www.rpped.com.br
REVISTA
PAULISTA
DE
PEDIATRIA
ORIGINAL
ARTICLE
Beta
2-adrenergic
receptor
gene
association
with
overweight
and
asthma
in
children
and
adolescents
and
its
relationship
with
physical
fitness
Neiva
Leite
∗,
Leilane
Lazarotto,
Gerusa
Eisfeld
Milano,
Ana
Claudia
Kapp
Titski,
Cássio
Leandro
Mühe
Consentino,
Fernanda
de
Mattos,
Fabiana
Antunes
de
Andrade,
Lupe
Furtado-Alle
UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil
Received8October2014;accepted26January2015 Availableonline28August2015
KEYWORDS
ADRB2gene; Asthma; Overweight; Physicalfitness
Abstract
Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of  2-adrenergicreceptorgene(ADRB2)withtheoccurrenceofasthmaandoverweightandthegene’s influenceonanthropometric,clinic,biochemicalandphysicalfitnessvariablesinchildrenand adolescents.
Methods: Subjectswereevaluatedforallelicfrequenciesofthe2-adrenergicreceptorgene, height,weight,bodymassindex(BMI),BMIZ-score,waistcircumference(WC),pubertalstage, restingheart rate(HRres),bloodpressure(BP),totalcholesterol(TC),glucose,insulin,high density lipoprotein(HDL-C),low densitylipoprotein(LDL-C), triglyceride(TG),Homeostasis Metabolic Assessment (HOMA2-IR),QuantitativeInsulin SensitivityCheck Index(QUICKI) and maximaloxygenuptake(VO2max).Theparticipantsweredividedinfourgroups:overweight
asth-matic(n=39),overweightnon-asthmatic(n=115),normalweightasthmatic(n=12),andnormal weightnon-asthmatic(n=40).
Results: RegardingtheGln27Glupolymorphism,highertotalcholesterolwasobservedinusual genotypeindividualsthaningeneticvariantcarriers(p=0.04).Noevidencewasfoundthatthe evaluatedpolymorphismsareinfluencingthephysicalfitness.TheArg16allelewasfoundmore frequentlyamongthenormalweightasthmaticgroupwhencomparedtothenormalweight non-asthmaticgroup(p=0.02),andtheGlu27allelewasmorefrequentlyfoundintheoverweight asthmaticsgroupwhencomparedtothenormalweightnon-asthmaticgroup(p=0.03). Conclusions: TheassociationofArg16allelewiththeoccurrenceofasthmaandoftheGlu27 allelewithoverweightasthmaticadolescentsevidencedthecontributionofthe2-adrenergic receptorgenetothedevelopmentofobesityandasthma.
©2015SociedadedePediatriadeS˜aoPaulo.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBY-license(https://creativecommons.org/licenses/by/4.0/).
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rpped.2015.01.012
∗Correspondingauthor.
E-mail:neivaleite@gmail.com(N.Leite).
PALAVRAS-CHAVE
GeneADRB2; Asma; Sobrepeso; Aptidãofísica
Associac¸ãodogeneADRB2comsobrepesoeasmaemcrianc¸aseadolescentesesua relac¸ãocomaaptidãofísica
Resumo
Objetivo: Investigar aassociac¸ãodos polimorfismosArg16Gly eGln27Glu dogene receptor 2-adrenérgico(ADRB2)comaocorrência de asmae sobrepeso,bemcomo ainfluênciado genesobrevariáveisantropométricas,clínicas,bioquímicasedeaptidãofísicaemcrianc¸ase adolescentes.
Métodos: Osindivíduosforamavaliadosquanto àfrequência alélicadogene ADRB2,altura, peso,índicedemassacorporal,IMC-escoreZ,circunferênciaabdominal,estágiopuberal, fre-quênciacardíacaderepouso,pressãosanguínea,colesteroltotal,glicose,insulina,lipoproteína de alta densidade, lipoproteína de baixa densidade, triglicerídeos, Homeostasis Metabolic Assessment(HOMA2-IR),QuantitativeInsulinSensitivityCheckIndex(QUICKI)econsumo máx-imo de oxigênio (VO2max). Os participantes foram divididos em quatro grupos: sobrepeso
asmático(n=39),sobrepesonãoasmático(n=115),pesonormalasmático(n=12)epesonormal nãoasmático(n=40).
Resultados: Comrelac¸ãoao polimorfismoGln27Glu,foiobservadomaiorvalor decolesterol totalnosindivíduosdogenótipousualdoquenaquelesquecarregamavariante(p=0,04).Não foi encontrada evidênciade que ospolimorfismosavaliadosinfluenciem a aptidãofísica.O aleloArg16foiencontradoemmaiorfrequêncianogrupodepesonormalasmático,comparado ao grupo de peso normalnão asmático (p=0,02),e oalelo Glu27 foi maisfrequentemente encontradonogrupodesobrepesoasmático,quandocomparadoaogrupodepesonormalnão asmático(p=0,03).
Conclusões: A associac¸ãodoaleloArg16comaocorrência deasmae aassociac¸ãodoalelo Glu27aadolescentescomsobrepesoasmáticosevidenciamacontribuic¸ãodogeneADBR2para odesenvolvimentodaobesidadeeasma.
©2015SociedadedePediatriadeS˜aoPaulo.PublicadoporElsevierEditoraLtda.Esteéumartigo OpenAccesssobalicençaCCBY(https://creativecommons.org/licenses/by/4.0/deed.pt).
Introduction
Overweight and asthma are chronic diseases that reach alarming prevalence andmorbidity.1 Excessof weighthas been associated with the emergence of respiratory prob-lems such as asthma.2 Although the complex interaction between environmental exposure and genetic predisposi-tiontooverweight andthe developmentof asthma isnot welldefined,studies haveshownthatgeneticfactorsmay influence the susceptibility to develop obesity,3 and the associationbetweengeneticpolymorphismsandasthmahas beenreported.4
Beta2-adrenergicreceptors(ADRB2)arefoundinseveral regionsofthebody,includingfatcells,bloodvessels,heart andairways.5Thesereceptorsplayanimportantroleinthe genesisofobesityandenergybalanceregulation.Theyare responsibleforthestimulationofthelipolyticactivityin adi-posetissue6andforthecontrolofbronchialsmoothmuscle,7 through relaxation and bronchodilation of airway smooth muscle.8
TheArg16Gly(rs1042713)andGln27Glu(rs1042714)
poly-morphisms in the ADRB2 gene seem to be related to the development of overweight, hypertension, metabolic syndrome,9,10andasthmaexacerbations.11,12Theyare asso-ciated with changes in the sympathetic nervous system activityandmayalterlipolysis,9metabolic and cardiovas-cular regulation,13 as well as decrease lung function and bronchodilatorresponsetotherapywith2-agonists.14
In children and adolescents, the association between
Arg16Gly and Gln27Glu polymorphisms with obesity or
asthma was investigated separately, with controversial results15,16;however,nostudyhasevaluatedthefrequencies ofthesepolymorphismsinchildrenandadolescents consid-ering obesity and asthma together. Association between
Gln27Glu polymorphism and physical fitness has been
observedonlyinadults.17
The aim of the present study was to investigate the associationoftheallelesoftheArg16GlyandGln27Glu poly-morphisms of ADRB2 genewiththe occurrence ofasthma andoverweightinchildrenandadolescentsandtoexamine whetherthosepolymorphismsinfluenceonanthropometric, clinic,lipidprofileandphysicalfitnessvariables.
Method
The sample consisted of 206 children and adolescents of bothsexes,10to16yearsoldfromsouthernBrazil,divided intofourgroups:overweightasthmatics(n=39),overweight non-asthmatics (n=115), normal weight asthmatic (n=12) andnormalweightnon-asthmatic(control)(n=40).The par-ticipantswerevolunteersfromthePediatricEndocrinology Ambulatory and from public schools of Curitiba, Paraná (Brazil).
Table1 AllelicfrequenciesoftheArg16GlyandGln27GlupolymorphismofADRB2geneamongthegroups.
Alleles Overweight/ asthmaticn(%)
Overweight/ non-asthmaticn(%)
Normalweight/ asthmaticn(%)
Normalweight/ non-asthmaticn(%)
Arg16Gly
Arg16 26(37%) 60(39%) 12(60%)a 22(31%)
Gly16 44(63%) 92(61%) 8(40%) 48(69%) Total 70(100%) 152(100%) 20(100%) 70(100%)
Gln27Glu
Gln27 22(50%) 98(66%) 13(65%) 41(71%) Glu27 22(50%)b 50(34%) 7(35%) 17(29%)
Total 44(100%) 148(100%) 20(100%) 58(100%)
a Significantlyhigherfrequencycomparedtonormalweightnon-asthmaticgroup(p=0.02). b Significantlyhigherfrequencycomparedtonormalweightnon-asthmaticgroup(p=0.03).
Organization(WHO)18and,forasthmaticparticipants,being diagnosedwith asthmaby medicalevaluation andclinical historyasrecommendedby theBrazilian ThoracicSociety (SociedadeBrasileiradePneumologiaeTisiologia-SBPT).19 Inthisstudy,participantswerenotclassifiedbythe sever-ityofasthma.Exclusioncriteriawere:presenceofdiabetes andtheuseofanorecticdrugsorothersthatmayinterfere withweightcontrol,insulinlevels,bloodpressure,glucose orlipidmetabolism.
Participants and their guardians signed the Informed ConsentForm, accordingtothe protocol approvedby the Institutional Review Board of the Federal University of Paraná(CEP/HC2460.067/2011-03).
Height wasmeasured in centimeters (cm) using a sta-diometerfixedtothewall(accurateto0.1cm),andweight wasmeasuredinkilograms(kg),usingadigitalscale (max-imum capacity of 150kg and a resolution of 100g). BMI, expressedin kg/m2,wascalculated andclassified accord-ingtothecutoffpointsforageandsexasproposedbythe WorldHealthOrganization.18Thewaistcircumference(WC) wasmeasuredincentimeterswithaflexibleand inextensi-ble anthropometric tape (accuracy 0.1cm).Systolic (SBP) and diastolic (DBP) blood pressures were measured after 10minutesofrest,withtheindividualseatedandwiththe rightarmsupportedatheartlevel.
Blood samples were collected in the clinical labora-tory in the morning, after 12h of fasting, to perform a complete blood count, measurement of glucose, insulin, total cholesterol (TC), high-density lipoprotein (HDL-C), low-densitylipoproteincholesterol(LDL-C),andtriglyceride (TG). The concentrations of TC, HDL-C, TG (mg/dL) and glucosewereanalyzedbyautomatedenzymatic colorimet-ricmethod (CHOD-PAP) (Lab Merck, Darmstadt, Germany; LaboratoryRoche,Indianapolis,IN,USA).
Fasting insulin concentration was measured by chemi-luminescence immunoassay technique immunometric U/mL. The HOMA Calculator v2.2 software was used to calculate the insulin resistance, and the Quantitative InsulinsensitivityCheckIndex(QUICKI),describedbyKatz etal.,20wasusedtoevaluateinsulinsensitivity.
Theaerobicfitnessanalysiswasmadeonthetreadmill, and ventilatory responses were measured using a cali-bratedbreath-by-breathmonitoringsystem(ParvoMedics, TrueMax2400,Utah,USA),whichprovidedinformationon
oxygenuptake(VO2),carbondioxideproduction(VCO2), pul-monaryventilation (LV),andratioofrespiratory exchange (RER=VCO2/VO2). These variables were monitored every 15s.Heartratewasmonitoredusingaheart ratemonitor (Polar---modelA1,Finland).Toensurethatparticipantshad achievedpeakoxygenuptake(VO2max),atleast2ofthe fol-lowing criteriawere observed: (a) exhaustion or inability tomaintaintherequiredspeed;(b)RER>1.0;(c)maximum heartrate(HR)>190bpm.
Bloodsamples(n=100)weresubmittedtoleukocyteDNA extraction by a salting-out method21 and diluted to the concentrationof20ng/L.Variantsweregenotypedby Taq-ManSNPGenotypingKit(AppliedBiosystems)onthedevice Realplex2Mastercycler(Eppendorf).Thereactionmix con-tained5.0LofTaqManUniversalPCRMasterMix,0.5Lof specified TaqManSNPGenotyping Kit, 2.5L of ultra-pure water and 2L of DNA (20ng/L). Four samples of each genotypeweresequencedformethodvalidation.
To verify the normality distribution of data, the Kolmogorov---Smirnov test was used. T test and Mann---Whitneytestwereusedforcomparisonsofmeansfor variableswithandwithoutnormaldistribution,respectively. The allelic frequencies between groups were evaluated by 2 tests using Clump software.22 Significance was set at ap-value <0.05,and the analysiswasperformed using StatisticaforWindowsv.10(StatSoftInc.,Tulsa,EUA)
Results
TheallelefrequenciesoftheArg16GlyandGln27Glu poly-morphismofADRB2geneineachofthegroupsareshownin Table1.TheArg16allelewasfoundwithahigherfrequency in the normalweight asthmatic group when compared to thenormal weight non-asthmatic group (p=0.02). Forthe
Gln27Glupolymorphism,asignificantlyhigherfrequencyof
theGlu27allelewasobservedintheoverweightasthmatic
Table2 Means±SDofanthropometric,cardiorespiratoryfitness,bloodpressure,biochemicalandmetabolicprofilevariables andcomparisonsbetweenmutationcarriers(ArgGly/GlyGly)andusualgenotypecarriers(ArgArg)accordingtotheArg16Gly polymorphismsitegenotypes.
Variables ArgArg ArgGly/GlyGly torZ p-value
Age 13.35±1.61 13.00±1.83 0.95 0.34
Weight(kg) 70.76±19.51 68.60±19.48 0.54 0.58
Height(cm)a 161.03±9.89 147.43±42.29 1.74 0.08
BMI(kg/m2) 26.91±5.89 26.86±6.65 0.03 0.97
BMIZ-scorea 1.96±1.47 2.00±1.51 0.14 0.88
WC(cm) 91.11±17.19 89.94±16.93 0.33 0.73 HRres(bpm) 79.88±9.18 80.15±12.17 −0.10 0.91 VO2max(mL/kg/min) 36.46±7.81 35.16±7.91 0.68 0.49
SBP(mmHg)a 108.34±13.08 104.20±12.49 1.87 0.06
DBP(mmHg)a 70.68±11.51 68.34±10.27 1.09 0.27
TC(mg/dL)a 167.32±36.39 161.79±29.31 0.37 0.70
HDL-C(mg/dL)a 47.55±9.73 49.95±12.43 −0.51 0.60
LDL-C(mg/dL)a 95.34±31.42 88.69±26.20 0.70 0.48
TG(mg/dL)a 115.20±78.23 105.34±61.36 0.11 0.91
Glucose(mg/dL) 88.80±7.10 88.25±7.96 0.31 0.74 Insulin(mU/mL)a 12.29±9.20 12.92±9.97 −0.37 0.70
HOMA2-IRa 1.57
±1.16 1.63±1.21 −0.39 0.69
HOMA2-IRa 1.57±1.16 1.63±1.21 −0.39 0.69
QUICKIa 0.35±0.04 0.35±0.04 0.39 0.69
BMI,bodymassindex;WC,waistcircumference;HRres;restingheartrate;SBP,systolicbloodpressure;DBP,diastolicbloodpressure;TC, totalcholesterol;HDL-C,highdensitylipoprotein;LDL-C,lowdensitylipoprotein;TG,triglyceride;HOMA2-IR,HomeostasisMetabolic Assessment;QUICKI,QuantitativeInsulinSensitivityCheckIndex;VO2max,maximaloxygenuptake.
aVariableswithoutnormaldistribution.
thepolymorphismsonanthropometric,clinic, lipidprofile andphysical fitness variables.When separated,according totheArg16Glysitegenotypes,intomutationcarriers(Arg Gly/GlyGly)andusualgenotypecarriers(ArgArg),the com-parisonsofthemeansofanthropometric,cardiorespiratory fitness,bloodpressure, biochemicaland metabolicprofile variableswerenotsignificantlydifferent(Table2).
When separated into mutation carriers (Gln Glu/Glu Glu) and usual genotype carriers (Gln Gln), according to
theGln27Glupolymorphismsitegenotypes,thecomparison
of the mean and SD of anthropometric, cardiorespiratory fitnessblood pressure, biochemical and metabolic profile variablesshowednosignificantdifferences,exceptfora sig-nificantlyhighermeanofTCobservedintheusualgenotype carriergroup(GlnGln)(Table3).
Discussion
The prevalence of overweight in the Brazilian population aged between 10 and 19 is 20.5%,23 whereas 10.3% of childrenand13.8% ofadolescentshave asthma.24 Genetic factorshavebeendemonstratedtocontributetothe devel-opment of obesity and asthma during childhood, but the rolesofspecificgenesandtheirinteractionarestilllargely unknown.3,4,15TheArg16GlyandGln27Glupolymorphismsin
theADRB2genehavebeen relatedtothedevelopmentof
overweight9andasthmaexacerbations.11,12
Thepreviouslydescribedpopulationfrequenciesforthe
Gly16alleleandfortheGln27allelesare60.4%and52.7%,
respectively.11 In obese children and adolescents similar
frequencies were found:59% for Gly16 alleleand 62%for
Gln27 allele.25 In arecent study,the allelefrequency for
Gly16in asthmaticchildrenandadolescentswas55%,and
83%forGln27.26
The higher frequency of the Arg16 allele of Arg16Gly
polymorphism observed in the present study in the asth-maticgroup,whencomparedtothecontrolgroup,suggests thatthepresenceofthisallelemaybeassociatedwiththe occurrenceofasthma.Atendencytoasignificantlyhigher frequencyoftheGly16allelewasobservedintheoverweight asthmaticgroupwhencomparedtothenormalweight asth-maticgroup (p=0.06),suggesting thatthepresenceof the
Gly16allelemayberelatedtooverweightinasthmatic
indi-viduals. Ellsworth et al.15 found an association between
Arg16Gly polymorphism and obesity in male participants:
thosewithGlyGlygenotypeshowedanincreaseinBMI dur-ing infancy until young adulthood. Different results were foundinadolescentgirls,showingthatcarriersoftheGlyGly genotypehavealowerprobabilityofobesitythanthosewith ArgGlyorArgArggenotypes(p=0.006),andgirls withGly GlygenotypehavelowerBMIcomparedtothosewithArgArg genotype(p=0.049),buthigherBMIcomparedtotheArgGly (p=0.062)genotype.16Inanotherstudy,femaleparticipants whowerecarriers ofthe ArgArggenotype showedhigher BMIwhencomparedtothosewiththeGlyGlygenotype.27 In thepresent study,genders wereanalyzedtogether due tothesmallsamplesize.Whenclassifiedbyusualgenotype versusmutationcarriersoftheArg16Glypolymorphismsite, nodifferenceswerefoundforanthropometricvariables.
FortheGln27Glupolymorphismsite,ahigherfrequency
Table3 Means±SDofanthropometric,cardiorespiratoryfitness,bloodpressure,biochemicalandmetabolicprofilevariables andcomparisonsbetweenmutationcarriers(GlnGlu/GluGlu)andusualgenotypecarriers(GlnGln)accordingtotheGln27Glu polymorphismsitegenotypes.
Variable GlnGln GlnGlu/GluGlu torZ p-value
Age 13.16±2.02 13.29±1.64 −0.42 0.67
Weight(kg) 64.81±19.37 71.63±22.31 −1.91 0.05
Height(cm)b 151.74±33.15 148.43±45.50 1.33 0.18
BMI(kg/m2) 25.50±6.38 27.10±7.48 −1.34 0.18
BMIZ-scoreb 1.69±1.57 1.98±1.64 0.86 0.38
WC(cm) 86.96±17.44 92.38±19.12 −1.76 0.08 HRres(bpm) 77.76±10.38 81.32±10.93 −1.73 0.08 VO2max(mL/kg/min) 35.86±7.22 37.34±6.55 −1.03 0.30
SBP(mmHg)b 104.81±13.06 105.02±13.99 0.12 0.90
DBP(mmHg)b 70.62±10.59 66.98±10.76 −1.45 0.14
TC(mg/dL)a,b 169.23±34.93 158.48±31.51 −1.99 0.04a
HDL-C(mg/dL)b 50.63±11.99 49.79±12.58 −0.10 0.91
LDL-C(mg/dL)b 95.39±33.67 88.20±30.95 −1.40 0.16
TG(mg/dL)b 108.67±71.94 102.53±60.71 0.03 0.97
Glucose(mg/dL) 87.72±7.76 87.65±6.76 0.05 0.95 Insulin(mU/mL)b 11.85±10.72 12.46±7.94 1.08 0.27
HOMA2-IRb 1.50
±1.29 1.58±0.98 1.11 0.26
QUICKIb 0.36±0.05 0.34±0.04 −1.03 0.30
BMI,bodymassindex;WC,waistcircumference;HRres,restingheartrate;SBP,systolicbloodpressure;DBP,diastolicbloodpressure;TC, totalcholesterol;HDL-C,highdensitylipoprotein;LDL-C,lowdensitylipoprotein;TG,triglyceride;HOMA2-IR,HomeostasisMetabolic Assessment;QUICKI,QuantitativeInsulinSensitivityCheckIndex;VO2max,maximaloxygenuptake.
a Statisticallysignificantdifference. b Variableswithoutnormaldistribution.
group when comparedtothe control group (p=0.03), and therewasatendency towardsignificance whencompared tothenon-asthmaticoverweightgroup(p=0.05),suggesting thattheGlu27allelemaybeinvolved inthedevelopment of asthma in overweight individuals. Large et al.9 found
theGlu27alleleassociatedwithobesity,andOchoaetal.28
foundnoassociationbetweenGln27Glupolymorphismand obesityin boys,butin femalecarriersof theGlu27allele theyfoundahigherriskofobesity.Researchhasshownthat AfricanAmericangirlswhoarecarriersoftheGlu/Glu geno-typehavehighermeanWCthangirlswithouttheallele,an association not found amongboys.29 Inthe present work, whenseparatedbyusualgenotypeandmutationcarriersfor
theGln27Glusite,nodifferenceswerefoundfor
anthropo-metricvariables.
There is evidence that adrenoceptor genetic variants havearoleinthephysiopathologyofhypertension,butthe results on the relationship between the ADRB2 polymor-phismsarestilldiscordant.10AstudyfromChouetal.16found an association of the Arg16Glypolymorphism with hyper-tensioninobese adolescents,showing thatcarriersof the
Gly/Glygenotypehavealowerprobabilityofhypertension thanpatientswithArg/GlyorArg/Arggenotypes(p=0.005). NootherstudysofarassociatedADRB2polymorphismsand bloodpressureinchildren andadolescents.Inthepresent study,noevidencewasfoundthattheevaluated polymor-phismsareactingonthebloodpressurevariables.
Adrenergicreceptorsplayanimportantroleinthe lipol-ysis regulation and energy expenditure, so it is possible thatpolymorphismsinthesegenescontributetothe emer-genceofmetabolicchanges.30 ABrazilianstudywithobese
childrendidnotfinddifferencesinmetabolicand biochemi-calvariables(glucose,TC,LDL-C,HDL-C,TG,leptin,insulin, glucoseareaandinsulin,andHOMA-IR)betweenhaplotypes
forArg16GlyandGln27Glupolymorphisms.13Inthepresent
work,when separated byusual genotype versus mutation carriersoftheArg16Glypolymorphismsite,nodifferences werefoundformetabolicandbiochemicalvariables.Asfor
theGln27Glu polymorphism site, the usual group showed
highermeanTCvaluewhencomparedtothemutation car-riergroup.
TheassociationoftheArg16allelewiththeoccurrence ofasthmaandoftheGlu27allelewiththedevelopmentof asthmainoverweightindividualsevidencedthecontribution tothedevelopmentofobesityandasthmaduringchildhood andadolescence.Thepossibleassociationbetweenstudied polymorphismsandgenderaswellastheseverityofthe dis-easecannotbeevaluated,sincethedivisionofthepatients intofourgroupsreducedthenumberofeach,andthiswas themainlimitationofthestudy.Furtherstudieswithlarger samplesizesmayallowthedifferentiationofgroupsby gen-der,aswellastheimplementationofmorerobuststatistical analysisregardingtherolesoftheArg16andGlu27alleles inchildhoodoverweight/obesityandasthma.Theevaluated polymorphismsseemnottoinfluenceonthephysicalfitness inchildhoodandadolescence.
Funding
Conflicts
of
interest
The first author is a researcher at the National Research Council(CNPq-ConselhoNacionaldeDesenvolvimento Cien-tíficoeTecnológico),andthelastauthorisaresearcherat theAraucáriaFoundation.
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