subjects222cc.com
222cc.com 时间:2021-03-20 阅读:()
RESEARCHOpenAccessCETPgenepolymorphismsandriskofcoronaryatherosclerosisinaChinesepopulationJunWang1,LiJunWang1,YongZhong1,2,PingGu3,JiaQingShao3,ShiSenJiang1*andJianBinGong1*AbstractBackground:Coronaryatherosclerosis,themostcommonformofcoronaryarterydisease(CAD),ischaracterizedbyaccumulationoflipidinthewallsofcoronaryarteries.
Recentdatafromclinicaltrialshaveshowedthathigh-densitylipoproteincholesterol(HDL-C)hascausalroleinthepathogenesisanddevelopmentofcoronaryatherosclerosis.
Cholesterylestertransferprotein(CETP)isanimportantregulatorofplasmaHDL-C.
SeveralgeneticmutationsintheCETPgenewerefoundtobeassociatedwithHDL-Clevels.
TheaimofthepresentstudyistoevaluatetheassociationofHDL-C-relatedCETPpolymorphismsandriskofcoronaryatherosclerosis.
Methods:Weinvestigatedtheassociationofsevensinglenucleotidepolymorphisms(SNP)(rs1800775,rs708272,rs5882,rs1532624,rs1864163,rs7499892,andrs9989419)intheCETPgenewiththeriskofcoronaryatherosclerosisandlevelsofHDL-Cinacase–controlstudyinChina.
Includedinthestudywere420patientswithcoronaryatherosclerosisand424healthycontrols.
SNPgenotypingwasperformedbyTaqManallelicdiscriminationassayandserumlipidlevelsweremeasuredbystandardlaboratorymethods.
Results:CarriersoftheAAandGA+AAgenotypesofrs708272hadsignificantlowerrisksofcoronaryatherosclerosis(OR=0.
55,95%CI:0.
36-0.
85,p=0.
003;OR=0.
67,95%CI:0.
50-0.
90,p=0.
007,respectively)comparedtothosewithGGgenotype.
Theserelationsremainedsignificantafteradjustmentforconfoundingeffectsofage,smoking,diabetesandhypertension.
Thers1800775polymorphismwassignificantlyassociatedwithserumlevelsofHDL-Cinhealthycontrols(p=0.
04).
Besides,rs708272wasincloselinkagedisequilibrium(LD)withrs1800775inthisstudy.
Conclusions:OurfindingsindicatedthatCETPrs708272maybeassociatedwiththeriskofcoronaryatherosclerosisandrs1800775mayinfluenceserumHDL-ClevelsinhealthycontrolsinChinese.
Keywords:Coronaryatherosclerosis,CETP,Geneticmutation,HDL-CBackgroundCoronaryatherosclerosis,achronicinflammatorydiseasecharacterizedbytheaccumulationoffattymaterialssuchascholesterolandtriglycerideonthewallsofthecoronaryarteries,istheprincipalcauseofcoronaryarterydisease(CAD)[1,2].
HDLisbelievedtobeaprotectivefactoragainstCAD,andtheinverserelationshipbetweenplasmaHDL-CandtheincidenceofCADiswellestablished[3,4].
PreliminarystudieshavesuggestedthatHDLinfusionscaninduceatherosclerosisregression[5].
ProtectiveeffectofHDLonatherosclerosismayduetoitsroleinpreventingoxidationorotheradverseeffectsoflow-densitylipoproteincholesterol(LDL-C)onendothelialcell,more-over,HDLalsocandirectlystimulateendothelialcelltoproducenitricoxide,beneficialanti-inflammatory,anti-apoptoticandanti-thromboticagentsaswellaspromoteendothelialrepairprocesses[6,7].
Cholesterylestertransferprotein(CETP)isahydro-phobicglycoprotein,whichhasanestablishedroleintransportingofcholesterolfromtheperipheraltissuestotheliverforeliminationthroughexchangingtriglyceridesofVLDLandLDLagainstcholesterylestersofHDL.
ThepossibilitythatincreasedfunctionofCETPmightbeproatherogenicandthatinhibitionofitsactivitymightbeantiatherogenicwasfirstraised>20yearsago[8].
CETPinhibitorsasnoveldrugshavebeendevelopedtoraiseHDL-CconcentrationsandimproveHDLfunction*Correspondence:zero991127@hotmail.
com;agong62@126.
comEqualcontributors1DepartmentsofCardiology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,ChinaFulllistofauthorinformationisavailableattheendofthearticle2013Wangetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Wangetal.
LipidsinHealthandDisease2013,12:176http://www.
lipidworld.
com/content/12/1/176inpatientswithcoronarydisease,althoughtheeffectandsafetystillneedtobeconfirmed[9].
SeveralmutationsintheCETPgenehavebeenidenti-fiedasacauseofCETPdeficiencyandchangeofHDL-Clevels,buttheassociationsofthesesinglenucleotidepolymorphisms(SNP)andsusceptibilitytoatherosclerosisstilllacksconsistency[10-12].
Besides,therelationbetweentheseSNPsandriskofcoronaryatherosclerosishasnotbeenfullystudiedinChinesepopulation.
TohelpclarifywhethertheCETPSNPswhichwerepreviouslyshowntobeassociatedwithplasmaHDL-Clevelsandalsoconfirmedinagenome-wideassociationstudy[10,13-17]areassociatedwithsusceptibilityofcoronaryatherosclerosisandplasmaHDL-Clevels,weexaminedsevenSNPsintheCETPgene(rs1800775,rs708272,rs5882,rs1532624,rs1864163,rs7499892,andrs9989419)inacase–controlstudyinChinesepopulation.
ResultsOurstudypopulationconsistedof420casesand424healthycontrols.
CharacteristicsofthestudysubjectsareshowninTable1.
Casesandcontrolswerecomparablewithrespecttoageandgender.
Casesweremoreprobablytosmokecigarettes(50.
9%vs.
32.
3%),havediabetes(21.
0%vs.
12.
0%)andhypertension(48.
7%vs.
38.
7%).
Besides,caseshavesignificantlowerlevelsofserumHDL-Candhigherlevelsofserumtotalcholesterol(TC)andLDL-Cthanthatincontrols.
TheassociationsofCETPvariantswithriskofcoronaryatherosclerosisarepresentedinTable2.
ThegenotypedistributionsofthesesevenvariantsshowednodeviationfromtheexpectedHardy-Weinbergequilibriumamongcontrols(p>0.
05).
OftheseSNPs,carriersoftheAAandGA+AAgenotypesofrs708272hadsignificantlowerriskofcoronaryatherosclerosis(OR=0.
55,95%CI:0.
36-0.
85,p=0.
003;OR=0.
67,95%CI:0.
50-0.
90,p=0.
007,re-spectively)comparedwithcarriersofthemajorgenotype.
Theseassociationsremainedstatisticallysignificantafterfurtheradjustmentforage,smoking,hypertensionanddiabetes.
NoneoftheotherSNPsexaminedwasassociatedwithcoronaryatherosclerosis.
FourSNPsintheCETPgene(rs1800775-rs1532624-rs708272-rs1864163)wereinlinkagedisequilibriumwithD'rangingfrom0.
66to1.
00andr2rangingfrom0.
07to0.
55.
However,wedidnotfindanyCETPhaplotypethatwassignificantlyassociatedwithriskofcoronaryathero-sclerosis(datanotshown).
Finally,weinvestigatedtheassociationsbetweenthesevenSNPsandserumHDL-Clevelsin424healthycontrols.
Inunivariateanalyses,CETPrs1800775wassignificantlyassociatedwithdecreasedserumlevelofHDL-C(p=0.
04).
Carriersofthemutantallelesofrs1800775(A/C:1.
45±0.
62mmol/L;C/C:1.
28±0.
41mmol/L)hadsignificantlydecreasedserumHDL-ClevelscomparedwithsubjectswithGGgenotype(1.
49±0.
72mmol/L).
WhenANCOVAmodelwasapplied,rs1800775stillshowedsignificantassociationwithHDL-Clevel(p=0.
04).
NoneoftheotherstudiedSNPswasassociatedwithserumHDL-Clevel(Table3).
DiscussionConsideringthecrucialroleofCETPinlipidmetabolism,weinvestigatedtheassociationofsevenSNPsinthisgeneandtheriskofcoronaryatherosclerosisinaChinesepopulation.
Ourresultsshowedthatrs708272polymorph-ismmayreducetheriskofcoronaryatherosclerosisandrs1800775mutationmaydecreaseserumHDL-Clevelsinhealthycontrolsinourpopulation.
ThehumanCETPgeneislocatedonchromosome16q21,andseveralmutationsinthisgenehavebeenreportedtoalterthefunctionofCETPandplasmaHDL-Clevels[10,13].
AmongtheseSNPs,CETPTaqIBsite(rs708272)isthemoststudiedone.
TheresultsofprospectiveWomen'sGenomeHealthStudy(WGHS),conductedinAmericanwomen,showedthatcarriersofB2B2andB1B2genotypes(56mg/dLand52mg/dL)hadsignificanthigherlevelsofplasmaHDL-CthancarriersofB1B1genotype(50mg/dL)[10].
Moreover,ameta-analysis,basedonthedatafromyear1970toTable1SelectedcharacteristicsofcasesandcontrolsCharacteristicsCases(n=420)Controls(n=424)PvalueAge(year)66(61–70)66(60–70)0.
97Sex(Male/female)167/253168/2560.
52Smoking(Yes/no)214/206137/28795%,andthecompletionratewas>99%.
Thequalityandpotentialmisclassificationofthegenotypingwereassessedbyre-evaluating5%ofduplicateDNAsamples(42totalsamples)thatwererandomlyselectedfromthewholepopulationandplacedwithinthesamereactionplatesusedforthestudysubjects.
Thecon-cordancerateforthequalitycontrolsampleswas100%.
StatisticalanalysisWeusedSASsoftware(version9.
3;SASInstitute,Inc.
)forthestatisticalanalyses.
χ2statisticsandthettestwereusedtoevaluatecase–controldifferencesinthedistributionofriskfactors.
VariablesweretestedfornormalitywithShapiro-Wilkstatistics.
Skeweddata,includingage,BMI,TC,HDL-CandLDL-Cwerelogtransformedandexpressedasmediansandinterquartileranges.
Theoddsratios(ORs)and95%confidenceintervals(CIs)fortheassociationsbetweentheSNPsanddiseaseriskwereestimatedbyunconditionallogisticregression.
Hardy-WeinbergequilibriumforgenotypicdistributionandlinkagedisequilibriumbetweenlociwereassessedbyHaploViewversion4.
0(DalyLabattheBroadInstitute,Cambridge,MA,USA)[26].
Associationsbetweenhap-lotypes(>1%frequency)andtheriskofcoronaryath-erosclerosiswereevaluatedbycomputingORand95%CIusingHAPSTAT,assuminganadditivemodel,usingthemostcommonhaplotypeasthereferentcategory[27].
BothunivariateANOVAandmultivariateANCOVAanalysesadjustingforage,smoking,diabetesandhyper-tensionwereperformedtodeterminetheeffectsoftheCETPpolymorphismsonserumHDL-Clevels.
AtwotailedP-valueof0.
05wasconsideredstatisticallysignificant.
AbbreviationsCAD:Coronaryarterydisease;HDL-C:High-densitylipoproteincholesterol;LDL-C:Low-densitylipoproteincholesterol;CETP:Cholesterylestertransferprotein;SNP:Singlenucleotidepolymorphisms;TC:Totalcholesterol;CHB:HanChineseinBeijing;BMI:Bodymassindex.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsJWandLJWdesignedthemoleculargeneticstudiesanddraftedthemanuscript.
YZandPGcarriedoutthegenotypingexperiments.
JQSperformedthestatisticalanalysis.
SSJandJBGparticipatedinthedesignofsamplecollectionandimprovedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisstudywassupportedbytheNaturalScienceFoundationofChina(81000352,30900697,&81100568),theNaturalScienceFoundationofJiangsuProvince(BK2011661),thePostdoctoralScientificFoundationofChina(20100471843),andthePostdoctoralScientificFoundationofJiangsuProvince(1001027C).
Authordetails1DepartmentsofCardiology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
2DepartmentsofHealth-Care,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
3DepartmentsofEndocrinology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
Wangetal.
LipidsinHealthandDisease2013,12:176Page4of5http://www.
lipidworld.
com/content/12/1/176Received:24October2013Accepted:20November2013Published:27November2013References1.
HanssonGK:Inflammation,atherosclerosis,andcoronaryarterydisease.
NEnglJMed2005,352:1685–1695.
2.
RathM,NiendorfA,ReblinT,DietelM,KrebberHJ,BeisiegelU:Detectionandquantificationoflipoprotein(a)inthearterialwallof107coronarybypasspatients.
Arteriosclerosis1989,9:579–592.
3.
MillerGJ,MillerNE:Plasma-high-density-lipoproteinconcentrationanddevelopmentofischaemicheart-disease.
Lancet1975,1:16–19.
4.
HausenloyDJ,YellonDM:Targetingresidualcardiovascularrisk:raisinghigh-densitylipoproteincholesterollevels.
Heart2008,94:706–714.
5.
TardifJC,GrégoireJ,L'AllierPL,etal:Effectsofreconstitutedhigh-densitylipoproteininfusionsoncoronaryatherosclerosis:arandomizedcontrolledtrial.
JAMA2007,297:1675–1682.
6.
RiwantoM,LandmesserU:High-densitylipoproteinsandendothelialfunctions:mechanisticinsightsandalterationsincardiovasculardisease.
JLipidRes.
inpress.
7.
YuhannaIS,ZhuY,CoxBE,etal:High-densitylipoproteinbindingtoscavengerreceptor-BIactivatesendothelialnitricoxidesynthase.
NatMed2001,7:853–857.
8.
BrownML,InazuA,HeslerCB,etal:Molecularbasisoflipidtransferproteindeficiencyinafamilywithincreasedhigh-densitylipoproteins.
Nature1989,342:448–451.
9.
LüscherTF,VonEckardsteinA,SimicB:TherapeutictargetstoraiseHDLinpatientsatriskorwithcoronaryarterydisease.
CurrVascPharmacol2012,10:720–724.
10.
RidkerPM,ParéG,ParkerAN,ZeeRY,MiletichJP,ChasmanDI:PolymorphismintheCETPgeneregion,HDLcholesterol,andriskoffuturemyocardialinfarction:genomewideanalysisamong18245initiallyhealthywomenfromtheWomen'sgenomehealthstudy.
CircCardiovascGenet2009,2:26–33.
11.
BarterPJ,BrewerHBJr,ChapmanMJ,HennekensCH,RaderDJ,TallAR:Cholesterylestertransferprotein:anoveltargetforraisingHDLandinhibitingatherosclerosis.
ArteriosclerThrombVascBiol2003,23:160–167.
12.
DeGroothGJ,KlerkxAH,StroesES,StalenhoefAF,KasteleinJJ,KuivenhovenJA:AreviewofCETPanditsrelationtoatherosclerosis.
JLipidRes2004,45:1967–1974.
13.
ThompsonA,DiAngelantonioE,SarwarN,etal:AssociationofcholesterylestertransferproteingenotypeswithCETPmassandactivity,lipidlevels,andcoronaryrisk.
JAMA2008,299:2777–2788.
14.
AhmadT,ChasmanDI,BuringJE,LeeIM,RidkerPM,EverettBM:PhysicalactivitymodifiestheeffectofLPL,LIPC,andCETPpolymorphismsonHDL-ClevelsandtheriskofmyocardialinfarctioninwomenofEuropeanancestry.
CircCardiovascGenet2011,4:74–80.
15.
DumitrescuL,CartyCL,TaylorK,etal:Geneticdeterminantsoflipidtraitsindiversepopulationsfromthepopulationarchitectureusinggenomicsandepidemiology(PAGE)study.
PLoSGenet2011,7:e1002138.
16.
PapachristouC,LinS:AconfidencesetinferencemethodforidentifyingSNPsthatregulatequantitativephenotypes.
HumHered2012,73:174–183.
17.
CliffordAJ,RinconG,OwensJE,etal:SinglenucleotidepolymorphismsinCETP,SLC46A1,SLC19A1,CD36,BCMO1,APOA5,andABCA1aresignificantpredictorsofplasmaHDLinhealthyadults.
LipidsHealthDis2013,12:66.
18.
KashaniFaridMA,AziziF,HedayatiM,DaneshpourMS,ShamshiriAR,SiassiF:AssociationbetweenCETPTaq1BandLIPC-514C/TpolymorphismswiththeserumlipidlevelsinagroupofTehran'spopulation:acrosssectionalstudy.
LipidsHealthDis2010,9:96.
19.
RuanX,MaL,WangS,etal:AssociationoftwoCETPpolymorphismswithHDLlevelsintheChineseobesepopulation.
Obesity(SilverSpring)2009,17:2196–2201.
20.
LuY,TayebiN,LiH,SahaN,YangH,HengCK:AssociationofCETPTaq1Band-629C>Apolymorphismswithcoronaryarterydiseaseandlipidlevelsinthemulti-ethnicSingaporeanpopulation.
LipidsHealthDis2013,12:85.
21.
DullaartRP,SluiterWJ:CommonvariationintheCETPgeneandtheimplicationsforcardiovasculardiseaseanditstreatment:anupdatedanalysis.
Pharmacogenomics2008,9:747–763.
22.
ThompsonJF,LloydDB,LiraME,MilosPM:Cholesterylestertransferproteinpromotersingle-nucleotidepolymorphismsinSp1-bindingsitesaffecttranscriptionandareassociatedwithhigh-densitylipoproteincholesterol.
ClinGenet2004,66:223–228.
23.
DachetC,PoirierO,CambienF,ChapmanJ,RouisM:Newfunctionalpromoterpolymorphism,CETP/-629,incholesterylestertransferprotein(CETP)generelatedtoCETPmassandhighdensitylipoproteincholesterollevels:roleofSp1/Sp3intranscriptionalregulation.
ArteriosclerThrombVascBiol2000,20:507–515.
24.
RadovicaI,FridmanisD,VaivadeI,Nikitina-ZakeL,KlovinsJ:TheassociationofcommonSNPsandhaplotypesinCETPgenewithHDLcholesterollevelsinLatvianpopulation.
PLoSOne2013,8:e64191.
25.
KlerkxAH,TanckMW,KasteleinJJ,etal:HaplotypeanalysisoftheCETPgene:notTaqIB,butthecloselylinked-629C/ApolymorphismandanovelpromotervariantareindependentlyassociatedwithCETPconcentration.
HumMolGenet2003,12:111–123.
26.
BarrettJC,FryB,MallerJ,DalyMJ:Haploview:analysisandvisualizationofLDandhaplotypemaps.
Bioinformatics2005,21:263–265.
27.
LinDY,ZengD,MillikanR:Maximumlikelihoodestimationofhaplotypeeffectsandhaplotype-environmentinteractionsinassociationstudies.
GenetEpidemiol2005,29:299–312.
doi:10.
1186/1476-511X-12-176Citethisarticleas:Wangetal.
:CETPgenepolymorphismsandriskofcoronaryatherosclerosisinaChinesepopulation.
LipidsinHealthandDisease201312:176.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
com/submitWangetal.
LipidsinHealthandDisease2013,12:176Page5of5http://www.
lipidworld.
com/content/12/1/176
Recentdatafromclinicaltrialshaveshowedthathigh-densitylipoproteincholesterol(HDL-C)hascausalroleinthepathogenesisanddevelopmentofcoronaryatherosclerosis.
Cholesterylestertransferprotein(CETP)isanimportantregulatorofplasmaHDL-C.
SeveralgeneticmutationsintheCETPgenewerefoundtobeassociatedwithHDL-Clevels.
TheaimofthepresentstudyistoevaluatetheassociationofHDL-C-relatedCETPpolymorphismsandriskofcoronaryatherosclerosis.
Methods:Weinvestigatedtheassociationofsevensinglenucleotidepolymorphisms(SNP)(rs1800775,rs708272,rs5882,rs1532624,rs1864163,rs7499892,andrs9989419)intheCETPgenewiththeriskofcoronaryatherosclerosisandlevelsofHDL-Cinacase–controlstudyinChina.
Includedinthestudywere420patientswithcoronaryatherosclerosisand424healthycontrols.
SNPgenotypingwasperformedbyTaqManallelicdiscriminationassayandserumlipidlevelsweremeasuredbystandardlaboratorymethods.
Results:CarriersoftheAAandGA+AAgenotypesofrs708272hadsignificantlowerrisksofcoronaryatherosclerosis(OR=0.
55,95%CI:0.
36-0.
85,p=0.
003;OR=0.
67,95%CI:0.
50-0.
90,p=0.
007,respectively)comparedtothosewithGGgenotype.
Theserelationsremainedsignificantafteradjustmentforconfoundingeffectsofage,smoking,diabetesandhypertension.
Thers1800775polymorphismwassignificantlyassociatedwithserumlevelsofHDL-Cinhealthycontrols(p=0.
04).
Besides,rs708272wasincloselinkagedisequilibrium(LD)withrs1800775inthisstudy.
Conclusions:OurfindingsindicatedthatCETPrs708272maybeassociatedwiththeriskofcoronaryatherosclerosisandrs1800775mayinfluenceserumHDL-ClevelsinhealthycontrolsinChinese.
Keywords:Coronaryatherosclerosis,CETP,Geneticmutation,HDL-CBackgroundCoronaryatherosclerosis,achronicinflammatorydiseasecharacterizedbytheaccumulationoffattymaterialssuchascholesterolandtriglycerideonthewallsofthecoronaryarteries,istheprincipalcauseofcoronaryarterydisease(CAD)[1,2].
HDLisbelievedtobeaprotectivefactoragainstCAD,andtheinverserelationshipbetweenplasmaHDL-CandtheincidenceofCADiswellestablished[3,4].
PreliminarystudieshavesuggestedthatHDLinfusionscaninduceatherosclerosisregression[5].
ProtectiveeffectofHDLonatherosclerosismayduetoitsroleinpreventingoxidationorotheradverseeffectsoflow-densitylipoproteincholesterol(LDL-C)onendothelialcell,more-over,HDLalsocandirectlystimulateendothelialcelltoproducenitricoxide,beneficialanti-inflammatory,anti-apoptoticandanti-thromboticagentsaswellaspromoteendothelialrepairprocesses[6,7].
Cholesterylestertransferprotein(CETP)isahydro-phobicglycoprotein,whichhasanestablishedroleintransportingofcholesterolfromtheperipheraltissuestotheliverforeliminationthroughexchangingtriglyceridesofVLDLandLDLagainstcholesterylestersofHDL.
ThepossibilitythatincreasedfunctionofCETPmightbeproatherogenicandthatinhibitionofitsactivitymightbeantiatherogenicwasfirstraised>20yearsago[8].
CETPinhibitorsasnoveldrugshavebeendevelopedtoraiseHDL-CconcentrationsandimproveHDLfunction*Correspondence:zero991127@hotmail.
com;agong62@126.
comEqualcontributors1DepartmentsofCardiology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,ChinaFulllistofauthorinformationisavailableattheendofthearticle2013Wangetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Wangetal.
LipidsinHealthandDisease2013,12:176http://www.
lipidworld.
com/content/12/1/176inpatientswithcoronarydisease,althoughtheeffectandsafetystillneedtobeconfirmed[9].
SeveralmutationsintheCETPgenehavebeenidenti-fiedasacauseofCETPdeficiencyandchangeofHDL-Clevels,buttheassociationsofthesesinglenucleotidepolymorphisms(SNP)andsusceptibilitytoatherosclerosisstilllacksconsistency[10-12].
Besides,therelationbetweentheseSNPsandriskofcoronaryatherosclerosishasnotbeenfullystudiedinChinesepopulation.
TohelpclarifywhethertheCETPSNPswhichwerepreviouslyshowntobeassociatedwithplasmaHDL-Clevelsandalsoconfirmedinagenome-wideassociationstudy[10,13-17]areassociatedwithsusceptibilityofcoronaryatherosclerosisandplasmaHDL-Clevels,weexaminedsevenSNPsintheCETPgene(rs1800775,rs708272,rs5882,rs1532624,rs1864163,rs7499892,andrs9989419)inacase–controlstudyinChinesepopulation.
ResultsOurstudypopulationconsistedof420casesand424healthycontrols.
CharacteristicsofthestudysubjectsareshowninTable1.
Casesandcontrolswerecomparablewithrespecttoageandgender.
Casesweremoreprobablytosmokecigarettes(50.
9%vs.
32.
3%),havediabetes(21.
0%vs.
12.
0%)andhypertension(48.
7%vs.
38.
7%).
Besides,caseshavesignificantlowerlevelsofserumHDL-Candhigherlevelsofserumtotalcholesterol(TC)andLDL-Cthanthatincontrols.
TheassociationsofCETPvariantswithriskofcoronaryatherosclerosisarepresentedinTable2.
ThegenotypedistributionsofthesesevenvariantsshowednodeviationfromtheexpectedHardy-Weinbergequilibriumamongcontrols(p>0.
05).
OftheseSNPs,carriersoftheAAandGA+AAgenotypesofrs708272hadsignificantlowerriskofcoronaryatherosclerosis(OR=0.
55,95%CI:0.
36-0.
85,p=0.
003;OR=0.
67,95%CI:0.
50-0.
90,p=0.
007,re-spectively)comparedwithcarriersofthemajorgenotype.
Theseassociationsremainedstatisticallysignificantafterfurtheradjustmentforage,smoking,hypertensionanddiabetes.
NoneoftheotherSNPsexaminedwasassociatedwithcoronaryatherosclerosis.
FourSNPsintheCETPgene(rs1800775-rs1532624-rs708272-rs1864163)wereinlinkagedisequilibriumwithD'rangingfrom0.
66to1.
00andr2rangingfrom0.
07to0.
55.
However,wedidnotfindanyCETPhaplotypethatwassignificantlyassociatedwithriskofcoronaryathero-sclerosis(datanotshown).
Finally,weinvestigatedtheassociationsbetweenthesevenSNPsandserumHDL-Clevelsin424healthycontrols.
Inunivariateanalyses,CETPrs1800775wassignificantlyassociatedwithdecreasedserumlevelofHDL-C(p=0.
04).
Carriersofthemutantallelesofrs1800775(A/C:1.
45±0.
62mmol/L;C/C:1.
28±0.
41mmol/L)hadsignificantlydecreasedserumHDL-ClevelscomparedwithsubjectswithGGgenotype(1.
49±0.
72mmol/L).
WhenANCOVAmodelwasapplied,rs1800775stillshowedsignificantassociationwithHDL-Clevel(p=0.
04).
NoneoftheotherstudiedSNPswasassociatedwithserumHDL-Clevel(Table3).
DiscussionConsideringthecrucialroleofCETPinlipidmetabolism,weinvestigatedtheassociationofsevenSNPsinthisgeneandtheriskofcoronaryatherosclerosisinaChinesepopulation.
Ourresultsshowedthatrs708272polymorph-ismmayreducetheriskofcoronaryatherosclerosisandrs1800775mutationmaydecreaseserumHDL-Clevelsinhealthycontrolsinourpopulation.
ThehumanCETPgeneislocatedonchromosome16q21,andseveralmutationsinthisgenehavebeenreportedtoalterthefunctionofCETPandplasmaHDL-Clevels[10,13].
AmongtheseSNPs,CETPTaqIBsite(rs708272)isthemoststudiedone.
TheresultsofprospectiveWomen'sGenomeHealthStudy(WGHS),conductedinAmericanwomen,showedthatcarriersofB2B2andB1B2genotypes(56mg/dLand52mg/dL)hadsignificanthigherlevelsofplasmaHDL-CthancarriersofB1B1genotype(50mg/dL)[10].
Moreover,ameta-analysis,basedonthedatafromyear1970toTable1SelectedcharacteristicsofcasesandcontrolsCharacteristicsCases(n=420)Controls(n=424)PvalueAge(year)66(61–70)66(60–70)0.
97Sex(Male/female)167/253168/2560.
52Smoking(Yes/no)214/206137/28795%,andthecompletionratewas>99%.
Thequalityandpotentialmisclassificationofthegenotypingwereassessedbyre-evaluating5%ofduplicateDNAsamples(42totalsamples)thatwererandomlyselectedfromthewholepopulationandplacedwithinthesamereactionplatesusedforthestudysubjects.
Thecon-cordancerateforthequalitycontrolsampleswas100%.
StatisticalanalysisWeusedSASsoftware(version9.
3;SASInstitute,Inc.
)forthestatisticalanalyses.
χ2statisticsandthettestwereusedtoevaluatecase–controldifferencesinthedistributionofriskfactors.
VariablesweretestedfornormalitywithShapiro-Wilkstatistics.
Skeweddata,includingage,BMI,TC,HDL-CandLDL-Cwerelogtransformedandexpressedasmediansandinterquartileranges.
Theoddsratios(ORs)and95%confidenceintervals(CIs)fortheassociationsbetweentheSNPsanddiseaseriskwereestimatedbyunconditionallogisticregression.
Hardy-WeinbergequilibriumforgenotypicdistributionandlinkagedisequilibriumbetweenlociwereassessedbyHaploViewversion4.
0(DalyLabattheBroadInstitute,Cambridge,MA,USA)[26].
Associationsbetweenhap-lotypes(>1%frequency)andtheriskofcoronaryath-erosclerosiswereevaluatedbycomputingORand95%CIusingHAPSTAT,assuminganadditivemodel,usingthemostcommonhaplotypeasthereferentcategory[27].
BothunivariateANOVAandmultivariateANCOVAanalysesadjustingforage,smoking,diabetesandhyper-tensionwereperformedtodeterminetheeffectsoftheCETPpolymorphismsonserumHDL-Clevels.
AtwotailedP-valueof0.
05wasconsideredstatisticallysignificant.
AbbreviationsCAD:Coronaryarterydisease;HDL-C:High-densitylipoproteincholesterol;LDL-C:Low-densitylipoproteincholesterol;CETP:Cholesterylestertransferprotein;SNP:Singlenucleotidepolymorphisms;TC:Totalcholesterol;CHB:HanChineseinBeijing;BMI:Bodymassindex.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsJWandLJWdesignedthemoleculargeneticstudiesanddraftedthemanuscript.
YZandPGcarriedoutthegenotypingexperiments.
JQSperformedthestatisticalanalysis.
SSJandJBGparticipatedinthedesignofsamplecollectionandimprovedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
AcknowledgementsThisstudywassupportedbytheNaturalScienceFoundationofChina(81000352,30900697,&81100568),theNaturalScienceFoundationofJiangsuProvince(BK2011661),thePostdoctoralScientificFoundationofChina(20100471843),andthePostdoctoralScientificFoundationofJiangsuProvince(1001027C).
Authordetails1DepartmentsofCardiology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
2DepartmentsofHealth-Care,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
3DepartmentsofEndocrinology,SchoolofMedicine,NanjingUniversity,JinlingHospital/NanjingGeneralHospitalofNanjingMilitaryCommand,305ZhongshanEastRoad,Nanjing,JiangsuProvince210002,China.
Wangetal.
LipidsinHealthandDisease2013,12:176Page4of5http://www.
lipidworld.
com/content/12/1/176Received:24October2013Accepted:20November2013Published:27November2013References1.
HanssonGK:Inflammation,atherosclerosis,andcoronaryarterydisease.
NEnglJMed2005,352:1685–1695.
2.
RathM,NiendorfA,ReblinT,DietelM,KrebberHJ,BeisiegelU:Detectionandquantificationoflipoprotein(a)inthearterialwallof107coronarybypasspatients.
Arteriosclerosis1989,9:579–592.
3.
MillerGJ,MillerNE:Plasma-high-density-lipoproteinconcentrationanddevelopmentofischaemicheart-disease.
Lancet1975,1:16–19.
4.
HausenloyDJ,YellonDM:Targetingresidualcardiovascularrisk:raisinghigh-densitylipoproteincholesterollevels.
Heart2008,94:706–714.
5.
TardifJC,GrégoireJ,L'AllierPL,etal:Effectsofreconstitutedhigh-densitylipoproteininfusionsoncoronaryatherosclerosis:arandomizedcontrolledtrial.
JAMA2007,297:1675–1682.
6.
RiwantoM,LandmesserU:High-densitylipoproteinsandendothelialfunctions:mechanisticinsightsandalterationsincardiovasculardisease.
JLipidRes.
inpress.
7.
YuhannaIS,ZhuY,CoxBE,etal:High-densitylipoproteinbindingtoscavengerreceptor-BIactivatesendothelialnitricoxidesynthase.
NatMed2001,7:853–857.
8.
BrownML,InazuA,HeslerCB,etal:Molecularbasisoflipidtransferproteindeficiencyinafamilywithincreasedhigh-densitylipoproteins.
Nature1989,342:448–451.
9.
LüscherTF,VonEckardsteinA,SimicB:TherapeutictargetstoraiseHDLinpatientsatriskorwithcoronaryarterydisease.
CurrVascPharmacol2012,10:720–724.
10.
RidkerPM,ParéG,ParkerAN,ZeeRY,MiletichJP,ChasmanDI:PolymorphismintheCETPgeneregion,HDLcholesterol,andriskoffuturemyocardialinfarction:genomewideanalysisamong18245initiallyhealthywomenfromtheWomen'sgenomehealthstudy.
CircCardiovascGenet2009,2:26–33.
11.
BarterPJ,BrewerHBJr,ChapmanMJ,HennekensCH,RaderDJ,TallAR:Cholesterylestertransferprotein:anoveltargetforraisingHDLandinhibitingatherosclerosis.
ArteriosclerThrombVascBiol2003,23:160–167.
12.
DeGroothGJ,KlerkxAH,StroesES,StalenhoefAF,KasteleinJJ,KuivenhovenJA:AreviewofCETPanditsrelationtoatherosclerosis.
JLipidRes2004,45:1967–1974.
13.
ThompsonA,DiAngelantonioE,SarwarN,etal:AssociationofcholesterylestertransferproteingenotypeswithCETPmassandactivity,lipidlevels,andcoronaryrisk.
JAMA2008,299:2777–2788.
14.
AhmadT,ChasmanDI,BuringJE,LeeIM,RidkerPM,EverettBM:PhysicalactivitymodifiestheeffectofLPL,LIPC,andCETPpolymorphismsonHDL-ClevelsandtheriskofmyocardialinfarctioninwomenofEuropeanancestry.
CircCardiovascGenet2011,4:74–80.
15.
DumitrescuL,CartyCL,TaylorK,etal:Geneticdeterminantsoflipidtraitsindiversepopulationsfromthepopulationarchitectureusinggenomicsandepidemiology(PAGE)study.
PLoSGenet2011,7:e1002138.
16.
PapachristouC,LinS:AconfidencesetinferencemethodforidentifyingSNPsthatregulatequantitativephenotypes.
HumHered2012,73:174–183.
17.
CliffordAJ,RinconG,OwensJE,etal:SinglenucleotidepolymorphismsinCETP,SLC46A1,SLC19A1,CD36,BCMO1,APOA5,andABCA1aresignificantpredictorsofplasmaHDLinhealthyadults.
LipidsHealthDis2013,12:66.
18.
KashaniFaridMA,AziziF,HedayatiM,DaneshpourMS,ShamshiriAR,SiassiF:AssociationbetweenCETPTaq1BandLIPC-514C/TpolymorphismswiththeserumlipidlevelsinagroupofTehran'spopulation:acrosssectionalstudy.
LipidsHealthDis2010,9:96.
19.
RuanX,MaL,WangS,etal:AssociationoftwoCETPpolymorphismswithHDLlevelsintheChineseobesepopulation.
Obesity(SilverSpring)2009,17:2196–2201.
20.
LuY,TayebiN,LiH,SahaN,YangH,HengCK:AssociationofCETPTaq1Band-629C>Apolymorphismswithcoronaryarterydiseaseandlipidlevelsinthemulti-ethnicSingaporeanpopulation.
LipidsHealthDis2013,12:85.
21.
DullaartRP,SluiterWJ:CommonvariationintheCETPgeneandtheimplicationsforcardiovasculardiseaseanditstreatment:anupdatedanalysis.
Pharmacogenomics2008,9:747–763.
22.
ThompsonJF,LloydDB,LiraME,MilosPM:Cholesterylestertransferproteinpromotersingle-nucleotidepolymorphismsinSp1-bindingsitesaffecttranscriptionandareassociatedwithhigh-densitylipoproteincholesterol.
ClinGenet2004,66:223–228.
23.
DachetC,PoirierO,CambienF,ChapmanJ,RouisM:Newfunctionalpromoterpolymorphism,CETP/-629,incholesterylestertransferprotein(CETP)generelatedtoCETPmassandhighdensitylipoproteincholesterollevels:roleofSp1/Sp3intranscriptionalregulation.
ArteriosclerThrombVascBiol2000,20:507–515.
24.
RadovicaI,FridmanisD,VaivadeI,Nikitina-ZakeL,KlovinsJ:TheassociationofcommonSNPsandhaplotypesinCETPgenewithHDLcholesterollevelsinLatvianpopulation.
PLoSOne2013,8:e64191.
25.
KlerkxAH,TanckMW,KasteleinJJ,etal:HaplotypeanalysisoftheCETPgene:notTaqIB,butthecloselylinked-629C/ApolymorphismandanovelpromotervariantareindependentlyassociatedwithCETPconcentration.
HumMolGenet2003,12:111–123.
26.
BarrettJC,FryB,MallerJ,DalyMJ:Haploview:analysisandvisualizationofLDandhaplotypemaps.
Bioinformatics2005,21:263–265.
27.
LinDY,ZengD,MillikanR:Maximumlikelihoodestimationofhaplotypeeffectsandhaplotype-environmentinteractionsinassociationstudies.
GenetEpidemiol2005,29:299–312.
doi:10.
1186/1476-511X-12-176Citethisarticleas:Wangetal.
:CETPgenepolymorphismsandriskofcoronaryatherosclerosisinaChinesepopulation.
LipidsinHealthandDisease201312:176.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
com/submitWangetal.
LipidsinHealthandDisease2013,12:176Page5of5http://www.
lipidworld.
com/content/12/1/176
- subjects222cc.com相关文档
- simple222cc.com
- www.philips.com/welcome
- CF222cc.com
- specific222cc.com
- aol222cc.com
- partnered222cc.com
HostKvm5.95美元起，香港、韩国可选
HostKvm发布了夏季特别促销活动，针对香港国际/韩国机房VPS主机提供7折优惠码，其他机房全场8折，优惠后2GB内存套餐月付仅5.95美元起。这是一家成立于2013年的国外主机服务商，主要提供基于KVM架构的VPS主机，可选数据中心包括日本、新加坡、韩国、美国、中国香港等多个地区机房，均为国内直连或优化线路，延迟较低，适合建站或者远程办公等。下面分享几款香港VPS和韩国VPS的配置和价格信息。...
Webhosting24：$1.48/月起，日本东京NTT直连/AMD Ryzen 高性能VPS/美国洛杉矶5950X平台大流量VPS/1Gbps端口/
Webhosting24宣布自7月1日起开始对日本机房的VPS进行NVMe和流量大升级，几乎是翻倍了硬盘和流量，价格依旧不变。目前来看，日本VPS国内过去走的是NTT直连，服务器托管机房应该是CDN77*（也就是datapacket.com），加上高性能平台（AMD Ryzen 9 3900X+NVMe），还是有相当大的性价比的。此外在6月30日，又新增了洛杉矶机房，CPU为AMD Ryzen 9...
傲游主机38.4元起,韩国CN2/荷兰VPS全场8折vps香港高防
傲游主机怎么样?傲游主机是一家成立于2010年的老牌国外VPS服务商，在澳大利亚及美国均注册公司，是由在澳洲留学的害羞哥、主机论坛知名版主组长等大佬创建，拥有多家海外直连线路机房资源，提供基于VPS主机和独立服务器租用等，其中VPS基于KVM或者XEN架构，可选机房包括中国香港、美国洛杉矶、韩国、日本、德国、荷兰等，均为CN2或者国内直连优秀线路。傲游主机提供8折优惠码：haixiuge，适用于全...
222cc.com为你推荐
-
microcenterccpc什么意思外挂购买什么外挂网好点老虎数码1200万相素的数码相机都有哪些款？大概价钱是多少？老虎数码86年属虎的吉祥数字和求财方向同一服务器网站一个服务器放多个网站怎么设置?sss17.com一玩棋牌吧（www.17wqp.com）怎么样？www.vtigu.com如图所示的RT三角形ABC中,角B=90°(初三二次根式）30 如图所示的RT三角形ABC中,角B=90°,点p从点B开始沿BA边以1厘米每秒的速度向A移动；同时，点Q也从点B开始沿BC边以2厘米每秒的速度向点C移动。问：几秒后三角形PBQ的面积为35平方厘米？PQ的距离是多少广告法新广告法哪些广告词不能用，广告违禁词大全dadi.tv1223tv影院首页地址是什么？1223tv影院在哪里可以找到？梦遗姐我姐姐很漂亮，她24了，我才15，晚上我和他睡在一起，我经常挨遗精，咋办？