Rev. Bras. Hematol. Hemoter. vol.39 número3

rev bras hematol hemoter. 2017;39(3):187–188

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Scientific

Comment

Understanding

population-wide

haplotype

frequencies

of

human

leukocyte

antigen

(HLA)

alleles

in

linkage

disequilibrium

is

important

for

hematopoietic

stem

cell

transplantation

夽

Folashade

Otegbeye

UniversityHospitalsClevelandMedicalCenter/SeidmanCancerCenter,Cleveland,UnitedStates

Linkagedisequilibrium(LD)referstothe non-random asso-ciation ofalleles atdifferent gene loci.Alleles that always randomlysortindependentofothersatsurroundingfociare saidtobeinlinkageequilibrium.Fortwoalleles,sayAand B,theprobabilityofanindividualhavingonehaplotypeABis afunctionofthepopulationfrequencyofA(pA)andB(pB). Ifthesetwoallelesareincompletelinkageequilibriumand soareindependentlysorted,thetruepopulationfrequencyof thehaplotypeABwouldequaltheproductofpAandpB.So pAB−(pA×pB)=0.

WhenalleleAandalleleBdonotindependentlysort,or arelinkedtogether despitebeing ondifferentloci,thetrue populationfrequencyofthehaplotypeABexceedsthe prod-uctoftheirindividualfrequencies.SopAB−(pA×pB)>0.The

valueofthisdifferencerepresentstheco-efficientoflinkage disequilibrium.Thehigherthispositivevalue,thestrongerthe linkagebetweenthesealleles,i.e.thehighertheLD.

Ofcourse,thecoefficientofLDcalculationgetsmore com-plicatedthemoreallelesbeingstudiedindefininghaplotypes ofinterest invarious diseases.Inparticular, themajor his-tocompatibility system has a significant number of genes exhibitingstronglinkagedisequilibrium.1_Thishasan

impor-tantbearingonidealdonoridentificationforhematopoietic stemcelltransplantation(HSCT)asitisrelatedtoriskofgraft

DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2017.01.006. 夽

SeepaperbyCostantinoetal.onpages229–36.

∗ _{Correspondingauthorat:DivisionofHematology&Oncology,UniversityHospitalsClevelandMedicalCenter/SeidmanCancerCenter,}

11100EuclidAvenue,BMTSuite/HumphreyB700/Mailstop5065,Cleveland,OH44106,USA. E-mailaddress:[email protected]

versushostdisease(GVHD)andimmunogenicityforgraft ver-sustumoreffect.

Coefficients

of

linkage

disequilibrium

determined

from

human

leukocyte

antigen

(HLA)

allele

frequencies

can

help

predict

probability

of

allele/haplotype

matches

when

only

low-resolution

donor

HLA

typing

is

available

Inthecontext ofHSCT,current selectionofidealunrelated donorsisbasedonallelelevelmatchingofhumanleukocyte antigen(HLA)-A,-B,-C,-DRB1,-DQB1andmorerecently-DPB1 (permissiveornon-permissivemismatches).Diseases requir-ingallogeneicHSCTparticularlyinadultsaremostoftenof anacutenatureanddelaystoHSCToftenresultindisease progression,significant morbidityand debilitation, preclud-ingHSCTasacurativeoption.Thisimpliesthatonceapatient inneedofHSCTisidentified,andfoundtohavenoavailable matchedsiblingdonor, thesearch foramatchedunrelated donor(MUD)hastoproceedrapidly.IfaMUDcannotbe iden-tified, havingthis knowledgeinatimelymannerfacilitates earlyclinicaldecision-makingwhethertotransplantwithan

http://dx.doi.org/10.1016/j.bjhh.2017.02.003

188

alternative donor (cord blood or haploidentical donor) or proceedwitha non-transplantstrategy. In the era priorto having search algorithms based on haplotype frequencies, searchesfor10/10MUDsindifferent Europeanpopulations rangedfromfourto11weeks.2_{Thisiswherean}

understand-ingofthedistributionoftheabundantHLA-allelesinthedonor poolpopulationiscrucial.

Theprobability ofanallele levelmatch can beinferred from HLAserologic typing whenpopulation frequenciesof eachalleleareknown.TransplantcentersintheUnitedStates, EuropeandJapannowusesearchalgorithmsdevelopedfrom frequenciesofcommon/well-documentedHLAallelesseenin theirregional/nationaldonorregistries.2–4_Haplogicwas

devel-opedbasedonUShaplotypefrequencydataandhas,since 2006, facilitatedsearches by rapidlydetermining the prob-abilityofMUDavailability.5,6 _{Similar haplotypefrequencies}

havebeen studiedinother populationsresulting insearch algorithms such as Optimatch (Germany) and EasyMatch (France). Mostof these donorpopulations are significantly homogeneousincludingtheUSregistrywhereCaucasiansare over-representedthereforeprobabilityestimatesarelimited forapplicationtonon-Caucasianpatients.6,7_{Largedatabases}

areneededforethnicallydiversepopulations.Thestudyby Costantinoet al.8 _{reviewingdonorsinaregionalyet}

ethni-callydiversedatabase(LIGH)inBrazilisanexampleofone fromwhichsearchalgorithmscouldbeconstructedto facili-tatetimelydonoridentification.

Human

leukocyte

antigen

(HLA)

haplotype

frequencies

calculated

for

alleles

in

high

linkage

disequilibrium

may

predict

for

non-HLA

antigen

match

versus

mismatch

Thereisincreasingevidencethat patientswithoneor two frequentlyoccurringhaplotypes(FH)encompassingbothHLA andsomenon-HLAantigensinhigh linkagedisequilibrium experiencelessacuteGVHD.9–11_{Thesenon-HLAgenesinclude}

genesthatcouldregulatetheimmuneresponse[e.g.tumor necrosisfactor (TNF)-block genes, majorhistocompatibility complex classIpolypeptide-related sequence A/B(MICA/B) andmicrosatellitemarkers].9_{Theassociationwithlessacute}

GVHD may also be explained by the increased probability thatpatientswiththesefrequenthaplotypeswillalsomatch atminorhistocompatibility antigensthatare notroutinely includedinbothdonorandpatientHLAtyping.

PresenceofFH alsopredicts probability offinding HLA-matched donors. Patients with at least two frequent HLA haplotypesinaDutchregistryofleukemiapatientsweremost likelytofinda10/10matchedunrelateddonorinasignificantly shortertimethanthosewithoutFH(35versus59days).9

Tosummarize,populationbasedstudiesofbothHLAallele levelandhaplotypefrequenciesandtheresultingestimates

ofLDfacilitatethedevelopmentofalgorithmstospeedily tar-getstemcelldonorsearches.Thesestudiesalsoenhanceour abilitytorecognizefrequenthaplotypesofbothHLAand non-HLAantigensinhighLDthatcouldaffectpost-transplantation outcomes.

Conflicts

of

interest

Theauthordeclaresnoconflictsofinterest.

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e

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