扩张型心肌病并发心力衰竭患者中micrornas的分布

扩张型心肌病并发心力衰竭患者中micrornas的分布

肝不好(hf),随机可接近或功能异常的减轻，而a-cli帕金氏合金氏合金氏合金氏合金

氏合金氏合金氏合金氏家族拥有高度的莫哈林蒂和莫哈林蒂。

Arachidonicacid(AA)isoneofthemostimportantpolyunsaturatedfattyacids

(PUFAs)presentintheplasmamembraneofcells.AAcanbeobtainedfromthe

animalproductsindiet,suchasfish,meat,eggs,etc

MicroRNAs(miRNAs)arcaclassof〜22ntlongsinglestrandnoncodingRNAs

whichmainlyfunctionbypairingwithmRNAstorepresstheirtranslationor

inducedegradation

Inthiswork,wecomparedtheexpressionofmiRNAsfromthehearttissuesof

DCM-mediatedHFpatientswiththoseofhealthydonorsusingtwopublic

datasets,identifieddifferentiallyexpressed(DE)miRNAsputativelytargeting

genesintheAAmctabolicpathways,andanalyzedthedistributionofknown

singlenucleotidepolymorphisms(SNPs)withinthesequencesofDEmiRNAs.Our

studywouldprovidecluesforfurtherfunctionalstudiesofmiRNAsinDCM-

mediatedHF.

1杏仁杏仁

1.1enephe-ene的平台

ThemiRNA-seqdatasetsusedinthisstudy(GSE53981andGSE135055)were

downloadedfromtheGeneExpressionOmnibus(GEO)database

(http://ww.nebi.nlm.nih.gov/geo/).TheGSE53081datasetwasgeneratedfromthe

leftventriclehearttissuesof34HFpatients(21patientswithDCM-mediated

HF)and8healthydonors

removalof3'eidaptorusingtheCutadciptprogram(version2.10)

1.3tam2.0.5.4,5.4与trtesholds/adjsting五轴相关定义/属性表1

TheDEmiRNAsbetweensamplesfromtheHFpatientsandhealthydonorswere

identifiedusingRpackageDESeq2withfoldchanged1.5andadjustedP

value<0.05(Benjamini-Hochbergadjustment)asthethresholds.

FunctionalenrichmentanalysisofDEmiRNAswasperformedusingonlinetool

TAM2.0(http://www.lirmed.com/lcim2/)

1.4fdemirnaswrepedictingmora使用网络以fdemirdb

ThetargetgenesofDEmiRNAswerepredictedbyniRDB(http://mirdb.org/)

1.5inedmir-随机性分布

SNPsinDEmiRNAswereobtainedfromthemiR-NASNP-v3database

(http://bioinfo.life.hust.edu.cn/miRNASNP/#!/)

2产品系统

2.1alityraftingalityraft国际习惯法sificien

ToidentifymiRNAswithdysregulatedexpressioninDCM-rnediatedHEpatients,we

firstcollectedthesmallRNAsequencingdataof39DCM-mediatedHFpatients

and17healthycontrolsfromtwopublicdatasets(GSE53081andGSE135055)in

theGEOdatabase.Thebasicinformationofsamplesinthesedatasetswaslisted

inTable1.Allsamplesweretakenfromtheleftventriclehearttissuesof

eithertheHFpatientsorthecontrols.Afterremovinglowqualityreadsand

quantifyingtheexpressionofknownhumanmiRNAs,atotalof101and88DE

miRNAswereidentifiedtobeup-ordown-regulated(21.5fold

change,Benjcimini-HochbergadjustedP<0,05)inDCV-mediatedHEpatientsfrom

datasetsGSE53081andGSE135055,respectively(Fig.1).AmongtheseDEmiRNAs,39

wereup-regulatedand62weredown-regulatedintheGSE53081dataset,whereas

55wereup-regulatedand33weredown-regulatedintheGSE135055dataset

(Fig.2AandB).

Usingfoldchange21.5asthethreshold,atotalof12DEmiRNAswereidentified

tobeup-ordown-regulatedinbothdatasets(Fig,2C,Table2).Tn

addition,majorityofDEmiRNAsfromthetwodatasetsshowedthesame

expressionchangetrends(foldchanged1.1)intheotherdataset

(Fig.2D),indicatingtheconsistentfunctionsofthesemiRNAsinregulating

DCM-mediatedHFinbothpatientgroups.Functionalenrichmentanalysisofthe

DEmiRNAsalsorevealedoverlappingrolesoftheDEmiRNAsinboth

datasets.Specifically,DEmiRNAsinthetwodatasetswerebothenrichedwith

functionsrelatedtocardiovascu1ar-associateddiseases,especially

hypertrophiccardiomyopathy(Fig.2EandF).Amongthe12DEmiRNAssharedby

bothdatasets,7havebeenreportedtobeassociatedwithHF(Table2).The

enrichedfunctionsofDEmiRNAsfromdatasetGSE53081alsoincludedheart

failure.

2.2平台项目的定义

TobetterunderstandtherolesofmiRNA-mediatedAAmetabolisminregulating

DCM-mediatedHF,wefocusedonDEmiRNAstargetinggenesoftheAAmetabolic

pathways.WefirstcollectedgenesinvolvedintheAAmetabolicpathwaysor

DCM-mcdiatedHFsfromtheKEGGdatabase(http://ww.genome,ad.jp/kegg/)

AmongtheAAmetcibolicpathwaygenestargetedbyDEmiRNAs,over1/3were

targetedbymorethanoneDEmiRNAineitherdataset(Fig.3D).Therewere13AA

genetargetssharedbybothdatasets(Fig.3E),ofwhich,PLA2G12A(amemberof

thecPLA2family)andCYP2U1(amemberoftheCYP2family)werepredictedtobe

targetedbymorethan10DEmiRNAs(Table3).Forthe12DEmiRNAssharedby

bothdatasets,5ofthemwerepredictedtotargetAAmetabolicpathway

genes,namelyPTGIS,PLA2G12A,ALOX12,CYP2U1,LTA4H(Table4).Inaddition,mostof

thesesharedDEmiRNAscouldalsotargetHF-relatedgenes,includingTPM1,TPM2

andSLC8A1,etc(Table4).

2.3.hsa-mir-843.4和ksa-mir-843.4e

SNPsarethemostcommonsourceofgeneticvariationsthatimpairthefunction

ofmiRNAs.ToinvestigatewhetherthefunctionsofmiRNAsinthisstudycould

beaffectedbySNPs,wecollectedknownSNPswithinthesequencesofDEmiRNAs

usingthemiRNASNP-v3database,whichcuratespreviouslyreportedSNPsinthe

precursorandmaturesequencesofhumanmiRNAs.Atotalof216and204SNP

sites(nucleotidepositionwithknownSNPs)wereidentifiedinthesequences

ofDEmiRNAsteirgetingAAmetabolicpathwaygenesindatasetsGSE53081and

GSE135055,respectively(Fig.4A).Amongthem,approximately25%oftotalSNPsites

ineachdatasetlocatedintheseedregionsoftheDEmiRNAs(Fig.4B).In

particular,hsa-miR-486-3pandhsa-miR-486-5pwerebothfoundtohavemorethan

15SNPsitesintheirsequences,ofwhich,6SNPsitesofhsa-miR-486-3pand4

SNPsitesofhsa-miR-486-5pwerelocatedintheseedregions(Fig.4Cand

D).Thepredictedtargetsofhsa-miR-486-3PincludedPLA2G6,whichisan

importantmemberofthecPLA2familyandfunctionstopromotetheproductionof

freeAA

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Asthefinaloutcomeofalltypesofcardiomyopathies,HFisachronicand

currentlyincurabledisease.AlthoughthedevelopnentofHEcanbeattributed

tomanygeneticornon-geneticfactors,theprogressionofHFisregulatedby

multiplemetabolitesoftheAApathways,fromboththebeneficialand

deleteriousaspects

Thetwodatasetsusedinthisstudy(GSE53081andGSE135055)werepublishedin

2014and2020,respectively

AlthoughouranalysisalmostrecapitulatedtheDEmiRNAsreportedintheabove

mentionedworks,thenumberofoverlappingDEmiR'JAsbetweenthetwodatasets

waslimited.Onepossibleexplanationforthisinconsistencycouldbe

that,althoughbothstudiesextractedmiRNAsfromtheleftventricularheart

tissuesofDCM-mediatedHEpatients,theaverageageofHFpatientsofthe

GSE53081daLaselwasabouL24yearselderthanLhaLoftheGSE135055dalasel

(Tabic1).AndthegenderdistributionoftheHFpatientsinthetwodatasets

wasalsodifferent.Inaddition,althoughonly12DEmiRNAswit