genes, lifestyle, and coronary artery disease amit v

Genes, Lifestyle, and Coronary Artery Disease

Amit V. Khera, MD MScMay 30, 2017

Kathiresan Lab (Broad)Connor Emdin, DPhil

Pradeep Natarajan, MDAlexander Bick, BS

Sekar Kathiresan, MD

Atherosclerosis Risk inCommunities

Eric Boerwinkle, PhD

Women’s Genome Health StudyDaniel Chasman, PhD

Nancy Cook, PhDPaul Ridker, MD

Malmö Diet and Cancer StudyIsabel Drake, PhD

Olle Melander, MD, PhDMarju Orho-Melander, PhD

BioImage StudyUsman Baber, MD

Roxana Mehran, MDDaniel Rader, MD

Valentin Fuster, MD

Acknowledgements

Broad Genomics PlatformNamrata Gupta, PhDStacey Gabriel, PhD

Myocardial infarction risk determined by interplay ofgenetic and lifestyle factors

JAMA (1951)

CasesN=100

ControlsN=146

FamilyHistory 27% 14%

Clinical interpretation of genetic testingfor heart attack risk

100 patients withmyocardial infarction

MonogenicLDL cholesterolTriglyceride clearanceLipoprotein(a)

A monogenic risk pathway mutation identified in 5% ofindividuals presenting with myocardial infarction

100 patients withmyocardial infarction Monogenic

LDL cholesterolLDLR, APOB

3.2-fold

2.3-fold

2.8-fold

Risk

Lipoprotein(a)LPA

Triglyceride clearanceLPL, APOA5

Clinical interpretation of genetic testingfor heart attack risk

100 patients withmyocardial infarction

Monogenic

Polygenic

LDL CholesterolTriglyceride ClearanceLipoprotein(a)

Polygenic Risk Score

>50 genetic variants associated with myocardial infarction

Kathiresan Nature Genetics (2009)Samani Nature Genetics (2011)Deloukas Nature Genetics (2013)Nikpay Nature Genetics (2015)

CasesN=60K

ControlsN=120K

Genetic variants associated with myocardial infarctionhighlight multiple underlying pathways

Author notesPlease check these fig

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Fig 1

Nature Reviews |Genetics

• SORT1• PCSK9• APOB• ABCG5–ABCG8• LPA• LIPA• LDLR• APOE

• LPL• TRIB1• APOA5/A4/C3/A1• ANGPTL4

• IL6R• CXCL12• SH2B3

• COL4A1–COL4A2• MIA3• REST–NOA1• ZC3HC1• 9p21• PDGFD• SWAP70• KSR2• ADAMTS7• BCAS3• FLT1• SMAD3

• GUCY1A3• EDNRA• NOS3• FURIN–FES

• PPAP2B• WDR12• VAMP5–VAMP8–GGCX• ZEB2• AK097927• MRAS• SLC22A4–SLC22A5• ANKS1A• PHACTR1• TCF21• KCNK5• PLG• HDAC9• ABO• SVEP1

• CYP17A1–CNNM2–NT5C2KIAA1462• ATP2B1• HHIPL1• MFGE8–ABHD2SMG6–SRRRASD1–SMCR3–PEMT• UBE2Z–GIP–ATP5G1–SNF8• PMAIP1–MC4RZNF507• SLC5A3–MRPS6–KCNE2POM121L9P–ADORA2A

Triglyceride-richlipoproteins

LDLcholesteroland lipoprotein(a)

n ammation Cellular proliferationand vascularremodelling

Vascular toneand nitric oxidesignalling

athway remainsuncertain

Vasodilation

Nature Reviews| GeneticsManuscript number NRG-15-099Kathiresan 29|11|16

Khera & Kathiresan | Nature Reviews Genetics | 2017

Kathiresan Nature Genetics (2009)Samani Nature Genetics (2011)Deloukas Nature Genetics (2013)Nikpay Nature Genetics (2015)

Polygenic risk score:Measure of inherited risk for coronary disease

Polygenic Risk Score

Polygenic risk score: Divide population into genetic riskgroups (low, intermediate, high)

Polygenic Risk Score

Bottom 20%LOW

Top 20%HIGHINTERMEDIATE

Building a polygenic risk score using 50 variants:Distribution in > 50,000 individuals

Atherosclerosis Riskin Communities

(N = 7,814)

Women’s GenomeHealth Study(N = 21,222)

Malmö Diet andCancer Study(N = 22,389)

Polygenic Risk Score Polygenic Risk Score Polygenic Risk Score

High genetic risk → 91% higher event rate

High genetic risk → 91% higher event rate

Atherosclerosis Riskin Communities

Women’s GenomeHealth Study

Malmö Diet andCancer Study

Clinical interpretation of genetic testing for heart attackrisk; where do we stand in 2017?

100 patients withmyocardial infarction

Monogenic risk

Polygenic risk

Monogenic & polygenic

3-fold

2-fold

6-fold

Risk

To what extent can a healthy lifestyle offset inherited riskof myocardial infarction?

Genetics Lifestyle

Myocardialinfarction

Nurses Health Study: N Eng J Med, 2000

Most favorable lifestyle (3% of women)associated with 83% decrease in coronary risk.

Building a healthy lifestyle score:

No current smoking

Avoiding obesity

Regular exercise

Healthy diet

Favorable lifestyle3-4 healthy lifestyle factors

Intermediate lifestyle2 healthy lifestyle factors

Unfavorable lifestyle0-1 healthy lifestyle factors

Favorable lifestyle → 50% lower event rate

Favorable lifestyle → 50% lower event rate

Atherosclerosis Riskin Communities

Women’s GenomeHealth Study

Malmö Diet andCancer Study

Among high polygenic risk individuals,favorable lifestyle decreases risk by ≈ 50%

Among high polygenic risk individuals,favorable lifestyle decreases risk by ≈ 50%

UnfavorableLifestyle: 10.7%

FavorableLifestyle: 5.1%

Among high polygenic risk individuals,favorable lifestyle decreases risk by ≈ 50%

Good genes / bad lifestyle ≈ bad genes / good lifestyle

Good genes/bad lifestyle

Bad genes/Good lifestyle

Good genes / bad lifestyle ≈ bad genes / good lifestyle

Good genes/bad lifestyle

Bad genes/Good lifestyle

Among high polygenic risk 1° prevention group,statins → 44% decrease in coronary risk

Natarajan et al. | Circulation| 2017

↓ 27%

↓ 44%

To what extent can inherited risk of myocardial infarctionbe offset by lifestyle or statin therapy?

DNA is not destiny.Among those at high genetic risk,

both healthy lifestyle and statin therapy→ 40-50% reduction in myocardial infarction.

Human genetics can stratify the population to guidetargeted therapy for myocardial infarction

Monogenic risk (5%) Polygenic risk (30%)

Triglyceride clearance

Familial hypercholesterolemia

Increased lipoprotein(a)

Statin, ezetimibe, PCSK9i

APOC3 inhibition

ASO Lp(a) inhibitor

Statin

Lifestyle Medications

NEJM 2016 Lancet 2015Circulation 2017

Author notesPlease check these fig

u

r escarefully and return any comments/amendments that you might have tome assoon aspossible. In particular, wewould like you to check the following:

• Do the fig

u

r esconvey the intendedmessage?• Areall the labelsaccurate and in the right place?• Areall thearrowsin the right place?• Areany chemical structurescorrect?• Have shapesand coloursbeen used consistently and accurately throughout the figu r es?• Haveany of the fig

ur esbeen previously published,or have they been supplied by acolleague(s)

who isnot anamed author on thearticle?

To mark up any corrections, please use the commenting tools in the PDF, or print and draw by hand,rather than directly edit ing the PDFs.

Fig 1

Nature Reviews |Genetics

• SORT1• PCSK9• APOB• ABCG5–ABCG8• LPA• LIPA• LDLR• APOE

• LPL• TRIB1• APOA5/A4/C3/A1• ANGPTL4

• IL6R• CXCL12• SH2B3

• COL4A1–COL4A2• MIA3• REST–NOA1• ZC3HC1• 9p21• PDGFD• SWAP70• KSR2• ADAMTS7• BCAS3• FLT1• SMAD3

• GUCY1A3• EDNRA• NOS3• FURIN–FES

• PPAP2B• WDR12• VAMP5–VAMP8–GGCX• ZEB2• AK097927• MRAS• SLC22A4–SLC22A5• ANKS1A• PHACTR1• TCF21• KCNK5• PLG• HDAC9• ABO• SVEP1

• CYP17A1–CNNM2–NT5C2KIAA1462• ATP2B1• HHIPL1• MFGE8–ABHD2SMG6–SRRRASD1–SMCR3–PEMT• UBE2Z–GIP–ATP5G1–SNF8• PMAIP1–MC4RZNF507• SLC5A3–MRPS6–KCNE2POM121L9P–ADORA2A

Triglyceride-richlipoproteins

LDLcholesteroland lipoprotein(a)

n ammation Cellular proliferationand vascularremodelling

Vascular toneand nitric oxidesignalling

athway remainsuncertain

Vasodilation

Nature Reviews| GeneticsManuscript number NRG-15-099Kathiresan 29|11|16

Author notesPlease check these fig

u

r escarefully and return any comments/amendments that you might have tome assoon aspossible. In particular, wewould like you to check the following:

• Do the fig

u

r esconvey the intendedmessage?• Areall the labelsaccurate and in the right place?• Areall thearrowsin the right place?• Areany chemical structurescorrect?• Have shapesand coloursbeen used consistently and accurately throughout the figu r es?• Haveany of the fig

ur esbeen previously published,or have they been supplied by acolleague(s)

who isnot anamed author on thearticle?

To mark up any corrections, please use the commenting tools in the PDF, or print and draw by hand,rather than directly edit ing the PDFs.

Fig 1

Nature Reviews |Genetics

• SORT1• PCSK9• APOB• ABCG5–ABCG8• LPA• LIPA• LDLR• APOE

• LPL• TRIB1• APOA5/A4/C3/A1• ANGPTL4

• IL6R• CXCL12• SH2B3

• COL4A1–COL4A2• MIA3• REST–NOA1• ZC3HC1• 9p21• PDGFD• SWAP70• KSR2• ADAMTS7• BCAS3• FLT1• SMAD3

• GUCY1A3• EDNRA• NOS3• FURIN–FES

• PPAP2B• WDR12• VAMP5–VAMP8–GGCX• ZEB2• AK097927• MRAS• SLC22A4–SLC22A5• ANKS1A• PHACTR1• TCF21• KCNK5• PLG• HDAC9• ABO• SVEP1

• CYP17A1–CNNM2–NT5C2KIAA1462• ATP2B1• HHIPL1• MFGE8–ABHD2SMG6–SRRRASD1–SMCR3–PEMT• UBE2Z–GIP–ATP5G1–SNF8• PMAIP1–MC4RZNF507• SLC5A3–MRPS6–KCNE2POM121L9P–ADORA2A

Triglyceride-richlipoproteins

LDLcholesteroland lipoprotein(a)

n ammation Cellular proliferationand vascularremodelling

Vascular toneand nitric oxidesignalling

athway remainsuncertain

Vasodilation

Nature Reviews| GeneticsManuscript number NRG-15-099Kathiresan 29|11|16

Healthy Lifestyle Factor Criteria

Healthy Lifestyle Factor CriteriaAbsence of Current Smoking No current smokingAbsence of Obesity BMI < 30 kg/m2 at baseline examinationRegular Physical Activity Self-reported physical activity ≥ once/week

Healthy Diet

At least 5 of the 10 characteristics:Fruits: ≥ 3 servings/dayNuts: ≥ 1 serving/week 3Vegetables: ≥3 servings/dayWhole grains: ≥ 3 servings/dayFish: ≥2 servings/weekDairy: ≥ 2.5 servings/dayRefined grains: ≤ 1.5 servings/dayProcessed meats: ≤ 1 serving/weekUnprocessed red meats: ≤ 1.5 servings/weekSugar sweetened beverages: ≤1 serving/week

Rare variant burden signals in 9 genes

CasesN=10K

ControlsN=12K

Sample size

Exome sequencing

Gene CarrierFrequency

Odds Ratiofor MI

LDLR 1 in 221 ≈ 4LPL 1 in 249 ≈ 2APOA5 1 in 216 ≈ 2

LPA 1 in 285 ≈ 0.8NPC1L1 1 in 650 ≈ 0.5ANGPTL4 1 in 360 ≈ 0.5APOC3 1 in 150 ≈ 0.6ASGR1 1 in 120 ≈ 0.7PCSK9 1 in 50 (Blacks) ≈ 0.2

Ri

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Background: Both genetic and lifestyle factors contributeto individual-level risk of coronary disease

“… in the future the fatalism concerning the familial inheritance ofdisease will be dispelled … through the application of preventive

measures … There may then come true the quotation fromShakespeare…Our remedies oft in ourselves do lie.”

Paul Dudley White, MDNEJM, 1957