常见多基因疾病的遗传咨询

常见多基因疾病的遗传咨询OutlineBackground--ComplexCommon

Diseases--HumanGenomeProject&Post-Genome

EraGeneticCounselingforCommonDiseaseAge-relatedmaculardegeneration(AMD)Type2diabetesmellitus(T2DM)Essentialhypertension

(EH)Alzheimerdisease(AD)Parkinson’sdisease(PD)BackgroundComplexCommon

DiseasesCentral

PointsPolygenictraitscontrolledbytwoormore

genesMultifactorialtraitsarepolygenicwithanenvironmental

componentManyothermultifactorial

traitsEvidenceforGeneticFactorsin

CommonComplex

DiseasesFamilial

aggregationTwin

studiesMendelianformsof

diseaseFamilial

AggregationIncreasedrisk

to

relatives: λRλSIDDMNIDDMλ1SchizophreniaAutism10-15410~100Maturityonsetdiabetesoftheyoung

(MODY)Associationand

LinkageASSOCIATIONofaspecificalleleatageneticlocus

withdiseaseina

population–

Candidate

geneLINKAGE.Co-segregationinfamilies

ofamarkerlocus,regardlessofspecificallele,with

disease.Diabetes

MellitusComplexDisease

Geneticsdiseasestatephenotype1phenotype2phenotype3phenotype4phenotype5environmentgenotypeother

genesJInternMed2008;263:16Threshold

ModelPredictionsfromThreshold

ModelRecurrencerisksare

averageRiskincreaseswith#ofaffectedrelativesRiskincreaseswithseverityof

malformationDifferentialriskincreasesasfrequencydecreasesSex

differencesHumanGenomeProject&Post-Genome

EraBackgroundHumanGenome

ProjectFebruary2010markedthe10thanniversaryofthecompletionofthehumangenomeprojectInitialsequencewas

finishedearlybecauseofadvancementsingenomesequence

technologyResultedindrasticallyreducedlabor&

deliverycostsHumanGenomeSequencingCosts2000–HumanGenome

Project$3

billion2007–James

Watson$2million2009–Illumina&

Helicos–

$50,0002010–Illumina

HiSeq–

$10,0002014–Multiple

companies–

$1,000CandidateGene

ApproachAretherepotentialcandidate

genes?Genesthatareselectedbasedonknownbiological,physiological,orfunctionalrelevancetothephenotype

underinvestigationApproachislimitedbyitsrelianceonexisting

knowledgeaboutthebiologyof

diseaseAssociationsmaybe

population-specificE.g.,type2diabetesGenesencodingmoleculesknowntoprimarilyinfluencepancreaticβ-cellorinsulin

actionABCC8(sulphonylureareceptor),INS,INSR,

etc.PLOSBio

2003;1:41Alternative

ApproachGenome-wideassociationstudies

(GWAS)Hypothesis:commongeneticvariants(>5%);

commondiseases

(traits)Limitednumberofvariants,eachwithasmall

effectNoapriorihypothesesPowertoidentifyrarevariants(1-5%)is

limitedFirstpublicationwasin

2005ComplementfactorH&age-relatedmacular

degenerationRequireLarge,well-characterized

populationsGenotypingacrosstheentiregenomeSophisticateddataanalysis

–collaborateon

this!!Monogeneticvs.Common

DisordersGWAS

ExampleNEJM2010;

362:166GWAS

ExampleNEJM2010;

362:166消化系统疾病心血管疾病代谢性疾病免疫系统疾病神经系统疾病肝脏酶测量脂类或脂蛋白测量炎症标志物测量血液学测量体重与身体测量心血管测量其他测量药物反应生物学过程癌症其他疾病其他性状Post-Genome

EraBackgroundHumanGenetic

VariationSinglenucleotidepolymorphisms(SNPs)Tandemrepeat

SequencesMicrosatellites(<8

bp)Minisatellites(VNTRs;8-100bp)Copynumbervariants(CNVs;1Kb–1Mb)Insertions–deletions(indels;100bp–

1Kb)Note:sizelimitationsarearbitrary–nobiologicalbasis&definitionsarenotconsistentacross

studiesSNPs‘Tag’Haplotype

BlocksNEJM2007;

356:1094CopyNumber

VariantsDNA

MicroarrayUsedto

genotype

500,000 –1+million

SNPsGeneticVariation

DatabasesDatabaseContentAddressdbSNPSNPscovering

thehuman

genomehttp://www.ncbi.nlm.nih.

gov/projects/SNPsHapMapCatalogofvariantsfromHapMap

Project1000Genome

ProjectExtensionofHapMap

–aimtocatalog95%ofvariantswith1%

freqUCSC

GenomeBioinformaticsReferencehumangenomesequence

withannotationEnsemblGenomebrowser,annotation,comparative

genomics/index.htmlGeneticVariation

DatabasesDatabaseContentAddressGeneCardsDatabaseofhumangeneslinkedto

relevantdatabaseshttp://www.genecards.or

gPharmGKBSNPsinvolvedin

drugmetabolismDGVDatabaseofGenomicVariants,including

CNVhttp://projects.tcag.ca/var

iationSCANSNP&CNVannotationbasedongene

function&

expressionhttp://www.scandb.org/n

ewinterfaceOMIMOnlineMendelianInheritanceinMan

–over12,000

geneshttp://www.ncbi.nlm.nih.g

ov/sites/entrez?db=omimBestPractResClinEndoMetab,2012.

26:119.GeneticCounselingforCommon

DiseaseWhatIsGenetic

Counseling?Geneticcounselingistheprocess

of:evaluatingfamilyhistoryandmedical

recordsorderinggenetic

testsevaluatingtheresultsofthis

investigationhelpingparentsunderstandandreachdecisionsaboutwhattodo

nextGeneticsClinic

EvaluationFamilyhistoryPregnancy,medical,developmental

historyPhysical

examDysmorphology

examDiagnostic

evaluationsGenetic

testingGenetic

counselingSupportandInformation

ResourcesGeneticCounselingforPolygenic

StrokePolygenicStrokePedigree

Example55HTN,dx

55Hyperlipidemia,dx

5077Stroke,

73HTN,dx

5053HTN,dx

52DM,dx

5275CABG,

64Stroke,

75HTN,dx

5575Healthyd.

70MIDM,dx

60d.72StrokeHTN,dx

62GeneticRiskAssessmentandCounseling

Issuesand

ManagementThe proband learns he is at increased risk for cardiovasculardisease

(CVD)This includes atherosclerosis

related to stroke

AND coronary heartdiseaseHe recognizes the importance ofgetting his hypertension undercontrolStartshypertensionmedicationsTherapeuticlifestylechangeshavenotbeeneffectiveenoughforthispatientinreducinghischolesterol

levelsStartsmedicationfor

hyperlipidemiaPatientalsostartsexerciseprogramandinformshissisterofherincreasedCVD

riskAt patient’s 3 and 6 month follow-up appointments, his bloodpressureandcholesterollevelsmeasureinthenormal

rangeUseofGeneticTestingfor

StrokeA valuable tool in

diagnosing

single-gene disordersassociatedwithstrokeNot currently recommended in patients

with commonmultifactorial(polygenic)

strokeFamily health history (FHH) remains gold standard in the“genetic”evaluationforpolygenic

strokePowerfultoolthatcanidentifyindividualsatincreaseddiseaseriskwhomaybenefitfromtargetedpersonalhealthpromotioneffortsandprevention

therapiesReflectssharedgeneticsusceptibilities,sharedenvironment,andcommon

behaviorsBotheasilyandinexpensivelyobtainedonaroutinehealthassessmentGeneticTestsfor

StrokeMorethan1000genetictestsarenowavailableforamultitudeofconditionsHundreds

more

are

moving

through

the

research

pipeline

to

clinicalapplicationDetermining the appropriate genetic test and testing laboratory iscriticalLaboratoriesmayofferdifferenttypesoftestsandusedifferentmethodswithvaryingsensitivitiesanddetection

ratesSomelabswillnotbillapatient’sinsurance

directlyGenetic tests can be costly, and may or may not be covered byinsuranceLettersofmedical

necessityInterpretation and implications of genetic tests are not alwaysstraightforward(variantsofuncertain

significance)Prudenttoconsultagenetics

professionalGoalsofGeneticRiskAssessmentfor

Strokeno

symptomsTypicalage

atdiagnosis50’ssymptomsRiskFactor

ModificationEarlyDetection,ProphylacticTreatment,and

Prevention30’sBirthDeathAgeatdiagnosis

withgenetic

counselingComplexitiesofGenetic

TestingBenefitsandlimitationsvarybasedon

circumstancesGenetictestingmayormaynotinfluencemedical

managementPsychosocialimplications-forpatientand

familymembersGenetic

determinismAnxietyParental

guiltEthicaldilemmas(e.g.revealingnon-paternity,testing

minors)Genetic

discriminationHealth,disability,lifeandlong-termcare

insuranceEmploymentRisksinPredictive

TestingBadoutcomesmayoccurregardlessofresultTimeofrisk

differsRiskfactorsforsuicideaftertesting

include:unemploymentpasthistoryof

depressioncontactwithpersonswithHuntington

diseasenochildren/no

partnerRisksfordepressionhigherwithresultdiscrepant

fromexpectationGeneticTestApplicationsinCommon

DiseasesPrenatal/preimplantation

testingDiagnostic

testingPresymptomatictestingPredisposition

testingCarrier

testingNewborn

screeningPredispositionGenetic

TestingTestingofhealthy/unaffectedpersonsfor

aconditionwithincomplete

penetranceExamples

include:BRCA1/2gene

mutationsHemochromatosisGeneticCounselingneedsaffectedbyavailabilityofinterventions,certaintyof

diseaseELSI: Genetic

TestingShouldtestingbedoneforsusceptibility

genes?– roleofenvironmentalfactorsindisease

developmentShouldparentshavetherighttohavetheirminorchildrentestedforadult-onset

diseases?Arecurrentgenetictestsreliableandinterpretablebythemedical

community?AwarenessofFamilyHealthHistoryasaRiskFactorfor

DiseaseSurveyofconsumersconductedbythe

CDC96.3% of respondents considered knowledge of familyhistoryimportanttotheirpersonal

health30%reportedactivelycollectinghealthinformationfromrelativestodevelopafamilyhealth

historyMMWR

11/12/04/53(44)Majorgeneticfactorsinvolvedinsusceptibilitytocommondiseaseslikediabetes,heartdisease,Alzheimer’sdisease,cancer,andmentalillnesswillbeuncoveredinthenext5-7years“Itwillbeimportanttoremember,however,thatmostofthesetestswillnotbe“yes”or“no”butratherwillpredictrelative

risk”WorldEconomic

ForumJanuary24,

2003Age-relatedmaculardegeneration

(AMD)AMD symptomsHowdoesAMD

Develop?MaculaRetinaRPEChoroidNormal

RetinaRETINARPEBruch’s

membraneCHOROIDHealthy

retinaEarlyAMD

-“Drusen”Normallynosymptomsbutat

riskof

progressionLipid

deposits(drusen)Notreatmentbutprogressionslowedbydietand

lifestylemodificationsDrusenEarly

AMDDry

AMD:Atrophyofretinal

tissue.

Graduallossofcentralvisionoveryearsendstagehassignificantvision

lossWet

AMD:Formationleakybloodvesselsunder

retinaRapidlosscentral

visionLateStagesof

AMDDry

AMD Wet

AMD RiskFactorsfor

MDAge%PrevalenceAMDby

ageRiskFactorsfor

AMDGenetics50

-70% caseshaveagenetic

link50%riskof

AMDifadirectfamilyhistoryAMDPrincipalgenesCFH&

ARMS2EarlyAMD75%

hadonerisk

alleleLateAMD93%had

onerisk

alleleRiskofdevelopingAMDby85yrs

increaseswithnumberof

allelesGenetics:Risk

AllelesCFHMainlydry

AMDInhibitoryeffect

oncomplement

pathway?Lesseffectiveinhibition

ofinflammatory

pathwayARMS2Mainlywet

MDGenelocated

inmitochondria?Interfereswith

normaloxidationRotterdamEye

StudyComplementinflammation

pathwaysCFBCFHExerciseComplementinflammation

pathwaysCFBCFHExerciseTobaccoCFHComplementinflammation

pathwaysCFHTobaccoCFBExerciseCFHHighfat

intakeComplementinflammation

pathwaysCFHTobaccoHDLCFBExerciseCFHHighfat

intakeMembraneAttack

ComplexCFHgeneSNPY402HandSCR

domainModifyingGeneticRisk

FactorsSmokingWith1CFHalleleRisk

of AMD:Nonsmokers

risk 12xSmokers

risk 34xDiet1CFH&/orARMS2

alleleHighdoseZn,omega3,

luteinrateclosetonogenetic

riskRiskFactorsfor

AMDSmokingSmokingincreasesrisk3to4

timesSmokersgetMD10yearsearlier,on

averageBUT20yearsafterquitting,asmoker’sriskisthesameasa

non-smokerEatingforEye

HealthLuteinDarkgreenandnaturallyyellowvegetablesandfruitevery

dayFish2-3timesper

week(salmon,sardines,mackerel,anchovies,

tuna)EatingforEye

HealthOmega

3Handfulofnutsper

week(brazilnuts,almonds,walnuts,pine

nuts)EatingforEyeHealthLimitfat

intakeLowGlycemicIndex

FoodsBreakdownmore

slowlyProlongenergy

releaseLeavelesswasteproducts

inthe

eyeChronic

diseaseDryAMD:dietandlifestyle

importantWetAMD:treatment

availabledietandlifestylealso

importantTreatmentsfor

AMDTreatmentforWetMDInjectionLucentisor

Avastinintothe

eyeAverageevery4–6

weeksEarlytreatmentsaves

sight!Aimtostabilisevisionandpreventfurthervision

loss.WetAMD:New

treatmentsVEGF

Trap-EyeSimilareffecttoLucentis/

Avastino

laststwomonthsAvailablelaterthisyearin

NZPazopanib(Eye

drop)Usedwithanti-VEGFinjectionsto

helpnumberof

injectionsInphase3

trialsspreadDryAMD:New

treatmentsFenretinideAtablet,derivedfromVitamin

ASlowsdevelopmentof

drusenReducesriskofwetAMDby2

foldInphase3

trialsBrimonidineAnimplantinside

eyeMayprotectagainstlatedry

AMDInphase2

trialsLaserforearly(dry)

AMDEllex2RT

(Laser)Ultra-shortduration,non-thermal

laserAppearstoreduceformationof

drusenMayimprovewastetransportin

retinaTrialsongoingGenetherapyforwet

AMDGenetherapyinsertsa‘normal’geneintocells

toreplacedisease-causing

genes.RetinoStat–gene-therapytostopnewbloodvessel

formation.Earlyclinical

trials.Retinalcell

transplantationManyanimalstudies,

somehuman

studiesOnlylimited

efficacyreportedVerydifficult

surgeryStemcell

treatmentArtificialvision“Bionic

eyes”Anelectronicprosthesistoreplacethefunctionofdeadretinalcells.NOTE:Current‘bioniceyes’provideMUCHLESSvisionthan

mostpeoplewithendstageAMDalready

possess.PotentialTargetsforAMD

TherapyMembraneAttack

ComplexSummaryAge-relatedmaculardegeneration(AMD),alsoknownassenilemaculardegeneration(SMD),isakindofatrophic

macular

degenerationdisorder,

alwaysleadingtoseverecentralvisionlossevenblindness,butthepathogenesisofAMDremainsunclear.Todate,CFH,HTRAl,C2/BF,TIMP3etc.arereportedtoincreasethesusceptibilityof

AMD.Type2diabetesmellitus

(T2DM)IntroductionDiabetesisagroupofmetabolicdiseasescharacterizedbyhyperglycemiaresultingfrominsulinresistanceand/orimpairedinsulinsecretionComplicationsincludeneuropathy,nephropathy,

vasculardisease,andretinopathyClassicSymptoms“Polys”–Polyuria,Polydipsia,

PolyphagiaUnexplainedweight

lossGlobalprevalenceof

diabetes1.942.23.3021.510.52.533.5全球DM患者总数（亿）2004

year2010

year2025

year排名国家1995国家2025(百万)(百万)1印度19.4印度57.22中国16.0中国37.63美国13.9美国21.94俄联邦8.9巴基斯坦14.55日本6.3印度尼西亚12.46巴西4.9俄联邦12.27印度尼西亚4.5墨西哥11.78巴基斯坦4.3巴西11.69墨西哥3.8埃及8.810Ukraine3.6日本8.5所有其他国家49.7所有其他国家103.6Total135.3300.0糖尿病患者数排名前10位的国家KingH,etal.DiabetesCare

1998;21:1414–31.2010年全世界20岁~79岁的成年人中有2.85亿罹患糖尿病，预计到2050年，患者总数将增至3.33亿。ClassificationEtiologicclassificationofdiabetesmellitus(1997

ADA 1999

WHO)Type1diabetes(T1DM)Type2diabetes(T2DM)Otherspecific

typesGestationdiabetes

mellitus(GDM)MayrangefrompredominantlyinsulinresistancewithrelativeinsulindeficiencytoapredominantlysecretorydefectwithinsulinresistanceTheriskofdevelopingthisformofdiabetesincreaseswithage,

obesityandlackofphysical

activityItisoftenassociatedwithastronggeneticpredisposition,morethanisthetype1

diabeteshigher

prevalenceType2diabetes

(T2DM)5%90%5%1型糖尿病2型糖尿病其他类型糖尿病Race/EthnicityGeneticsHealth

CareEnvironmentCultureLifestyleT2DMRiskPrevalenceOutcomesInfluencesonT2DMRisk,Prevalence,and

OutcomesEpigeneticModifications&

T2DMImportanceofFamily

HistoryIfasinglefirstdegreerelativehasdiabetes,theprevalence

ofdiabetesincreasestoabout15%,i.e.anoddsratioofabout

5Cliniciansshouldaskaboutwhetherotherfamily

membershave:DiabetesObesityHypertensionChronicKidneyDisease

(CKD)CoronaryHeart

DiseaseStrokeGeneticsand

DMBothtwinandpopulation-basedstudiessuggestthat

T2DMhasastronggenetic

componentComplexinteractionsbetweenamultitudeof

genes.Genesseemtobestronglyinfluencedbyenvironmental

andbehavioral

factors.Aretherespecificgenesthathavebeen

identified?GeneticPolymorphismand

DMGenesMechanismTranscriptionfactor7-like2

gene(TCF7L2)B-celldysfunction(not

insulinresistance)PPAR-gammaInsulin

resistanceKCNJ11B-cell

dysfunctionCDKAL1B-cell

dysfunctionCDKN2A/BB-celldysfunctionFTOObesityHHEX/IDEB-cell

dysfunctionIGF2BP2B-celldysfunctionorinsulin

resistanceSLC30A8B-cell

dysfunctionTCF2B-celldysfunctionWF

tly toS1he for

deB-cell

dysfunctionManycandidatesbutlittle

certaintyEtiologyand

pathogenesisType2

DMGenetic

susceptibilityEnviromentalfactors(obese,richdiet,oldLessphysicalactivity

)Insulin

deficiency(ID)Insulin

resistance(IR)IGR (IGT,

IFG)T2DMLowborn

weightInsulin

resistance

: definitionInsulin

sensitivityTheability

of insulin todegradedissociation

glucoseconcentrationstimulatetoutilizeglucose:muscleand

fatinhibittogenerateglucose:

liverInsulin

resistanceLossinginsulinsensitivityleadto

hyperinsulinemiaendodermisfunctionaldisturbanceAcceleratetogenerate

atherosclerosiscardiovascular

diseaseType

2DMIGT

-cell

decompensationMicrovascularcomplicationHyperinsulinemiaCentral

obesityhypertensionhypertriglyceridemiaHDL

cholesterolplasminogenSystem

dysfunctionpolycystic

ovariansyndromemechanismof

actioninsulin

resistanceCusi

K,DiabetesCare,

2000Mechanismof

actioninsulin

resistanceDiagnosticcriteria(1999,

WHO)Plasmaglucose

(mmol/L)FPG RPG OGTT

2hNormal

range <

6.1 and <

7.8Diabetes

mellitus ≥7.0 or

≥

11.1 or ≥

11.1IGRIFG ≥6.1---<

7.0 <7.8IGT <7.0 ≥7.8---<

11.1Chronic

complicationMacrovascular(CHD,CVD,

PVD)-metabolic

syndrome-IRMicrovascular(kidney,reticular,

nerve)-thickeningofthecapillarybasement

membraneMacrovascularmorbidityrate

highyoungageof

onsetpathogeneticconditionprogress

quicklyMultiorgantobeinvolved

inmainlydeathcauseintype2

DMintermittent

lameness

(间歇性跛行)MicrovascularMarkablechange:microcirculation

disturbancemicroangiomato

shape

micrangiumbasalmembranethickeningCentrecomponentelement:HyperglycemiaPathogenesisProliferativeDiabetic

RetinopathyDiabetic

neuropathyPeripheralpolyneuropathy(symmetry/multiple/slowlyprogressing/lowerlimb

severity)Mononeuropathy(oculomotornerve/abducent

nerve)

Autonomicneuropathy(stomachintestine/urinarysystem/sexualorgan/cardiovascular

system)SkininfectionTreatmentEarly,longterm,integrated,

individualizedDietcontrolPhysicalactivityDrugtherapyeducationSelf-monitoringDietTotalcaloriecontrol(ideal

bodyweight)Carbohydrate

(50-60%)Protein(15-20%)Lipid(20-25%)Distribution(eg.1/5,

2/5,2/5)Lifestyle

modification---- eatless,walk

more30minutes,

moderateexercise, 5/7daysHealth

dietWeight

lossLifestylemodification

(Finland)Weightloss2.4kgin5years,T2DMdecreased

58%DPPWeightloss4.3kgin3years,T2DMdecreased

58%Oralhypoglycemic

agentsSulfonylureas——glyburide,glipizide,

glimeperideGlinides——

retaglinide，nateglinidBiguanides——

metformin

glucosidaseinhibitor——acarbose,miglitol

,vogliboseThiazolidiones——rosiglitazone,

pioglitazonePreventionofDMLifestyle

ModificationNursesHealth

studyUpto85%ofT2DMcouldbepreventedbybehaviormodification(e.g.,healthydiet,exercise,BMI<25

kg/m2)DiabetesPreventionProgram

(DPP)PlaceboMetforminLifestyle

Modification(Diet/

Exercise)Incidenceof

T2DM(%peryear)11.0%6.8%4.8%Reductionin

incidencecomparedtoplacebo----31%58%Hu,NEJM,2001;

DPP,InterplaybetweenRisk

FactorsLifestyleModificationand

GeneticsPolymorphism

rs7903146CCandCTgenotype

similarTTvariantwasassociatedwithincreasedriskof

DMLifestylemodification/behaviorchangecanoverwhelmgenetic

riskFlorez.NEJM,

2006.Withlifestyle

modification(diet/exercise):TTvariantnolonger

associatedwithincreasedriskof

DMSummaryType2diabetesmellitus(T2DM),alsoknownasNon-insulin-dependentdiabetesmellitus(NIDDM),isoneofthecommondisordersofendocrinesystem,mightberelatedtoinsulinresistance.T2DMisthoughttobedeterminedbycomplexinteractionsbetweengeneticpredispositionandmaternal

environment.TCF7L2, KCNJ11, KCNQ1 etc. are reported to playimportantrolesin

T2DM.Essentialhypertension

(EH)IntroductionDefinition:Hypertensionisdefinedaselevatedarterial

bloodpressure.Hypertensionisthemostprominentriskfactorinmostallcardiovasculardiseases

(CVD).HP Essential

HP

(95%) SecondaryHP

(5%)Definition:Persistentlyhigharterialblood

pressure.Systolicbloodpressure≥140

mmHgDiastolicbloodpressure≥90

mmHgHypertensionisamajor

publichealth concern,

affecting10-20%ofadults

worldwide1Number

ofpeoplewithEHworldwidein

20001972

millionIncreasein

thenumberofadults

withEHgloballyby

2025160%Percentofall

globalhealthcare

spendingattributabletohighblood

pressure210%Annualworldwidecost

ofhypertension2$370

billion1.KearneyPM,WheltonM,ReynoldsK,MuntnerP,WheltonPK,HeJ.Globalburdenofhypertension:analysisofworldwidedata.Lancet.2005Jan15-21;365(9455):217-23.GazianoTA,AsafB,SAnand,et.al.Theglobalcostofnonoptimalbloodpressure.JHypertens2009;27(7):

1472-1477.1.6

BillionEHpatients

estimatedby

2025EUPrevalenceof

EH~81MillionAdultshaveelevatedBlood

PressureLloyd-JonesD:Circulation2010;121:e46–e215PersellSD:Hypertension

2011;57:1076-1080EUPatientswithEH

81.0MDiagnosedEH

78%TreatedEH

68%UncontrolledEH38%ResistantEH9%-

$7.2M81MPatientswith

EHDiagnosed

EHTreated

EHUncontrolled

EHHTN=Hypertension9876543210120/80 140/90 160/100 180/110SystolicBP/DiastolicBP

(mmHg)CVmortalityriskdoublesforevery20mmHgincreaseinsystolicblood

pressure.1,2EHleadstoanincreasedriskofdeathfrom

strokeandheartdisease8x4x2xCardiovascularMortality

RiskChobanianetal.Hypertension2003;42:1206-1252;2Lancet

2002;360:1903-1913EtiologyGeneticEnvironmentDietary:Salt

intakeAlcoholintakeObesityInfant

dysnutritionLinkageanalysisof

EH/entry/145500doi:10.1016/j.tem.2005.02.009125125AssociationsofACEI/D,AGTM235Tgene

polymorphismsandhypertensioninChinesepopulation:a

meta-analysisLocationGeneSNP1p36.22MTHFRrs173675044q21.21FGF5rs169980736p22.2HFErs17999458p23.2CSMD1rs99532210q24.3CYP17A1rs100446712q21.33ATP2B1rs268147212q24.12SH2B3rs318450415q24.1CSKrs137894215q25.3AKAP13rs1163876216q23.3CDH13rs1164621317q21.33ZNF652rs1294088720p12.2JAG1rs132723520q12.32GNAS–EDN3rs601545022q11.21COMTrs4680SusceptiblegeneofEHfromGWAS

studiesRiskFactorsforCardiovascular

DiseaseSmokingHyperlipidaemiaHighsaltintakeHomocysteinaemiaLackofexerciseObesityDiabetesAlcohol>4pintsof

beer/dayGeneticInteractionbetweenEnvironmental&GeneticfactorsPathogenesisHighactivityoftheSNS(SympatheticNervous

System)RAAS(Renin-AngiotensionAldosterone

System)RenalSodium

HandlingVascular

RemodellingEndothelialCell

DysfunctionInsulin

ResistancePeripheral

VascularResistanceCardiac

OutputRenal

FunctionEfferent:fromthebrainAfferent:tothe

brainCardiac

Effects:LV

HypertrophySystolic

HFHFpEFArrhythmiaKidney

Effects:

-Sodium&Volume

Retention-DecreasedRenalBloodFlowduetoVasoconstriction-RAS

ActivityHyperactiveSympatheticNervousSystemDrives

HypertensionDoumasetal.AmJCardiol2010;105:570-576,ClevelandClinicJournalofMedicine2012;79:

501-10Thepathologicalchangesofsmall

arteryThepathologicalchangeofthe

HeartLeftventricularhypertrophy(LVH)Heart

failureCoronaryartery

atherosclerosisMyocardial

infarctionPathologicalchangeofthe

BrainStroke:Ischemic

strokeHemorrhagic

stokePathologicalchangeofRenalHypertensioninducednephrosclerosis,atrophyofrenal

cortexClinical

FeaturesThebloodpressurevarieswidelyovertime,dependingonmanyvariables,includingSNSactivity,posture,

stateofhydration,andskeletalmuscle

tone.Symptoms:AlwaysasymptomaticSymptomsoftenattributedto

hypertension:headache,tinnitus,dizziness,

faintingFlame

shapedhemorrhagePepilledemaHypertensive

RetinopathyDiagnosis&Differential

DiagnosisClassificationofbloodpressurefor

adultCategorySBP

(mmHg)DBP

(mmHg)Normal<

120<

80High

normal120-13980-89Hypertension≥140≥90Stage

1140-15990-99Stage

2160-179100-109Stage

3≥180≥110Systolic