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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