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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.
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doi:10.
1186/1476-511X-12-176Citethisarticleas:Wangetal.
:CETPgenepolymorphismsandriskofcoronaryatherosclerosisinaChinesepopulation.
LipidsinHealthandDisease201312:176.
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