10 year old girl - EvolutionMedicine · malaria: seizures, coma Severe anemia, red cells burst...
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8/27/08 1 Evolution of Sickle Cell Disease 10 year old girl Goes to clinic with severe chest pain Many visits for joint pains & exhaustion Labeled a hypochondriac Blood count revealed low rbcs
Transcript of 10 year old girl - EvolutionMedicine · malaria: seizures, coma Severe anemia, red cells burst...
8/27/08
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EvolutionofSickleCellDisease
10yearoldgirl
Goestoclinicwithseverechestpain Manyvisitsforjointpains&exhaustion
Labeledahypochondriac Bloodcountrevealedlowrbcs
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Bloodsmear
SickleCellDisease
70millionAmericanshaveSickleCellDisease
2millionarecarriersofSickleCellTrait
MosthaveSubSaharanAfricanAncestry
1in12AfricanAmericanshasSickleCellTrait
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SickleCellDisease
Catastrophicdiseaseofchildren Attacksoccurwhenoxygenlevelsinblooddrop
Redbloodcellsdeform&assumesickleshape Sicklecellstendtotrapotherbloodcells,cause“sludging”.
Severesludgingdeprivestissuesofoxygenandcankillmuscleandbone.
Sicklecelldisease–Why?
Proximatehypothesis?
Ultimatehypothesis?
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Hemoglobin
Hemoglobin
Oxygentransport–Picksupoxygenfromthepulmonaryveins–dropsoffoxygenintissuesandcapillarybeds
Containsiron Redbloodcells
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MutationofBetaHemoglobin
Blockageofcirculation
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HumanVariation
HbAA–homozygote“normalhemoglobin”
HbAS–heterozygotesicklecelltrait
HbSS–homozygotesicklecell
Inheritance
SickleCellisinheritenceisautosomalrecessive
HbAA HbAS–usuallynosymptoms HbSS–manifestsassicklecelldisease
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SickleCellDisease
HighMortality: MaleswithHbSSAge42years FemaleswithHbSSAge48years Anemia ChestPain Stroke SusceptibilitytoBacterialInfections
Geography
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Geography
SCDoccursinplaceswithmalaria FirstdescribedinsouthernItaly ThennoticedinsubsaharanAfrica SicklecelltraitabsentinplaceslikeKenyanhighlandswheremosquitoandmalariaabsent
Inheritance
SickleCellisinheritenceisautosomalrecessive
HbAA Hb AS – Benefit in Malaria? HbSS–manifestsassicklecelldisease
Concept–balancedpolymorphism Heterozygousadvantage.
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AnotherCase
January2006,aUSfamilyof5kidsvisitNigeria
Pre‐trip:pediatriciangivesantidiarrhealsonly
Nochemoprophylaxis 3kidsallgivenFansidar
forfeverduringtrip. Kidsfeltbetter
3hadreturnoffeverinUS
Diagnosedwithflu Givenantibioticsatthe
localclinic Thentheygotsicker Momnotices1childis
veryweakandhasyelloweyes!
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YellowKid
Yellowpupils Anemic LowBloodSugar 1in20rbcsparasitized PlacedonVentilator Transfused All5kidstestedposfor
falciparummalaria
Malaria
400millioncasesworldwide Malariakills1,500,000yearly Youngchildrenandpregnantwomen
Immunitypartial,notdurable 30,000travelers:preventableillness
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MalariaVector&Pathogen
FemaleAnopheles‐Crepuscularhours. Congenitalandtransfusion‐relatedcases Autochthonous:singlemosquitotransmitsdiseasefrom1humantoanother
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SevereMalaria
Cerebralmalaria:seizures,coma Severeanemia,redcellsburst Hemoglobininurine Fluidinlungs Lossofplatelets Cardiovascularcollapseandshock Bloodbecomesacidic
MalariaPathogenesis
MalariaparasitesdigestRBCproteinsanduseglucosetolacticacidasenergy,thushypoglycemia&acidosis.
InjureRBCmembrane:hemolysis,splenicclearance&anemia.
Makesbloodcellssticky‐obstructmicrocirculation
Thrombocytopenia‐splenicsequestration
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Malariabenefit?
Carriersofsicklecelltraithavebettersurvivalfromearlyboutsofmalaria
Couldprotectionfrommalariabeselectiveforcethatmaintainssicklecellrbcmutationinthepopulation?
HbSS
Fullblownsicklecelldisease Increasedmortalityfromsicklecellattacks. InlocationslikeChicago,withnomalaria,thisgeneticpolymorphismwouldbesubjecttonegativeselection.
WhataboutincoastalKenya?
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HbAS
Admittedtohospitallessinmalariousregions DielessoftenthanHbAAinmalariousregions Protectagainstseveremalariainfection Infectedrbcssickle40timesmorereadilythannoninfectedcells
Decreasedparasitereproduction Increasedclearancefromthepopulation.
SelectionforHbAS
OutweighsnegativeselectionforHbSS MaintainsHbSalleleinpopulation Frequencyofalleleisdependentonpresenceofmalaria
Balancedpolymorphism
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SohowdoesHbASprotectagainstmalaria?
Evolutionaryhypothesiscanleadtoinsightsintotheproximatemechanismsofdisease.
Physiologyandpathophysiologyintersect…
SickleCellAnemiaHbSS:
Cellssickle–causeobstructionofmicrocirculation
Anemia‐Sickledcellshaveenhancedremovalfromcirculation
Increasedphagocytosisofrbcs Increasedoxidativestressonrbcmembrane Spelenicsequestrationofrbcs
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Malaria:Sickletraitpromotesremovalofparasites! HbSSwithoutmalaria: Cellssickle–cause
obstructionofmicrocirculation
Anemia‐Sickledcellshaveenhancedremovalfromcirculation
IncreasedphagocytosisIncreasedoxidativestressonrbcmembrane
Sequestrationofabnormalrbcs
HbASandMalaria: Cellssickle–cause
obstructionofmicrocirculation
Anemia‐Sickledcellshaveenhancedremovalfromcirculation
Increasedphagocytosis Increasedoxidative
stressonrbcmembrane Sequestrationof
abnormalrbcs
Otherpolymorphismsthatmayprotectagainstmalaria
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Language
Compare: Redbloodcelldefectsandmalaria
MolBiochemParasitol.2006Oct;149(2):121‐7.Epub2006Jun9
Erythrocytevariantsandthenatureoftheirmalariaprotectiveeffect
CellularMicrobiology7(6):753‐7632005
Hostdefensesorpathogenvirulencefactors?
Genesthatcausedisease
Iftheyarecommon,theyprobablyhavesomecurrentorhistoricalselectivepressurethatkeepsthemaround
Deleteriousmutationsoccuratrates1:50,000 Somegenesareveryfrequente.g.20%ofpopulationormore:raisequestions
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FactorVLeiden
MostcommonhypercoagulablestatethatassociatedwithDeepVeinThrombosis
Waytoocommontobeasporadicmutation–upto20%insomepopulations
Positiveselectivepressurepromotesitspersistence?
Whatmightthatbe?
Summary
Malaria–sicklecelltraitisabalancedpolymorphism
Geneticpolymorphismsaskevolutionaryquestion–whatselectivepressureorbenefitkeepstheminpopulation
Frequencyofpolymorphismisaclue
