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常見多基因疾病的遺傳咨詢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消化系統(tǒng)疾病心血管疾病代謝性疾病免疫系統(tǒng)疾病神經(jīng)系統(tǒng)疾病肝臟酶測量脂類或脂蛋白測量炎癥標志物測量血液學測量體重與身體測量心血管測量其他測量藥物反應生物學過程癌癥其他疾病其他性狀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患者總數(shù)(億)2004
year2010
year2025
year排名國家1995國家2025(百萬)(百萬)1印度19.4印度57.22中國16.0中國37.63美國13.9美國21.94俄聯(lián)邦8.9巴基斯坦14.55日本6.3印度尼西亞12.46巴西4.9俄聯(lián)邦12.27印度尼西亞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所有其他國家49.7所有其他國家103.6Total135.3300.0糖尿病患者數(shù)排名前10位的國家KingH,etal.DiabetesCare
1998;21:1414–31.2010年全世界20歲~79歲的成年人中有2.85億罹患糖尿病,預計到2050年,患者總數(shù)將增至3.33億。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型糖尿病其他類型糖尿病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
(間歇性跛行)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
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