Human Genetics and CV Risk AssessmentCV Risk Assessment Nathan Stitziel, MD, PhD Assistant Professor...
Transcript of Human Genetics and CV Risk AssessmentCV Risk Assessment Nathan Stitziel, MD, PhD Assistant Professor...
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.
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?
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)
What genetic factors associate with CAD?
Stratifying CAD risk
Modifying genetic CAD risk
Can genetics inform risk assessment?
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.
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
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
What genetic factors associate with CAD?
Stratifying CAD risk
Modifying genetic CAD risk
Can genetics inform risk assessment?
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
Secondary preventionCARE PROVEITSummary
JUPITER ASCOTSummary
Secondary preventionCARE PROVEITSummary
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
Low Genetic Risk High Genetic RiskIntermediate Genetic Risk
Number needed to treat
1 / Absolute risk reduction
High genetic risk → greater benefit
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 High Genetic RiskIntermediate Genetic Risk
Number needed to treat
1 / Absolute risk reduction
Low genetic risk ASCOT trialNNT ~ 100
High genetic risk → greater benefit
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 High Genetic RiskIntermediate Genetic Risk
Number needed to treat
1 / Absolute risk reduction
Low genetic risk ASCOT trialNNT ~ 100
High genetic risk ASCOT trial
NNT ~ 33
High genetic risk → greater benefit
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