Genetic Basis of Thoracic Aortic AneurysmsGenetic Basis of Thoracic Aortic AneurysmsAnd Acute Aortic Dissections

Dianna M. Milewicz, M.D. Ph.D.University of Texas Health Science Center at Houston

McGovern Medical SchoolMcGovern Medical School

SyndromicFamilial

Genetic Risk for Thoracic Aortic Disease

Familial

SporadicSporadic

Genetic variants thatconfer a low risk

Rare variants withhigh risk,high risk,

“mutations”

FBN1 fibrillin-1

Heritable Thoracic Aortic Disease GenesHeritable Thoracic Aortic Disease Genes

FBN1 fibrillin-1MFAP5 microfibril associated protein 2LOX lysyl oxidase

TGFBR1 TGF-β receptor type I

ECM

TGFBR1 TGF-β receptor type ITGFBR2 TGF-β receptor type I SMAD3 Smad3TGF-β SMAD3 Smad3SMAD4 Smad4TGFB2 TGF-β2TGFB3 TGF-β3

TGF-βSignaling

TGFB3 TGF-β3SMAD2 Smad2

ACTA2 SM α-actinSMC

ACTA2 SM α-actinMYH11 SM myosin heavy chainMYLK myosin light chain kinasePRKG1 cGMP-dependent kinase I

SMCContraction

PRKG1 cGMP-dependent kinase I

MAT2A methionine adenosyltransferases IIαFOXE3 forkhead transcript factor E3

Medial Layer of the Aorta:Smooth Muscle Cells and ElastinSmooth Muscle Cells and Elastin

“Smooth Muscle Cell to Elastic Lamina Connections in Developing Mouse Aorta”, Davis. Elaine, 1993, Laboratory Investigation, 68 (1), p. 97

Mutations Decreasing SMC contraction:HTN

Mutations Decreasing SMC contraction:ACTA2, MYH11, MYLK, and PRKG1

HTN

SMC “mechnosensor” for aortic forcesthrough the elastin – contractile unitsthrough the elastin – contractile units

Activation of SMC cellular “repair” pathways:Activation of SMC cellular “repair” pathways:Angiotensin II and TGF-β signaling; increased MMPs and proteoglycans

Thoracic Aortic Aneurysm and Dissection

increased MMPs and proteoglycans

Thoracic Aortic Aneurysm and Dissection

Milewicz et al. Ann Rev Hum Gen Genomics, 2008

Humphrey, Milewicz, Schwartz and Tellides, Science 2014

SyndromicFamilial

Genetic Risk for Thoracic Aortic Disease

Familial

SporadicSporadic

Genetic variants thatconfer a low risk

Rare variants withhigh risk,high risk,

“mutations”

• 355 T ypeA and B dissectionscases;85% HT N• 355 T ypeA and B dissectionscases;85% HT N

• 9% had am utationinaHT AD gene

• 30% had ararevariantinaknow ngenebutnot• 30% had ararevariantinaknow ngenebutnotknow nm utation

• Highly significantincreased burdenw hen• Highly significantincreased burdenw hencom paredtocontrols(OR 2.775 (95% CI 2.08 -3.7); p= 9.0 x 10-11)3.7); p= 9.0 x 10-11)

• We hypothesize that these HTAD gene rarevariants predispose to dissections but require avariants predispose to dissections but require asecond hit.

D o My h 11R247 C M ic e GetThorac ic A ortic D iseasewith aS ec ond H it?

* * n=30

*P <0.05

P =0.03n=39 *

Type A dissection with

2Section 1 Section 2

aorta

Type A dissection withpericardial tamponade Type B dissections

1

aorta

C harac terization ofP ostnatalMy h 11R247C A ortas

W T My h 11R247C

C harac terization ofH TN W T and My h 11R247C A ortas

W T My h 11R247C

Hypertension activates pathways downstream of focal adhesions Hypertension activates pathways downstream of focal adhesions

Therapeutic Manipulation of Aortic DissectionRates in the Myh11R247C MiceRates in the Myh11R247C Mice

P =0.002

P =0.05

HT AD isagenetically heterogeneousHT AD isagenetically heterogeneouscondition

Com m onpathw ay todiseaseisalteredCom m onpathw ay todiseaseisalteredm echanosensingthroughtheelastin-m echanosensingthroughtheelastin-contractileunit.

S poradicdiseaseisduetoalow riskS poradicdiseaseisduetoalow riskvariantinapresdisposinggeneplusasecondhit.secondhit.

UTHSC at Houston (UTHealth)Dongchuan Guo, Ph.DEllen Regalado, M.S.

Baylor College of MedicineSuzanne Leal, Ph.D.Regie Santos-Cortez, Ph.D.Ellen Regalado, M.S.

Stephanie Wallace, M.S.Shanzhi Wang, Ph.D.Jiyuan Chen, Ph.D.Callie Kwartler, Ph.D.

Regie Santos-Cortez, Ph.D.Scott LeMaire, M.D.Joseph Coselli, M.D.Shaine Morris, M.D.

Callie Kwartler, Ph.D.Shuongtao Ma, Ph.D.Ginger Tsai, M.S.Siddharth Prakash, M.D. Ph.D.

University of WashingtonDeborah Nickerson, Ph.D.Michael Bamshad, M.D.Siddharth Prakash, M.D. Ph.D.

Zhen Zhou, Ph.D.Anthony L. Estrera, M.D.Hazim J. Safi, M.D.

Michael Bamshad, M.D..

Hazim J. Safi, M.D.

Yale UniversityJay D. Humphrey, Ph.D. GenTACJay D. Humphrey, Ph.D.George Tellides, M.DMartin A. Schwartz, Ph.D.

GenTAC

TGF-β Cellular Signaling:Loss of function mutations cause TAADLoss of function mutations cause TAAD

TGF-βTGF-β2/3

Smad3

My h 11R247 C A lters M yosin Fu nc tion:D oes NotC au se A ortic A neu rysm sD oes NotC au se A ortic A neu rysm s

De

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B ac u loviru s expression A ortic Ring C ontrac tion

1p<0.05

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WT Myh11R247C

W T M yh11R247 C

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W T M yh11R247 C

WT Myh11R247C

H&E

WT Myh11R247C

Elastin