> res<lts.

mailto:[email protected]

Does knowledge of 9p21 status

improve risk prediction?

Annals of Internal Medicine Article

Impact of Adding a Single Allele in the 9p21 Locus to Traditional Risk Factors on Reclassification of Coronary Heart Disease Risk and Implications for Lipid-Modifying

Therapy in the Atherosclerosis Risk in Communities Study

Ariel Brautbar, MD; Christie M. Ballantyne, MD; Kim Lawson, MS; Vijay Nambi, MD; Lloyd

Chambless, PhD; Aaron R. Folsom, MD; James T. Willerson, MD; Eric Boerwinkle, PhD

Cardiovascular Disease Risk Prediction With and Without Knowledge of Genetic Variation at Chromosome 9p21.3Nina P. Paynter, PhD; Daniel I. Chasman, PhD; Julie E. Buring, ScD; Dov Shiffman, PhD; Nancy R. Cook, ScD; and Paul M Ridker, MD, MPH

>20,000 white women from Women’s Genome Health Study: Median age 52

No improvement over traditional risk factorsPaynter et al. Annals Int Med 2009

~10,000 white men and women from ARIC: Median age 54

Minimal improvement over traditional risk factorsBrautbar et al. Circ Cardvasc Gen 2009

Top loci associated with MI or CAD

Locus Risk allele frequencyOdds ratio of disease

for risk allele

9p21 46% 1.29

SLC5A3–MRPS6-KCNE2 85% 1.12

LDLR 23% 1.14

WDR12 15% 1.14

MIA3 26% 1.11

SORT1 22% 1.09

PSCK9 8% 1.07

Schunkert et al. Nat Gen 2011

Odds ratio of CAD at most loci:

between 1.05 – 1.3

1. Individual loci of weak effect unlikely

to effectively stratify risk

2. What if we could combine information

from all CAD loci together?

Articles

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary preventiontrials

Jessica L Mega*,NathanOStitziel*, JGustav Smith, Daniel I Chasman,Mark JCaulfield, James JDevlin, FrancescoNordio, Craig L Hyde,

ChristopherP Cannon, FrankMSacks, Neil RPoulter, PeterS Sever, PaulMRidker, EugeneBraunwald, OlleMelander, SekarKathiresan*,

MarcSSabatine*

SummaryBackground Genetic variants have been associated with the risk of coronary heart disease. In this study, we testedwhether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heartdisease events and identify those individuals who derive greater clinical benefit from statin therapy.

Published Online

March 4, 2015

http://dx.doi.org/10.1016/

S0140-6736(14)61730-X

Mega and Stitziel, et al, Lancet 2015

http://dx.doi.org/10.1016/

Prevention of coronary and stroke events with atorvastatin

in hypertensive patients who have average or lower-than-average

cholesterol concentrations, in the Anglo-Scandinavian Cardiac

Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre

randomised controlled trial

Peter S Sever, Björn Dahlöf, Neil R Poulter, Hans Wedel, Gareth Beevers, Mark Caulfield, Rory Collins, Sverre E Kjeldsen,

Arni Kristinsson, Gordon T McInnes, Jesper Mehlsen, Markku Nieminen, Eoin O’Brien, Jan Östergren, for the ASCOT

investigators*

Articles

The n e w e n g l a n dj o u r n a l of m e d i c i n e

e s t a b l i s h e d i n 1812 a p r i l 8 , 2004 v o l . 350 no. 15

Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes

Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D.,

Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D.,

and Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis

in Myocardial Infarction 22 Investigators*

The New England

Journal of Medicine© Copyr ight, 1 9 9 6 , by the Massachusetts Medical Soc i e t y

V O L U M E 335 O C T O B E R 3 , 1 9 9 6 NUMB ER 14

T H E E F F E C T OF PRAVASTATIN ON CORONARY EVEN TS AFTER MYOCARDIAL INFARCTION IN PATIENTS

WITH AVERAGE C H O L E S T E RO L LEVELS

F R A N K M. S A C K S , M.D., M A R C A. PF E F F E R , M.D., PH.D., L E M U E L A. M O Y E , M.D., PH.D., J E A N L. R O U L E A U , M.D.,

J O H N D. R U T H E R F O R D , M.D., T H O M A S G. C O L E , PH.D., L I S A B R O W N , M.P.H., J . W A Y N E W A R N I C A , M.D.,J . M A L C O L M O. A R N O L D , M.D., C H U A N -C H U A N W U N , PH.D., B A R R Y R. DA V IS , M.D., PH.D.,

A N D E U G E N E B R A U N W A L D , M.D., F O R T H E C H O L E S T E R O L A N D R E C U R R E N T E V E N T S T R I A L I N V E S T I G A T O R S *

Calculated genetic risk for >48,000

participants of four statin therapy trialsThe new england

journal of medicineestablished in 1812 november 20,2008 vol. 359 no. 21

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest,M.D.,

Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby,M.D.,

Alberto J. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Børge G. Nordestgaard, M.D., James Shepherd, M.D.,

James T. Willerson, M.D., and Robert J. Glynn, Sc.D., for the JUPITER StudyGroup*

Genetic risk score

27 genetic markers associated with

MI

Incre

asin

g r

isk

540 Number of risk alleles

Genetic risk score

“Low risk” Bottom 20%

“Intermediate risk”

“High risk” Top 20%

Genetic Risk

Score Category Ratio 95% CI

Low

Intermediate

High

Lower Risk Higher Risk

1.25 2.00.80 1.0

Ratio (95% CI)

Reference

1.34

1.72

1.22-1.47

1.55-1.92

P-Value

<0.0001

<0.0001

In placebo arms, genetic score stratifies risk

*Adjusted for traditional CV risk factors





There are genetic markers that are definitely

associated with CAD in collected studies

There are genetic markers that are definitively

associated with CAD in collected studies

1. Do those genetic factors prospectively

predict risk in independent populations?

Yes

2. Is genetic risk useful to measure and

is genetic risk modifiable?

Figure 8 LDL cholesterol burden in individualswith orwithout familial hypercholesterolaemiaas afunction of the age of initiationof statin therapy.

Data derived from Huijgen et al.20 and Starr et al.21 LDL, low-density lipoprotein; LDL-C, LDL cholesterol; HDL-C, high-density lipoprotein chol-

esterol; CHD, coronary heart disease; FH, familial hypercholesterolaemia.

Monogenic risk assessment and modification

Nordestgaard et al. EHJ 2013

Can we modify polygenic risk if

2/3 of loci are non-lipid?

Gold standard: Randomized trial

• Test the hypothesis that genetic

information will improve risk stratification

and that those individuals benefit from

early therapy

Young individuals

without ASCVD

Men 30-40,Women 40-50

High genetic risk

Low genetic risk

Randomize: Statin vs Placebo

Randomize: Statin vs Placebo

Follow for

clinical events

Many years

Prevention of coronary and stroke events with atorvastatin

in hypertensive patients who have average or lower-than-average

cholesterol concentrations, in the Anglo-Scandinavian Cardiac

Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre

randomised controlled trial

Peter S Sever, Björn Dahlöf, Neil R Poulter, Hans Wedel, Gareth Beevers, Mark Caulfield, Rory Collins, Sverre E Kjeldsen,

Arni Kristinsson, Gordon T McInnes, Jesper Mehlsen, Markku Nieminen, Eoin O’Brien, Jan Östergren, for the ASCOT

investigators*

Articles

The n e w e n g l a n dj o u r n a l of m e d i c i n e

e s t a b l i s h e d i n 1812 a p r i l 8 , 2004 v o l . 350 no. 15

Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes

Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D.,

Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D.,

and Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis

in Myocardial Infarction 22 Investigators*

The New England

Journal of Medicine© Copyr ight, 1 9 9 6 , by the Massachusetts Medical Soc i e t y

V O L U M E 335 O C T O B E R 3 , 1 9 9 6 NUMB ER 14

T H E E F F E C T OF PRAVASTATIN ON CORONARY EVEN TS AFTER MYOCARDIAL INFARCTION IN PATIENTS

WITH AVERAGE C H O L E S T E RO L LEVELS

F R A N K M. S A C K S , M.D., M A R C A. PF E F F E R , M.D., PH.D., L E M U E L A. M O Y E , M.D., PH.D., J E A N L. R O U L E A U , M.D.,

J O H N D. R U T H E R F O R D , M.D., T H O M A S G. C O L E , PH.D., L I S A B R O W N , M.P.H., J . W A Y N E W A R N I C A , M.D.,J . M A L C O L M O. A R N O L D , M.D., C H U A N -C H U A N W U N , PH.D., B A R R Y R. DA V IS , M.D., PH.D.,

A N D E U G E N E B R A U N W A L D , M.D., F O R T H E C H O L E S T E R O L A N D R E C U R R E N T E V E N T S T R I A L I N V E S T I G A T O R S *

Calculated genetic risk for >48,000

participants of four statin therapy trialsThe new england

journal of medicineestablished in 1812 november 20,2008 vol. 359 no. 21

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein

Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest,M.D.,

Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby,M.D.,

Alberto J. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Børge G. Nordestgaard, M.D., James Shepherd, M.D.,

James T. Willerson, M.D., and Robert J. Glynn, Sc.D., for the JUPITER StudyGroup*

Comparison of hazard ratios across

genetic risk score categories

Hazard ratio (95%CI) Risk ratio (95% CI)

Genetic riskscore category

Trial

Low risk

Intermediaterisk

High risk

PrimarypreventionJUPITER ASCOTSummary

Secondary preventionCARE PROVEITSummary

PrimarypreventionJUPITER ASCOTSummary


JUPITER ASCOTSummary


0·68 (0·26–1·78)0·64 (0·26–1·56)0·66 (0·34–1·27)

0·79 (0·45–1·39)1·24 (0·67–2·29)0·97 (0·63–1·51)0·87 (0·61–1·23)

0·68 (0·42–1·10)0·68 (0·44–1·04)0·68 (0·49–0·94)

0·79 (0·60–1·04)0·63 (0·45–0·88)0·72 (0·58–0·90)0·71(0·59–0·84)

Primaryprevention0·41 (0·16–1·06)0·54(0·29–1·01)0·50 (0·30–0·84)

0·54 (0·32–0·91)1·51(0·28–0·94)0·53 (0·35–0·78)0·52 (0·37–0·71)

Comparison of hazard ratios across genetic risk score categories:p=0·0277

10·2 0·5

Favoursstatin

0·1 2 5 10

Favours control/ lower intensity statin

Low risk

Intermediate

risk

High risk

High genetic risk → greater benefit

from statin therapy

0

0.3

0.4

0.5

0.6

0.7

1

Ab

so

lute

Ris

kR

ed

uc

tio

ns

(%)

0

0.2

0.5

0.1

1

1.5

2

2.5

0.9

3

0.8

3.5

JUPITER ASCOT

Low Genetic Risk High Genetic RiskIntermediate Genetic Risk

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Ab

so

lute

Ris

kR

ed

uc

tio

ns

(%)

0

0.5

1

1.5

2

2.5

3

3.5

JUPITER ASCOT


Number needed to treat

1 / Absolute risk reduction


from statin therapy

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Ab

so

lute

Ris

kR

ed

uc

tio

ns

(%)

0

0.5

1

1.5

2

2.5

3

3.5

JUPITER ASCOT




Low genetic risk ASCOT trialNNT ~ 100


from statin therapy

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Ab

so

lute

Ris

kR

ed

uc

tio

ns

(%)

0

0.5

1

1.5

2

2.5

3

3.5

JUPITER ASCOT




Low genetic risk ASCOT trialNNT ~ 100

High genetic risk ASCOT trial

NNT ~ 33


from statin therapy

Ongoing work

• Incorporate information from across the

genome to improve risk stratification

• Preliminary results suggest modest but

significant improvements

Summary: Genetics and CV risk

• Genetic factors identify graded risk of CAD– Top 20% of population: ~70% increased risk

• Independent of traditional risk factors

• Inexpensive; can be measured early in life

• May have a role in allocating preventive therapies

www.stitziellab.org

Thank you.

http://www.stitziellab.org/

Human Genetics and CV Risk AssessmentCV Risk Assessment Nathan Stitziel, MD, PhD Assistant Professor of Medicine and Genetics ... Kiran Musunuru1,2, Eric E Schadt8, Lee Kaplan9, Derrick

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