Cardiology Grand Rounds at Massachusetts General Hospital May 9, 2018 by Sekar Kathiresan, MD

1. Genetic basis for
myocardial infarction
Sekar Kathiresan, M.D.
Director, Center for Genomic Medicine, MGH
Director, Cardiovascular Disease Initiative, Broad
May 9, 2018

2. Acknowledgments
Kathiresan laboratory
Broad Genomics Platform
Stacey
Gabriel, PhD
Collaborators

3. 911 call: 42yo male with
dizziness, profuse sweating

4. 42yo male with cardiac arrest due
to acute myocardial infarction (MI)

5. Anoxic brain injury
Expired after 10 days in hospital

6. Total cholesterol 198 mg/dl
LDL cholesterol 124 mg/dl
HDL cholesterol 40 mg/dl
Triglycerides 170 mg/dl
Blood pressure 122/78
Body mass index 26
Non-smoker
No type 2 diabetes
Family history: father with MI at 54
MI risk factors prior to event
42yo male with fatal, early-onset MI

7. ACC/AHA10y ASCVD risk calculator typically
used for statin allocation decision:
1.7% (‘low-risk’)

8. Three questions
v
What is genetic
basis for MI?

9. Three questions
v
Beyond LDL, what
lipid pathways
cause MI?
What is genetic
basis for MI?

10. Three questions
v
What
non-lipid
mechanisms
contribute
to MI?
Beyond LDL, what
lipid pathways
cause MI?
What is genetic
basis for MI?

11. Myocardial infarction (MI)
Symptoms
EKG change
Elevation in
cardiac
biomarkers
• Complex trait with heritable & lifestyle components
• ~½ all MIs, 1st presentation sudden death

12. HDL LDL
IDL VLDL
Chylomicron
Remnant
apo A-I apo B apo B apo B apo B48
Cholesterol
Triglyceride
Lipoproteins: risk factors
Lp(a)
apo B
apo(a)
Triglyceride-rich lipoproteins (TRLs)

13. Age onset at MI
To understand genetic basis for early MI,
we began (in 1997) enrolling MGH patients
with MI at young age
MI at age < 50
Chris O’Donnell Calum MacRae

15. Age onset at MI
What are genetic paths to early MI?
MI at age < 50
Monogenic
Polygenic

16. Monogenic model:
Is there a gene where a single mutation
can drive patient to early MI?
Exome
Sequencing
Cases
N=5000
Controls
N=5000
Do et al., Nature (2015)
Systematically search for Risk Mutation
signal across each of ~18,000 genes
Early MI
Men≤50
Women≤60

17. Four genes where coding mutations confer
‘large’ effects on MI risk
Lipoprotein
lipase (LPL)
Gene Carrier
frequency
Clinical
Effect
Blood
biomarker
Low-density
lipoprotein
receptor (LDLR)
Apolipoprotein
A5 (APOA5)
Apolipoprotein(a)
(LPA)
Do*, Stitziel* et al., Nature (2015)
Khera*,Won* et al., JAMA (2017)
Clarke et al., N Engl J Med (2009)
1 in 250
1 in 500
1 in 3000
1 in 100
TRL
Lp(a)
LDL
2.8-fold
1.8-fold
4.5-fold
3.2-fold

18. Monogenic model:
Exome
Sequencing
Cases
N=5000
Controls
N=5000
Do et al., Nature (2015)
These four genes account for roughly
4% of cases (~200 cases)
What about the remaining 4,800?

19. Polygenic model:
Do common DNA polymorphisms
contribute to MI risk?
Systematically search for allele frequency
differences between cases and controls at
millions of polymorphisms across genome
Cases
N=60K
Controls
N=120K
Genotyping

20. Common variants for MI:
95 gene regions
Klarin et al., Nature Genetics (2017)
Nikpay et al., Nature Genetics (2015)
Deloukas et al., Nature Genetics (2013)
Samani et al., Nature Genetics (2011)
Kathiresan et al., Nature Genetics (2009)
Cases
N=60K
Controls
N=120K
McPherson et al., Science (2007)
Helgadottir et al., Science (2007)
WTCCC et al., Nature (2007)

21. Age onset at MI
Does a polygenic model
contribute to early MI?
MI at age < 50
Monogenic
Polygenic

22. ‘N’
polymorphisms
0,1,or 2 copies
of the risk allele
Score ranging
from 0 to 2N
for each person
Concept: polygenic risk scores
Kathiresan,N Engl J Med (2008)
Ripatti, Lancet (2010)
Khera, N Engl J Med (2016)

23. Polygenic risk scores: move from top SNPs
to a genome-wide set of 6.6M for prediction
Khera*, Chaffin*,
bioRxiv 2017
AmitV. Khera

24. Hypothesis: a polygenic score including a genome-
wide set of SNPs can identify individuals with risk
equivalent to a monogenic mutation
Step 1
Training data set:
effect sizes for
6.6 millionvariants
from genome-wide
associationstudy
Cases
N = 60K
Controls
N = 120K
Khera*, Chaffin*, bioRxiv (2017)
Genotypes: from arrays + imputation

25. Hypothesis: a polygenic score including a genome-
wide set of SNPs can identify individuals with risk
equivalent to a monogenic mutation
Khera*, Chaffin*, bioRxiv (2017)
Step 2
Validation
Dataset: ~125K
Cases
N = 4K
Controls
N = 120K
Genotypes: from arrays + imputation
Cases
N = 60K
Controls
N = 120K
Step 1
Training data set:
effect sizes for
6.6 millionvariants
from genome-wide
associationstudy

26. Hypothesis: a polygenic score including a genome-
wide set of SNPs can identify individuals with risk
equivalent to a monogenic mutation
Khera*, Chaffin*, bioRxiv (2017)
Step 2
Validation
Dataset: ~125K
Cases
N = 4K
Controls
N = 120K
Step 3
Testing
Dataset: ~300K
Cases
N = 8.7K
Controls
N = 288K
Genotypes: from arrays + imputation
Cases
N = 60K
Controls
N = 120K
Step 1
Training data set:
effect sizes for
6.6 millionvariants
from genome-wide
associationstudy

27. A new quantitative metric of
genetic liability to heart attack
Polygenic score of
6.6 million common variants
Polygenic score of
6.6 million common variants
0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density
Khera*, Chaffin*, bioRxiv (2017)

28. Genome-wide polygenic score:
little correlation with
currently measured MI risk factors
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0
10
20
30
40
50
60
−4 −3 −2 −1 0 1 2 3
Polygenic Score
ACC/AHAPooledCohortsEquations10−YearRisk,%
Correlation with ACC/AHA
Pooled Cohorts Equation
Correlation
coefficient
r = 0.02
Khera*, Chaffin*, bioRxiv (2017)

29. Using polygenic model, can we identify
group with risk for MI equivalent to
monogenic mutations?

30. 0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density
What if we label top 5% tail of distribution as
‘carriers’ and remainder as ‘non-carriers’?
Polygenic score of
6.6 million common variants
Top
5%
Remainder of
distribution
Khera*, Chaffin*, bioRxiv (2017)

31. 0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density
Polygenic score of
6.6 million common variants
High
polygenic
score
definition
Odds
ratio
Top 5% 3.3
Top 1% 4.7
Top
5%
Remainder of
distribution
Khera*, Chaffin*, bioRxiv (2017)
Top 5% of polygenic MI score:
risk equivalent to monogenic mutations

32. 0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density
Polygenic score of
6.6 million common variants
High
polygenic
score
definition
Odds
ratio
Top 5% 3.3
Top 1% 4.7
Top
5%
Remainder of
distribution
Khera*, Chaffin*, bioRxiv (2017)
In UK Biobank, top 5% of polygenic score
risk equivalent to monogenic mutations
but what about external validation?

33. 2,081 Early-onset MI patients | 3,761 Controls
MI Cases:
• VIRGO: Patients
hospitalized across US with
first MI at age ≤ 55 years
Controls:
• MESA: Multiethnic
population free of
cardiovascular disease

34. Contributions of monogenic and polygenic
models to early MI
100 patients with
myocardial
infarction
Khera*, Chaffin*, under review

35. Monogenic familial hypercholesterolemia mutation
identified in 1.7% patients -> 3.8-fold increased risk
100 patients with
myocardial
infarction
à
Risk
Monogenic 3.8-fold
Khera*, Chaffin*, under review

36. Carriers of familial hypercholesterolemia mutations
can be distinguished by high LDL cholesterol
0
50
100
150
200
250
300
350
No Yes
Monogenic Mutation
LDLcholesterol,mg/dl
Mean LDL Cholesterol
Carriers: 206 mg/dl
Non-carriers: 124 mg/dl

37. High polygenic score identified in 17% of
patients and confers a 3.7-fold increase in risk
100 patients with
myocardial
infarction
à
Risk
Monogenic 3.8-fold
High polygenic 3.7-fold
Khera*, Chaffin*, under review

38. 0
50
100
150
200
250
300
350
No Yes
High polygenic score
LDLcholesterol,mg/dlHigh polygenic score individuals can NOT be
distinguished by high LDL cholesterol
Mean LDL Cholesterol
High polygenic: 132 mg/dl
Non-carriers: 124 mg/dl

39. Mode of detection
Odd ratio for MI
Monogenic Polygenic
3.8
↑ LDL cholesterol
3.7
Currently
UNAWARE
Prevalence among
early MI cases
1.7% 17%
Mechanism of risk apoB lipoproteins ‘Gemish’
Polygenic score identifies 10x than
monogenic mutations

40. Mode of detection
Odd ratio for MI
Intervention
Monogenic Polygenic
3.8
↑ LDL cholesterol
Lifestyle
Medications
3.7
Currently
UNAWARE
?
Prevalence among
early MI cases
1.7% 17%
Mechanism of risk apoB lipoproteins ‘Gemish’
Is high polygenic risk modifiable?

41. Lifestyle Medicines
Is polygenic risk for MI modifiable?
Yes
↓48% ↓44%
Khera, N Engl J Med (2016)
Mega*, Stitziel*, Lancet (2015)
Natarajan, Circulation (2017)

42. In individuals at high polygenic risk,
can favorable lifestyle counter-balance?

43. Lifestyle score: 4 factors
No smoking Body mass
index <30
Regular
physical
activity
Healthy diet
pattern
3 or 4 - Favorable
2 - Intermediate
0 or 1 - Unfavorable

44. In high polygenic risk individuals,
adherence to favorable lifestyle cuts risk by ~50%
Khera*, Emdin*,N Engl J Med (2016)
10.7%
5.1%

45. Do those at high polygenic risk derive greater
benefit from statin therapy?
Determined polygenic risk score for participants of
three statin RCTs to prevent first heart attack
The new england
journal of medicine
established 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 Study Group*
Abstr act

46. Evaluate clinical benefit of statin therapy in
genetic risk subgroups:
High genetic risk versus all others
Mega*, Stitziel*,Lancet (2015)
Natarajan*,Young*, Circulation (2017)

47. Natarajan*,Young*, Circulation (2017)
Among those at high polygenic risk,
statins confer greater benefit
(to prevent first MI)
RRR = 24% RRR = 44%
Pradeep Natarajan

48. Lifestyle Medicines
Is polygenic risk for MI modifiable?
Yes
↓48% ↓44%
Khera, N Engl J Med (2016)
Mega*, Stitziel*, Lancet (2015)
Natarajan, Circulation (2017)

49. Genome-wide polygenic score
a number that captures inherited susceptibility to MI
suspect in 5-10y, most will know this number similar to LDL today
Polygenic score of
6.6 million common variants
Polygenic score of
6.6 million common variants
0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density
Khera*, Chaffin*, bioRxiv (2017)

50. Three questions
v
Beyond LDL, what
lipid pathways
cause MI?

51. Total cholesterol 198 mg/dl
LDL cholesterol 124 mg/dl
HDL cholesterol 40 mg/dl
Triglycerides 170 mg/dl
Blood pressure 122/78
Body mass index 26
Non-smoker
No type 2 diabetes
Family history: father with MI at 54
MI risk factors prior to event
42yo male with fatal, early-onset MI

52. Observational epidemiology
LDL
MIRisk
Plasma Level
MIRisk
Plasma Level
HDL
MIRisk
Plasma Level
TRL

53. Genetics and therapy:
two approaches to distinguish cause from mere correlation
Epidemiology Genetics Therapy
LDL
MIRisk
Plasma Level
MIRisk
Plasma Level
HDL
MIRisk
Plasma Level
TRL

54. LDL: best validated causal pathway
Epidemiology Genetics Therapy
LDL
MIRisk
Plasma Level
MIRisk
Plasma Level
HDL
MIRisk
Plasma Level
TG
LDLR
NPC1L1
PCSK9
Statins
Ezetimibe
PCSK9 mAb

55. Genetic test of HDL hypothesis

56. Genetic test of HDL hypothesis:
Rare variant raising HDL
Endothelial lipase
(LIPG)
HDL
15%
Humans with high HDL-C
Extremes of a
distribution
1 in 40 individuals
are heterozygous for
LIPG Asn396Ser
Clinical EffectSequencing
Voight*, Peloso* et al., Lancet (2012)Gina Peloso

57. LIPG Asn396Ser has no effect on MI
in studies totaling 116,320 individuals
Voight*, Peloso* et al., Lancet (2012)

58. Genetic test of HDL hypothesis:
Rare variant raising HDL -> no effect on MI
HDL
15%
MI
Humans with high HDL-C
Extremes of a
distribution
1 in 40 individuals
are heterozygous for
LIPG Asn396Ser
Endothelial lipase
(LIPG)
Clinical EffectSequencing
N.S.
Voight*, Peloso* et al., Lancet (2012)

59. Lipid pathways for MI:
High lipoprotein (HDL) cholesterol
Epidemiology Genetics TherapyMIRisk
Plasma Level
HDL
Common variants:
no effect on MI
Rare variants:
no effect on MI
Plasma Level
TG
MIRisk
LDL
Plasma Level
LDLR
PCSK9
NPC1L1
Statins
PCSK9 Abs
Ezetimibe

60. Pharmacologic test of HDL hypothesis

61. Dalcetrapib inhibits CETP and
markedly raises HDL cholesterol
Schwartz et al., N Engl J Med (2012)

62. Schwartz et al., N Engl J Med (2012)
…but had no effect on CV outcomes

63. HDL cholesterol
Old View: “Good Cholesterol”
Emerging View: Non-causal marker

64. Pathways for MI:
High lipoprotein (HDL) cholesterol
Epidemiology Genetics Therapy
HDL-
raising
therapy
Common variants:
no effect on MI
Rare variants:
no effect on MI Failed
Plasma Level
TRL
MIRisk
Plasma Level
HDL
MIRisk
LDL
Plasma Level
LDLR
PCSK9
NPC1L1
Statins
PCSK9 Abs
Ezetimibe

65. If HDL non-causal,
why is the epidemiology so robust?
High HDL
cholesterol
↓ MI risk
High HDL tracks
with
Low
Triglyceride-rich
lipoproteins
(TRL)

66. Are there more
protective pathways
beyond low LDL?
low triglyceride-rich lipoproteins:
ANGPTL3

67. Triglycerides:19 mg/dl
LDL cholesterol:37 mg/dl
HDL cholesterol:18 mg/dl
Corporate Health Fair

68. ? ?
I
II
III
1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Anna’s family
Gustav Schonfeld, M.D.
Washington University, St. Louis

69. Kiran Musunuru James Pirruccello Ron Do
2010: exome sequencing to find gene
N Engl J Med (2010)

70. ? ?
I
II
III
1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1 2 3 4 5 6 7 8 9 10 11 12 13 14
125.7
156.3
37.0
83.0
65.7
33.3
316.0
102.5
39.0
114.3
95.7
51.0
148.0
105.7
30.3
51.0
73.2
44.2
97.8
98.8
35.0
174.3
134.0
33.3
378.0
155.0
39.0
24.3
34.7
16.3
22.3
30.8
15.8
17.0
29.0
22.0
63.7
112.3
38.7
19.1
36.8
17.8
343.7
214.3
40.3
66.7
87.0
35.5
44.8
68.2
48.2
53.7
121.8
49.4
224.2
147.6
37.6
87.6
88.5
36.8
42.1
73.9
57.4
49.8
92.0
62.0
31.0
75.0
74.0
45.0
91.5
46.0
43.7
86.7
47.7
77.7
97.3
45.7
56.3
84.5
45.3
29.8
61.4
40.4
145.5
65.3
37.8
144.0
61.2
37.0
106.8
102.7
34.7
55.5
71.5
49.0
31.7
54.3
51.3
17.0
40.0
53.0
42.7
28.3
42.3
92.0
110.5
49.0
90.7
116.3
36.3
80.0
85.0
89.0
Triglycerides
LDL-C
HDL-C
From her mother, Anna inherited
one broken gene copy of ANGPTL3
S17X

71. ? ?
I
II
III
1 2 3 4 5 6 7 8
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
1 2 3 4 5 6 7 8 9 10 11 12 13 14
125.7
156.3
37.0
83.0
65.7
33.3
316.0
102.5
39.0
114.3
95.7
51.0
148.0
105.7
30.3
51.0
73.2
44.2
97.8
98.8
35.0
174.3
134.0
33.3
378.0
155.0
39.0
24.3
34.7
16.3
22.3
30.8
15.8
17.0
29.0
22.0
63.7
112.3
38.7
19.1
36.8
17.8
343.7
214.3
40.3
66.7
87.0
35.5
44.8
68.2
48.2
53.7
121.8
49.4
224.2
147.6
37.6
87.6
88.5
36.8
42.1
73.9
57.4
49.8
92.0
62.0
31.0
75.0
74.0
45.0
91.5
46.0
43.7
86.7
47.7
77.7
97.3
45.7
56.3
84.5
45.3
29.8
61.4
40.4
145.5
65.3
37.8
144.0
61.2
37.0
106.8
102.7
34.7
55.5
71.5
49.0
31.7
54.3
51.3
17.0
40.0
53.0
42.7
28.3
42.3
92.0
110.5
49.0
90.7
116.3
36.3
80.0
85.0
89.0
Triglycerides
LDL-C
HDL-C
Father with different null mutation;
Anna with both copies of ANGPTL3 broken
S17X
E129X
compound
heterozygote

72. Anna (& 2 brothers) who are ANGPTL3
deficient: no plaque in coronary arteries
Stitziel*,Khera* et al.,J Am Coll Cardiol (2017)
ANGPTL3 -/- ANGPTL3 +/+
Coronary CT Angiogram of Right Coronary Artery
Nate Stitziel

73. 1 in 300 US
Null mutation in
ANGPTL3 gene
Lower
triglycerides
34% lower risk
MI
Dewey et al.,N Engl J Med (2017)
Angiopoietin-like 3 (ANGPTL3)
Stitziel*,Khera* et al.,J Am Coll Cardiol (2017)

74. Medicines now developed
to mimic ANGPTL3 null mutations
Dewey et al., N Engl J Med (2017)
Graham et al., N Engl J Med (2017)

75. I in 150 people
Null mutation in
ANGPTL3 gene
Lower
triglycerides
34% lower risk
MI
Monoclonal
antibody
(Regeneron)
Antisense
oligonucleotide
(Ionis)
Block ANGPTL3
✔️ Lower
triglycerides
? MI risk
Will ANGPTL3 inhibitors
reduce MI risk in the clinic?

76. Average risk of
heart attack
Lower
risk
Develop
medicine
that mimics
protective
mutation
Lower
risk

77. Now, seven protective mutation examples for MI
PCSK9 NPC1L1 LPA APOC3 ANGPTL3 ANGPTL4 ASGR1
1 in 40 1 in 650 1 in 71 1 in 150 I in 300 1 in 360 I in 120
LDL LDL Lp(a) TRL TRL TRL TRL
80%
lower risk
53%
lower risk
24%
lower risk
40%
lower risk
34%
lower risk
53%
lower risk
34%
lower risk
alirocumab,
evolocumab,
ezetimibe
Antisense in
development
Antisense in
development
In
development
Monoclonal
antibodies in
development
In
development
Lower
MI risk

78. Summary: beyond low LDL,
lipoprotein lipase-mediated lipolysis is
protective pathway for MI
APOC3,ANGPTL3,ANGPTL4
Kathiresan, Nature (2017)

79. Three questions
v
What
non-lipid
mechanisms
contribute
to MI?

82. Clonal hematopoiesis
Sperling et al., Nature Reviews Cancer (2017)

83. Clonal hematopoiesis: age dependent
Jaiswal et al.,N Engl J Med (2014)

84. 403
72
57
33 31 27 22 12 11 8
0
100
200
300
400
D
N
M
T3A
TET2
ASXL1
TP53
JAK2
SF3B1
G
N
B1
C
BL
SFR
S2
G
N
AS
Number
DNMT3A, TET2 frequently mutated;
detectable with sequencing of blood
Jaiswal et al.,N Engl J Med (2014)

85. Presence somatic mutation ups risk for
hematologic cancer & coronary heart disease
Jaiswal et al.,N Engl J Med (2014)

86. Clonal hematopoiesis &
cardiovascular disease
Jaiswal et al.,N Engl J Med (2017)Sidd Jaiswal Ben EbertPradeep Natarajan

87. Clonal hematopoiesis:
strong risk effect
for early-onset MI (odds ratio 4.0)
Jaiswal et al.,N Engl J Med (2017)

88. Patients with early-onset MI Controls without MI
Clonal hematopoiesis
in cases: ~2-3%
~2-3% of early MI cases
carry clonal mutations

89. Loss of Tet2: more atherosclerosis in mice
Jaiswal et al.,N Engl J Med (2017)

90. Loss Tet2: heightened inflammation,
particularly IL1-beta pathway
Fuster et al., Science (2017)

91. Monoclonal antibody targeting IL1-beta:
just proven to reduce CVD risk
Ridker et al., N Engl J Med (2017)

92. Hypothesis: those who carry clonal hematopoiesis
derive the greatest benefit from canakinumab
Ridker et al., N Engl J Med (2017)

93. New opportunities for screening,
prevention, and treatments
v
What is genetic
basis for MI?
Beyond LDL, what
lipid pathways
cause MI?
What
non-lipid
mechanisms
contribute
to MI?
Polygenic score a
new risk factor
Lipoprotein lipase
pathway and
triglyceride-rich
lipoproteins
Clonal
hematopoiesis

94. Summary:
Genetic basis for early MI
100 patients
with early MI
Monogenic risk
Polygenic risk
Monogenic &
polygenic
3-4 fold
3-4 fold
6-8 fold
à
Risk%
Clonal
hematopoiesis
4 fold