Rev. Bras. Hematol. Hemoter. vol.36 número5

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rev bras hematol hemoter. 2014;36(5):315–318

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

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

Scientific

comment

Comment

on

“Molecular

analysis

and

association

with

clinical

and

laboratory

manifestations

in

children

with

sickle

cell

anemia”

夽

Marilda

Souza

Goncalves

a,b

a_Fundac¸ão_Instituto_Oswado_Cruz_(Fiocruz),_Salvador,_BA,_Brazil

b_Universidade_Federal_da_Bahia_(UFBA),_Salvador,_BA,_Brazil

Sicklecellanemia(SCA)isaseverediseasecharacterizedby a recessive autosomal inheritance.However, despite being a monogenic disease, SCA has clinical heterogeneity as differentindividualswiththesamegenotypehavedifferent clinicalaspects.1_Thus,_the_clinical_diversity_of_SCA_has_been

attributedtosocioeconomicandenvironmentalfactors,and alsotogeneticmodulators,which havebeen widely inves-tigatedinordertoexplaintheheterogeneouspatternofthe disease.1_Regarding_the_classic_genetic_modulators_associated

withSCA,we canmentionthe beta (␤)-globingenecluster haplotypes,alpha-thalassemia (␣-Thal),aswellasepistatic geneticvariationsrelatedtoquantitativetraitloci(QTLS)of severalgeneswhichactsinglyorinteractingwitheachother, forinstancethepresenceofagenepolymorphisminBCL11A

andtheolfactoryreceptorgeneanditsassociationwithfetal

hemoglobin (Hb F) concentration.2–4 _Genome-wide _studies

emphasizemultigeneinteractionsandtheclinicalprofileof SCApatients.5,6_␤_-globin_gene_cluster_haplotypes_have_been

described and named according to the geographic region wheretheywerefirstidentified,andhavealsobeencorrelated todifferential Hb Flevels,7,8 _with _some_haplotypes _(Bantu

andBenin)associatedwithlowerHbFlevelsandlessdisease severity.9,10 _Several_studies _related _to_␤_-globin _gene_cluster

haplotypeshavebeen performedandshowdifferential dis-tributionrelatedtothestudiedgroupasthesemarkershave been usedas ananthropological tool,as well astheir role inmodulatinglaboratorialandclinicalcharacteristicsofSCA patients.9–16

DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2014.06.002.

夽

SeepaperbyCamilo-AraújoRFetal.onpages334–9.

Correspondingauthorat:Fundac¸ãoInstitutoOswaldoCruz(Fiocruz),CentrodePesquisasGonc¸aloMoniz,LaboratórioHematologia

GenéticaeBiologiaComputacional(LHGB),RuaWaldemarFalcão,121,Candeal,40296-710Salvador,BA,Brazil. E-mailaddress:mari@bahia.fiocruz.br(M.S.Goncalves).

␣-Thal is characterized by a deficiency or absence of ␣-globin chain synthesis and its combination with ␤

chain variants decreases the concentration of abnormal hemoglobin.17–19 _The_reduced_synthesis_of_the_alpha_globin

chain results in changes in hematological parameters, decreasingthedegreeofhemolysisandcellulardehydration, and increasingthe ratio between the volume and the cell membraneareaofredbloodcellsinsicklecellpatients.17,20

Thecoexistenceof␣-ThalwithSCAhasbeenassociatedto greatersurvival,andalsowithareductionintheoccurrence ofchroniculcersinthemalleolarregion.However,withthe reductionofhemolysisandincreaseofhematocrit,thereisan increaseofbloodviscosity;thisisariskforvaso-occlusion,and consequently,anincreaseinthefrequencyofpainfulcrises and otherclinicalcomplications, suchasretinopathies and bonenecrosis.21 _Kato_et_al.,_in_a_review_of_reports_related_to

sickle celldisease phenotypes,proposed thatpatientswith the ␣-Thal traithave less hemolysisand endothelial alter-ations,butpresentasub-phenotypeassociatedtoincreases inbloodviscosityandvaso-occlusion.22_Therefore,_the

coex-istenceof␤-globin geneclusterhaplotypes and␣-Thal has shownchangesintheseverityoftheclinicalprofileofsickle celldiseasepatients(Table1).

Despite severalstudies describingthepresenceofthese markersand theirpossibleinfluenceson thephenotypeof SCApatients,changesdescribedinaspecificpopulationare notnecessarilyfoundinothers;thisconsolidatestheconcept thatalthoughthegeneticeventisuniqueandrelatedtoone

http://dx.doi.org/10.1016/j.bjhh.2014.07.018

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revbrashematolhemoter.2014;36(5):315–318

Table1–Descriptionofstudiesrelatedtothecoexistenceof␤-globingenehaplotypesand␣-Thalandpossiblechanges intheseverityofclinicalprofileofsicklecelldisease(SCD).

Descriptionofstudy Possiblechanges Author

Associationof␤-globinhaplotypeand chronicinflammatoryprofileinsickle cellanemia(SCA)

␤-Globinhaplotypeisassociatedwithinflammatoryprofile Bandeiraetal.23

Influenceofthe␤(S)haplotypeand ␣-thalassemiaonstrokedevelopment inSCA.

Resultsuggestthatonlythe␤(S)haplotypesandthe␣ (3.7kb)-thalassemiagenotypemodulatetheprevalenceof strokeinthestudiedSCApopulation

Domingosetal.24

StudyofpediatricseverityscoreinSCD patients

Alpha-genedeletionswerenotassociatedwithalower pediatricseverityscore,butpatientswereclearly differentiatedbytheir␤-globingenotype

Jolyetal.25

Geneticpolymorphismsand cerebrovasculardisease(CVD)in childrenwithSCA

ChildrenwithBantu/Atypical␤(S)-globingenehaplotypehad 15timesmorechanceofCVDandtherewasnodifferencein CVDamong␣-Thalcarriers

Filhoetal.26

Associationof␤-globingenehaplotypes and␣-Thalasariskfactorof glomerulopathyinSCA

Resultssuggestastrongprotectiveeffectof␣-Thalagainst glomerulopathyinadultSCApatients

Neboretal.27

Influenceof␤-globingenehaplotype, co-inherited␣-ThaltraitandHbFon steady-stateserumbilirubinlevelsin SCA

The␤-globinhaplotypeandco-existing␣-Thaltraitdidnot haveanysignificantinfluenceonserumbilirubinlevels

Adekileetal.28

The␤-globingeneclusterhaplotypesin SCA

␤-Globingenehaplotypesshoweddifferencesrelatedonlyto HbFlevelsandbloodtransfusiontherapy,presenceof␣-Thal wasassociatedtohematologicalalterationandspleen sequestrationevents

Adornoetal.29

Molecularcharacteristicsofpediatric patientswithSCAandstroke

Neonateswithfourormorealpha-genes,whose␤-haplotypeis Ben/CAR,atypical,orCAR/CARseemtobeatahigherriskfor stroke

Sarnaiketal.30

Effectofmicrodeletionsinthealpha globingeneandsicklecell glomerulopathy

Coinheritanceofmicrodeletionsinthealpha-globingenelocus inSCApatientsconfers“renoprotection”

Guaschetal.31

Genotype-phenotypecorrelationofSCD intheUnitedArabEmirates

Africanhaplotypes(BantuandBenin)arerelatedtoasevere clinicalpresentation,andcoinheritanceof␣-Thaltraitinthe Africanhaplotypeshadanamelioratingeffectonhemolytic episodes,butvaso-occlusivecrisesweremorefrequent

el-Kallaetal.32

Effectof␣-ThalonSCAlinkedtothe Arab-IndianhaplotypeinIndia

␣-Thalisapowerfulandadditionalepistaticfactoronthe Indiansubcontinent

Mukherjeeetal.33

␤(S)haplotypeandalpha-globingene patternsamongSCApatientsinKuwait

SCApatientswithcoexistentalpha-Thaltraitdidnothave severerecurrentinfectionsandnonehadgallstones.Thehigh frequenciesoftheSaudiArabia/India␤(S)haplotypeand ␣-Thaltraitcontributetothemildnatureofthediseaseamong KuwaitiArabs

Adekileetal.34

Influenceof␣-Thaltraitonspleen functioninSCApatientswithhighHbF

␣-Thaltraitappearstobeassociatedwithnormalsplenic functioninSCApatients

Adekileetal.35

Effectof␣-Thaland␤-globingenecluster haplotypesonthehematologicaland clinicalfeaturesofSCAinBrazil

TheCARhaplotypemaybeassociatedwithmoresevere disease

Figueiredoetal.36

␤(S)haplotypes,alpha-globingenestatus, andhematologicaldataofSCDpatients inGuadeloupe

␤-Haplotypesandalpha-genestatushavebeencorrelatedwith hematologicalparametersinthesepatients

Keclardetal.37

Genderandhaplotypeeffectsupon hematologicalmanifestationsofadult SCA

AlphathalassemiareducedtheMCV,increasedhemoglobin concentration,andloweredreticulocytecounts,regardlessof haplotype.HbFlevelswerenotaffectedbythepresenceof ␣-Thal,andgenderand␤-globingeneclusterhaplotype interactsignificantlyinthemodulationofHbFandanemiain adultswithhemoglobinSS

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Table1(Continued₎

Descriptionofstudy Possiblechanges Author

␤-Globingeneclusterhaplotypeand ␣-Thaldonotcorrelatewiththeacute clinicalmanifestationsofSCDin children

Absenceofassociationof␤-globingeneclusterhaplotypeand ␣-ThalinacuteclinicalpatternofSCDpatients

deMontalembertetal.39

TheSenegalDNAhaplotypeisassociated withtheameliorationofanemiain African-AmericanSCApatients

TheSenegal␤-likeglobingeneclusterhaplotypeisassociated withanameliorationofthehemolyticanemiathat

characterizesSCD

Nageletal.40

pointmutationinthe␤globingene(HBB),theclinicalpattern ofthediseaseinvolvesmultipleorgansandsystems,which affectstheactivationofacomplexnetworkofmechanisms andpathwaysnotclearlyunderstood.Inthiscontext,thereis ahighdiversityoffindingswhicharenotyetglobally consol-idatedaboutacommonprognosticmarkerinvolvingtheSCA profile,exceptthegeneticoriginofthedisease,thepresence ofhemoglobinS.

InthisissueoftheRevistaBrasileiradeHematologiae Hemoter-apia,Camilo-Araújopresentananalysisofthefrequencyof

␤S-globinhaplotypesandalpha-thalassemia,andtheir influ-enceonclinicalmanifestationsandthehematologicalprofile ofchildrenwithsicklecellanemia.41

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1. SteinbergMS,ForgetBG,HiggsDR,NagelRL.Genetics, pathophysiology,andclinicalmanagement.Cambrige, England:CambrigeUniversityPress;2001.

2. MiltonJN,GordeukVR,Taylor6thJG,GladwinMT,Steinberg MH,SebastianiP.Predictionoffetalhemoglobininsicklecell anemiausinganensembleofgeneticriskpredictionmodels. CircCardiovascGenet.2014;7(2):110–5.

3. BaeHT,BaldwinCT,SebastianiP,TelenMJ,Ashley-KochA, GarrettM,etal.Meta-analysisof2040sicklecellanemia patients:BCL11AandHBS1L-MYBarethemajormodifiersof HbFinAfricanAmericans.Blood.2012;120(9):1961–2.

4. SebastianiP,WangL,NolanVG,MelistaE,MaQ,BaldwinCT, etal.Fetalhemoglobininsicklecellanemia:Bayesian modelingofgeneticassociations.AmJHematol. 2008;83(3):189–95.

5. MiltonJN,SebastianiP,SolovieffN,HartleySW,BhatnagarP, ArkingDE,etal.Agenome-wideassociationstudyoftotal bilirubinandcholelithiasisriskinsicklecellanemia.PLoS ONE.2012;7(4):e34741.

6. FertrinKY,CostaFF.Genomicpolymorphismsinsicklecell disease:implicationsforclinicaldiversityandtreatment. ExpertRevHematol.2010;3(4):443–58.

7. CheblouneY,PagnierJ,TrabuchetG,FaureC,VerdierG,Labie D,etal.Structuralanalysisofthe5′_flanking_region_of_the beta-globingeneinAfricansicklecellanemiapatients: furtherevidenceforthreeoriginsofthesicklecellmutation inAfrica.ProcNatlAcadSciUSA.1988;85(12):4431–5.

8. NagelRL,RanneyHM.Geneticepidemiologyofstructural mutationsofthebeta-globingene.SeminHematol. 1990;27(4):342–59.

9.PowarsDR.Sicklecellanemia:betaS-gene-clusterhaplotypes asprognosticindicatorsofvitalorganfailure.Semin

Hematol.1991;28(3):202–8.

10.PowarsDR.Betas-gene-clusterhaplotypesinsicklecell anemia.Clinicalandhematologicfeatures.HematolOncol ClinNorthAm.1991;5(3):475–93.

11.AntonarakisSE,BoehmCD,GiardinaPJ,KazazianJrHH. Nonrandomassociationofpolymorphicrestrictionsitesin thebeta-globingenecluster.ProcNatlAcadSciUSA. 1982;79(1):137–41.

12.ZagoMA,FigueiredoMS,OgoSH.Bantubetascluster haplotypepredominatesamongBrazilianblacks.AmJPhys Anthropol.1992;88(3):295–8.

13.CostaFF,ArrudaVR,Gonc¸alvesMS,MirandaSR,CarvalhoMH, SonatiMF,etal.␤S-Gene-clusterhaplotypesinsicklecell anemiapatientsfromtworegionsofBrazil.AmJHematol. 1994;45(1):96–7.

14.GoncalvesMS,NechtmanJF,FigueiredoMS,KerbauyJ,Arruda VR,SonatiMF,etal.SicklecelldiseaseinaBrazilian

populationfromSãoPaulo:astudyofthe␤Shaplotypes.Hum Hered.1994;44(6):322–7.

15.SerjeantGR.Naturalhistoryanddeterminantsofclinical severityofsicklecelldisease.CurrOpinHematol. 1995;2(2):103–8.

16.NagelRL,SteinbergMH.Roleofepistatic(modifier)genesin themodulationofthephenotypicdiversityofsicklecell anemia.PediatrPatholMolMed.2001;20(2):123–36.

17.SonatiMF.Talassemiaalfacomdeficiênciagênicaemuma populac¸ãonegroidebrasileira[thesis].SãoPaulo:

UniversidadeEstadualdeCampinas;1990.p.70.

18.BaysalE,QinWB,HuismanTH.Alpha-thalassemiaandfetal hemoglobin.Blood.1994;84(9):3241–2.

19.CoutoFD,DeAlbuquerqueAB,AdornoEV,DeMouraNetoJP, DeFreitasAbbehusenL,DeOliveiraJL,etal.

Alpha-thalassemia2,3.7kbdeletionandhemoglobinAC heterozygosityinpregnancy:amolecularandhematological analysis.ClinLabHaematol.2003;25(1):29–34.

20.TakekoshiKJ,OhYH,WestermanKW,LondonIM,LeboulchP. Retroviraltransferofahumanbeta-globin/delta-globin hybridgenelinkedtobetalocuscontrolregionhypersensitive site2aimedatthegenetherapyofsicklecelldisease.Proc NatlAcadSciUSA.1995;92(7):3014–8.

21.SteinbergMH.Modulationofthephenotypicdiversityof sicklecellanemia.Hemoglobin.1996;20(1):1–19.

22.KatoGJ,GladwinMT,SteinbergMH.Deconstructingsicklecell disease:reappraisaloftheroleofhemolysisinthe

developmentofclinicalsubphenotypes.BloodRev. 2007;21(1):37–47.

23.BandeiraIC,RochaLB,BarbosaMC,EliasDB,QueriozJA, FreitasMV,etal.Chronicinflammatorystateinsicklecell anemiapatientsisassociatedwithHBB(*)Shaplotype. Cytokine.2014;65(2):217–21.

24.DomingosIF,FalcãoDA,HatzlhoferBL,CunhaAF,SantosMN, AlbuquerqueDM,etal.Influenceofthe␤(s)haplotypeand

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318

populationwithsicklecellanaemia.AnnHematol. 2014;93(7):1123–9.

25.JolyP,PondarreC,BardelC,FrancinaA,MartinC.The alpha-globingenotypedoesnotinfluencesicklecelldisease severityinaretrospectivecross-validationstudyofthe pediatricseverityscore.EurJHaematol.2012;88(1):61–7.

26.FilhoIL,LeiteAC,MouraPG,RibeiroGS,CavalcanteAC, AzevedoFC,etal.Geneticpolymorphismsand

cerebrovasculardiseaseinchildrenwithsicklecellanemia fromRiodeJaneiro.BrazilArqNeuropsiquiatr.

2011;69(3):431–5.

27.NeborD,BroquereC,BrudeyK,MougenelD,TarerV,Connes P,etal.Alpha-thalassemiaisassociatedwithadecreased occurrenceandadelayedage-at-onsetofalbuminuriain sicklecellanemiapatients.BloodCellMolDis.

2010;45(2):154–8.

28.AdekileA,KutlarF,McKieK,AddingtonA,ElamD,HolleyL, etal.Theinfluenceofuridinediphosphateglucuronosyl transferase1Apromoterpolymorphisms,beta-globingene haplotype,co-inheritedalpha-thalassemiatraitandHbFon steady-stateserumbilirubinlevelsinsicklecellanemia.EurJ Haematol.2005;75(2):150–5.

29.AdornoEV,ZanetteA,LyraI,SouzaCC,SantosLF,MenezesJF, etal.Thebeta-globingeneclusterhaplotypesinsicklecell anemiapatientsfromNortheastBrazil:aclinicaland molecularview.Hemoglobin.2004;28(3):

267–71.

30.SarnaikSA,BallasSK.Molecularcharacteristicsofpediatric patientswithsicklecellanemiaandstroke.AmJHematol. 2001;67(3):179–82.

31.GuaschA,ZayasCF,EckmanJR,MuralidharanK,ZhangW, ElsasLJ.Evidencethatmicrodeletionsinthealphaglobin geneprotectagainstthedevelopmentofsicklecell glomerulopathyinhumans.JASN.1999;10(5): 1014–9.

32.el-KallaS,BaysalE.Genotype-phenotypecorrelationofsickle celldiseaseintheUnitedArabEmirates.PediatrHematol Oncol.1998;15(3):237–42.

33.MukherjeeMB,LuCY,DucrocqR,GangakhedkarRR,Colah RB,KadamMD,etal.Effectofalpha-thalassemiaon sickle-cellanemialinkedtotheArab-Indianhaplotypein India.AmJHematol.1997;55(2):104–9.

34.AdekileAD,HaiderMZ.Morbidity,betaShaplotypeand alpha-globingenepatternsamongsicklecellanemiapatients inKuwait.ActaHaematol.1996;96(3):150–4.

35.AdekileAD,TuliM,HaiderMZ,Al-ZaabiK,MohannadiS, OwunwanneA.Influenceofalpha-thalassemiatraiton spleenfunctioninsicklecellanemiapatientswithhighHbF. AmJHematol.1996;53(1):1–5.

36.FigueiredoMS,KerbauyJ,GoncalvesMS,ArrudaVR,SaadST, SonatiMF,etal.Effectofalpha-thalassemiaandbeta-globin geneclusterhaplotypesonthehematologicalandclinical featuresofsickle-cellanemiainBrazil.AmJHematol. 1996;53(2):72–6.

37.KeclardL,OllendorfV,BerchelC,LoretH,MeraultG.betaS haplotypes,alpha-globingenestatus,andhematologicaldata ofsicklecelldiseasepatientsinGuadeloupe(F.W.I.).

Hemoglobin.1996;20(1):63–74.

38.SteinbergMH,HsuH,NagelRL,MilnerPF,AdamsJG, BenjaminL,etal.Genderandhaplotypeeffectsupon hematologicalmanifestationsofadultsicklecellanemia.Am JHematol.1995;48(3):175–81.

39.deMontalembertM,Maier-RedelspergerM,GirotR,BelloyM, VilmerE,DucrocqR,etal.Beta-globingeneclusterhaplotype andalpha-thalassemiadonotcorrelatewiththeacute clinicalmanifestationsofsicklecelldiseaseinchildren. Blood.1993;82(8):2595–6.

40.NagelRL,ErlingssonS,FabryME,CroizatH,SusukaSM, LachmanH,etal.TheSenegalDNAhaplotypeisassociated withtheameliorationofanemiainAfrican-Americansickle cellanemiapatients.Blood.1991;77(6):1371–5.