American Society of Human Genetics Curt Stern Award 2018 Acceptance Speech Sekar Kathiresan, MD

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

4. Lipid
Total cholesterol 241 mg/dl
LDL cholesterol 167 mg/dl
HDL cholesterol 40 mg/dl
Triglycerides 170 mg/dl
Non-lipid
Blood pressure 120/80 mm/Hg
Body mass index 26 kg/m2
Non-smoker
No type 2 diabetes
heart attack risk factors
42yo male with fatal
myocardial infarction (MI) or heart attack

5. Average risk of
heart attack

6. Average risk of
heart attack
v
What is
genetic basis for
risk?
What is
genetic basis for
resistance?

7. MI at age < 50
To understand inherited basis for risk, we began (in 1997)
enrolling patients with heart attack at young age
age-of-onset MI

8. age-of-onset MI
Three genetic paths to MI risk
Monogenic
Polygenic
Somatic
MI at age < 50

9. Monogenic mutations identified
in ~2% of early MI patients
100 patients
with early
myocardial
infarction
à
Risk
Monogenic 3.8-fold
Khera*, Chaffin*, under review
Do*, Stitziel*,Won*, Nature (2015)

10. Mechanism monogenic mutations:
raised cholesterol or triglycerides
0
50
100
150
200
250
300
350
No Yes
Monogenic Mutation
LDLcholesterol,mg/dl
124
mg/dl
206
mg/dl

11. Polygenic model:
capture risk through 6.6M common variants,
distill genomic risk into a single #
Gaussian distribution in population
Khera*, Chaffin*, Nature Genetics (2018)
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)
WTCC, Nature (2007)
McPherson et al., Science (2007)
Helgadottir et al., Science (2007)
Cases
N=60K
Controls
N=120K
0.0
0.1
0.2
0.3
0.4
−4 −2 0 2 4
Polygenic Score
Density

12. High polygenic score identified
in 17% of early MI patients
à
Risk
Monogenic 3.8-fold
High polygenic 3.7-fold
100 patients
with early
myocardial
infarction
Khera*, Chaffin*, under review
Do*, Stitziel*,Won*, Nature (2015)

13. High polygenic score identified
in 17% of early MI patients
à
Risk
Monogenic 3.8-fold
High polygenic 3.7-fold
100 patients
with early
myocardial
infarction
Khera*, Chaffin*, under review
Do*, Stitziel*,Won*, Nature (2015)
CURRENTLY UNAWARE OF RISK

14. Mechanism polygenic risk:
a work in progress, but not lipids
0
50
100
150
200
250
300
350
No Yes
High polygenic score
LDLcholesterol,mg/dl
124
mg/dl
132
mg/dl
Top 5%

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

16. Clonal hematopoiesis: somatic mutations in
hematopoietic stem cells
Jaiswal et al.,N Engl J Med (2014)
Sperling et al., Nature Reviews Cancer (2017)

17. Clonal hematopoiesis identified
in 2% of early MI patients
à
Risk
Monogenic 3.8-fold
High polygenic 3.7-fold
Clonal
hematopoiesis
4.0-fold
100 patients
with early
myocardial
infarction

18. Jaiswal et al.,N Engl J Med (2017)
Fuster et al., Science (2017)
Mechanism clonal hematopoiesis:
excess inflammation

19. Average risk of
heart attack
v
What is
genetic basis for
risk?
What is
genetic basis for
resistance?

20. Epidemiology Therapy
Plasma Level
LDL
MIRisk
Lipoprotein pathways & MI
Resistance
Mutation
PCSK9 null Anti-PCSK9
mAb↓LDL, ↓MI

21. Epidemiology Therapy
Plasma Level
HDL
MIRisk
Plasma Level
LDL
MIRisk
Lipoprotein pathways & MI
Resistance
Mutation
PCSK9 null Anti-PCSK9
mAb
HDL-
raising
therapy
HDL-raisingvariants
no effect on MI
↓LDL, ↓MI

22. Epidemiology Therapy
Plasma Level
HDL
MIRisk
Plasma Level
LDL
MIRisk
Lipoprotein pathways & MI
Resistance
Mutation
PCSK9 null Anti-PCSK9
mAb
HDL-
raising
therapy
HDL-raisingvariants
no effect on MI
Failed
↓LDL, ↓MI

23. Epidemiology Therapy
Plasma Level
TRL
MIRisk
Plasma Level
HDL
MIRisk
Plasma Level
LDL
Vascepa
MIRisk
Lipoprotein pathways & MI
Resistance
Mutation
PCSK9 null Anti-PCSK9
mAb
HDL-
raising
therapy
HDL-raisingvariants
no effect on MI
Failed
ANGPTL3 null
APOC3 null
ANGPTL4 null
↓LDL, ↓MI
↓TRL, ↓MI

24. ANGPTL3 APOC3 ANGPTL4
I in 300 1 in 150 1 in 360
TRL TRL TRL
34% lower risk 40% lower risk 53% lower risk
Monoclonal
antibodies,
antisense in
development
Antisense in
development
Monoclonal
antibodies in
development
Lower
MI risk
Medicines being developed to
mimic resistance mutations in TRL lipolysis pathway

25. APOC3,ANGPTL3,ANGPTL4
Kathiresan,Nature (2017)
Beyond low LDL, lifelong low TRL by enhanced
lipolysis confers resistance to heart attack

26. 911 call: 42yo male with dizziness, profuse sweating

28. Risk
Interpret genome (early in life)
to identify individuals at risk
for premature heart attack
Deliver proven, risk-reducing
interventions
(lifestyle ± medicines)
Resistance
Understand non-lipid
pathways and develop new
treatments
What can we do to prevent such tragedies?
1
2
3

29. Trainees 2008-

32. Genetic basis for heart attack
à
Risk
Monogenic 3.8-fold
High polygenic 3.7-fold
Clonal
hematopoiesis
4.0-fold
100 patients
with early
myocardial
infarction