Egg consumption and risk of coronary heart disease and stroke: dose-response meta-analysis of prospective cohort studies.

0.6 MB·English

by  Rong, Ying

BMJ2013;346:e8539doi:10.1136/bmj.e8539(Published7January2013) Page1of13
Research
RESEARCH
Egg consumption and risk of coronary heart disease
and stroke: dose-response meta-analysis of
prospective cohort studies
OPENACCESS
Ying Rong doctoral student12, Li Chen research fellow12, Tingting Zhu research fellow12, Yadong
Song research fellow12, Miao Yu research fellow12, Zhilei Shan research fellow12, Amanda Sands
doctoral student3, Frank B Hu professor3, Liegang Liu professor12
1DepartmentofNutritionandFoodHygiene,HubeiKeyLaboratoryofFoodNutritionandSafety,TongjiMedicalCollege,HuazhongUniversityof
ScienceandTechnology,430030Wuhan,People’sRepublicofChina;2MinistryofEducationKeyLabofEnvironmentandHealth,SchoolofPublic
Health,TongjiMedicalCollege,People’sRepublicofChina;3DepartmentsofNutritionandEpidemiology,HarvardSchoolofPublicHealth,Boston,
MA,USA
Abstract ConclusionsHigherconsumptionofeggs(uptooneeggperday)is
ObjectiveToinvestigateandquantifythepotentialdose-response notassociatedwithincreasedriskofcoronaryheartdiseaseorstroke.
associationbetweeneggconsumptionandriskofcoronaryheartdisease Theincreasedriskofcoronaryheartdiseaseamongdiabeticpatients
andstroke. andreducedriskofhemorrhagicstrokeassociatedwithhigheregg
consumptioninsubgroupanalyseswarrantfurtherstudies.
DesignDose-responsemeta-analysisofprospectivecohortstudies.
DatasourcesPubMedandEmbasepriortoJune2012andreferences Introduction
ofrelevantoriginalpapersandreviewarticles.
Cardiovasculardiseaseisnowapublichealthcrisis,affecting
EligibilitycriteriaforselectingstudiesProspectivecohortstudies millionsofpeopleinbothdevelopedanddevelopingcountries.
withrelativerisksand95%confidenceintervalsofcoronaryheartdisease Althoughtherateofdeathattributabletothediseasehasdeclined
orstrokeforthreeormorecategoriesofeggconsumption. indevelopedcountriesinthepastseveraldecades,itisstillthe
ResultsEightarticleswith17reports(nineforcoronaryheartdisease, leadingcauseofdeathandextortsaheavysocialandeconomic
eightforstroke)wereeligibleforinclusioninthemeta-analysis(3081 tollglobally.1-3Inlowandmiddleincomecountries,the
269personyearsand5847incidentcasesforcoronaryheartdisease, prevalenceofcardiovasculardiseasehasincreaseddramatically.
and4148095personyearsand7579incidentcasesforstroke).No By2020,thediseaseisforecastedtobethemajorcauseof
evidenceofacurvelinearassociationwasseenbetweenegg morbidityandmortalityinmostdevelopingnations.4
consumptionandriskofcoronaryheartdiseaseorstroke(P=0.67and Inrecentdecades,concernhasmountedregardingthehigh
P=0.27fornon-linearity,respectively).Thesummaryrelativeriskof prevalenceandcostsassociatedwithcardiovasculardisease,
coronaryheartdiseaseforanincreaseofoneeggconsumedperday withgrowinginterestinalteringriskfactorsandreversingthis
was0.99(95%confidenceinterval0.85to1.15;P=0.88forlineartrend) globalepidemic.Amongtheknownriskfactorsfor
withoutheterogeneityamongstudies(P=0.97,I2=0%).Forstroke,the cardiovasculardisease,levelsoflowdensitylipoprotein(LDL)
combinedrelativeriskforanincreaseofoneeggconsumedperday cholesterolhavearousedparticularattention.IntheWomen’s
was0.91(0.81to1.02;P=0.10forlineartrend)withoutheterogeneity HealthStudy,afterameanfollow-upofeightyears,participants
amongstudies(P=0.46,I2=0%).Inasubgroupanalysisofdiabetic withthehighestlevelsofLDLcholesterolshowedanotably
populations,therelativeriskofcoronaryheartdiseasecomparingthe higherriskofcardiovasculareventsthanthosewiththelowest
highestwiththelowesteggconsumptionwas1.54(1.14to2.09;P=0.01). levels.5Inaddition,severalmeta-analysesofobservational
Inaddition,peoplewithhighereggconsumptionhada25%(0.57to studiesandrandomizedcontrolledtrialshavefoundthata
0.99;P=0.04)lowerriskofdevelopinghemorrhagicstroke. reductioninconcentrationsofLDLcholesterolcould
significantlyreducetheriskofcoronaryheartdiseaseandstroke
Correspondence to: L Liu [email protected]
Extra material supplied by the author (see http://www.bmj.com/content/346/bmj.e8539?tab=related#webextra)
Web appendix:Web tables
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incidenceandmortality.6-9Dietisanimportantdeterminantof Data extraction
serumcholesterol,butdietarycholesterolhasonlyamodest
Dataextractionwascarriedoutindependentlybytwoauthors
contributiontoplasmaconcentrationsofLDLcholesterol.10On
(YRandLC)usingastandardextractionform.Weextracted
theotherhand,dietarycholesterolmayprompttheoxidationof
thefollowinginformationfromeachstudy:authors,yearof
LDLandincreasepostprandiallipemia,whichcouldraisethe
publication,studyname,studylocation,yearsoffollow-up,
riskofvasculardisease.11Tominimizetheelevationofblood
samplesize(numberofparticipantsandincidentcases),
cholesterolandreducetheriskofcardiovasculardisease,the
participants’characteristics(ageandsex),endpoints(coronary
AmericanHeartAssociation(AHA)hasrecommendedthe
heartdisease,stroke,orboth),outcomesascertainment,egg
publictoconsumelessthan300mg/dayofcholesterol.1213
consumptioncategories,covariatesadjustedinthemultivariable
Sinceeggsareamajorsourceofdietarycholesterol,withone analysis,andrelativerisks(95%confidenceintervals)forall
largeeggcontainingalmost210mgofcholesterol,thepublic categoriesofeggconsumption.
hasbeenrecommendedtolimiteggconsumptionunlessthe
Qualityassessmentwasperformedaccordingtothe
intakeofotherfoodshighincholesterolisrestricted.14However, Newcastle-Ottawaqualityassessmentscale,22whichisa
eggsarealsoaninexpensiveandlowcaloriesourceofmany
validatedscalefornon-randomisedstudiesinmeta-analyses.
othernutrients,includingminerals,proteins,andunsaturated
Thisscaleawardsamaximumofninepointstoeachstudy:four
fattyacids,whichcouldlowertheriskofcardiovascular
forselectionofparticipantsandmeasurementofexposure,two
disease.15Additionally,inpopulationsfollowingacarbohydrate
forcomparabilityofcohortsonthebasisofthedesignor
restricteddiet,dietarycholesterolfromeggscouldincrease
analysis,andthreeforassessmentofoutcomesandadequacy
plasmaconcentrationsofhighdensitylipoprotein(HDL)
offollow-up.Weassignedscoresof0-3,3.5-6,and6.5-9for
cholesterol,16whichhasbeensuggestedtoprotectagainst
low,moderate,andhighqualityofstudies,respectively.When
vasculardisease.1718Therefore,someorganizationshave
studieshadseveraladjustmentmodels,weextractedthosethat
recommendedthatreducingeggintakemightnotbeimportant
reflectedthemaximumextentofadjustmentforpotentially
forhealthypeoplewithnormallevelsofcholesterolinthe
confoundingvariables.
blood.19Foodbaseddietaryguidelinesfromcountriesincluding
Forstudiesthatreportedeggintakeasservingsperweekorday,
Nepal,Thailand,andSouthAfricarecommendconsumingeggs
everydayorregularlyaspartofahealthydiet.20 weassumedthateachservingwasequivalenttooneegg.For
studiesthatlackedtheunitofconsumption,thecategorieswere
Severalprospectivecohortstudieshaveexaminedtheassociation
estimatedbymultiplyingthefrequencyofconsumptionfrom
betweeneggconsumptionandriskofcoronaryheartdisease
thefoodfrequencyquestionnaireswithanaverageportionsize
andstroke.However,therelationbetweeneggconsumption
accordingtothemeanintakederivedfromthe24hdiaries.We
andriskofcardiovasculardiseaseremainscontroversial.
contactedtheauthorsifthedataofinterestwerenotdirectly
Therefore,weconductedadose-responsemeta-analysisof
showninthepublications.Toresolvediscrepancies,weused
prospectivecohortstudiestoquantifytheassociationbetween
groupconsensusandconsultedathirdreviewer.
eggconsumptionandriskofcoronaryheartdiseaseandstroke.
Statistical analysis
Methods
Inthismeta-analysis,therelativerisksand95%confidence
Search strategy intervalswereconsideredastheeffectsizeforallstudies,and
thehazardratiosweredeemedequivalenttorelativerisks.Any
WeconductedaliteraturesearchofPubMed(Medline)and
resultsstratifiedbysexweretreatedastwoseparatereports.
EmbasefromJanuary1966throughJune2012forprospective
Thosearticlesreportingbothcoronaryheartdiseaseandstroke
cohortstudiesexaminingtheassociationbetweenegg
werealsotreatedastwoseparatereports.Owingtothedistinct
consumptionandriskofCHDandstroke.PubMedsearchterms
cut-offpointsforcategoriesindifferentarticles,wecomputed
were“CardiovascularDiseases”[MeSH]or“Stroke”[MeSH]or
arelativeriskwith95%confidenceintervalforanincreased
“CoronaryDisease”[MeSH]or“myocardialinfarction”[MeSH]
intakeofoneeggperdayforeachreport.Themethoddescribed
orCHD)andegg.SimilarsearchtermswereusedforEmbase.
byGreenlandandLongnecker23andOrsiniandcolleagues24was
Inaddition,wescrutinizedreferencesfromrelevantoriginal
usedtocalculatethetrendfromthecorrelatedestimatesforlog
papersandreviewarticlestoidentifyfurtherpertinentstudies.
relativeriskacrosscategoriesofeggconsumption.Theamount
Nolanguagerestrictionswereimposed.Wefollowedthe
ofeggconsumption,distributionsofcasesandpersonyears,
standardcriteriaforconductingmeta-analysesofobservational
studiesandreportingtheresults.21 andrelativerisksand95%confidenceintervalswereextracted
accordingtothismethod.
Study selection Themedianormeaneggconsumptionineachcategorywas
usedasthecorrespondingdoseofconsumption.Themidpoint
Studieswereincludedinthismeta-analysisiftheysatisfiedthe
oftheupperandlowerboundarieswasconsideredthedoseof
followingcriteria:thestudydesignwasprospective,the
eachcategoryifthemedianormeanintakepercategorywas
exposureofinterestwaseggconsumption,theoutcomewas
notavailable.Ifthehighestcategorywasopenended,the
coronaryheartdiseaseorstroke,andtheinvestigatorsreported
midpointofthecategorywassetat1.5timesthelower
relativeriskswith95%confidenceintervalsforatleastthree
boundary.Ifthenumberofcasesandpersonyearswerenot
quantitativecategoriesofeggintake.Additionally,weexcluded
available,weusedtherelativeriskscomparingthehighestversus
reviews,editorials,non-humanstudies,andletterswithout
lowestcategoriesofeggintaketoobtainasummaryestimate.
sufficientdata.Studiesofotherexposuresanddiseaseswere
alsoexcluded.Ifstudypopulationswerereportedmorethan Inaddition,weevaluatedapotentialcurvelinearassociation
once,weusedtheresultwiththelongestfollow-uptime. betweeneggconsumptionandriskofcoronaryheartdisease
andstroke,usingrestrictedcubicsplineswiththreeknotsat
percentiles10%,50%,and90%ofthedistribution.25APvalue
forcurvelinearityornon-linearitywascalculatedbytestingthe
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nullhypothesisthatthecoefficientofthesecondsplineisequal assessment(score0-9)yieldedascoreof6.5orabove(high
tozero. quality)forallstudies,withanaveragescoreof7.6(web
TheheterogeneityamongstudieswasestimatedbytheCochran appendix,tablesAandB).
QtestandI2statistic.26Heterogeneitywasconfirmedwitha
significancelevelofP≤0.10.TheI2statisticdescribesthe Association between egg consumption and
risk of coronary heart disease
percentageoftotalvariationinpointestimatesthatcanbe
attributedtoheterogeneity.FortheI2metric,weconsidered Sixarticles34363740-42withninereportswereincludedinthe
low,moderate,andhighI2valuestobe25%,50%,and75%, dose-responseanalysisofeggconsumptionandriskofcoronary
respectively.2627Weusedafixedeffectmodel(Mantel-Haenszel heartdisease.Usingarestrictedcubicsplinesmodel,wefound
method)whenheterogeneitywasnegligible,andarandomeffect noevidenceofacurvelinearassociationbetweenegg
model(DerSimonianandLairdmethod)whenheterogeneity consumptionandriskofcoronaryheartdisease(P=0.67for
wassignificant.28Forestplotsandfunnelplotswereusedto non-linearity;fig2⇓).Thesummaryrelativeriskofcoronary
examinetheoveralleffectandassessthepublicationbias, heartdiseaseforanincreaseofoneeggperdaywas0.99(95%
respectively. confidenceinterval0.85to1.15;P=0.88forlineartrend).We
Wealsoconductedanalysesstratifiedbysex,studylocation, sawnoheterogeneityamongstudies(P=0.97,I2=0%;fig3⇓).
numberofcasesandparticipants,durationoffollow-up,repeated Additionally,BeggandEggerregressiontestsprovidedno
eggconsumptionmeasurements,studyquality,andwhether evidenceofsubstantialpublicationbias(P>0.05forbothtests).
dietvariablesorcholesterollevelswerecontrolledforinmodels. Amongtheincludedstudies,twoarticles3437(fourtotalreports)
AllstatisticalanalyseswereperformedwithStataversion11 examinedtherelationbetweeneggconsumptionandriskof
(StataCorp),andalltestsweretwosidedwithasignificance coronaryheartdiseaseinpopulationswithdiabetes.Owingto
levelof0.05. thelackofdataforpersonyearsindiabeticpopulations,we
obtainedthesummaryrelativeriskcomparingthehighestwith
Results thelowesteggconsumptionforcoronaryheartdiseasein
diabeticpatients(relativerisk1.54(1.14to2.09);P=0.01;table
Literature search 3⇓;webappendix,tableC).
Figure1⇓showstheresultsofliteratureresearchandselection.
Association between egg consumption and
Weidentified616articlesfromPubMedand824articlesfrom
risk of stroke
Embasepriorto20June2012.Afterexclusionofduplicates
andstudiesthatdidnotfulfilltheinclusioncriteria,16remaining Thisdose-responseanalysisinvolvedsixarticles3437-394142with
articlesseemedtoberelevantforthismeta-analysis.After eightreportsoneggconsumptionandstrokerisk.Wedidnot
evaluatingthefulltextsofthese16publications,weexcluded findacurvelinearassociationbetweeneggconsumptionand
eightarticlesasfollows.Twoarticles2930wereexcludedowing riskofstroke(P=0.27fornon-linearity;fig4⇓).Thecombined
tolackofsufficientdataforestimationofrelativerisks.Another relativeriskofstrokeforanincrementofoneeggconsumed
twoarticles3132wereexcludedbecausetheydidnotseparately perdaywas0.91(95%confidenceinterval0.81to1.02;P=0.10
reporttherelativerisksand95%confidenceintervalsfor forlineartrend;fig5⇓).Noheterogeneityofeffectestimates
coronaryheartdiseaseorstroke.Wealsoexcludedonereport33 onrelativeriskswasobserved(P=0.46,I2=0%).Neitherthe
becauseitwasthemeetingabstractofthestudybyScrafford BeggtestnortheEggertestforpublicationbiasreached
andcolleagues.34AstudybyHeandcolleagues35wasexcluded significance(P>0.05forbothtests).Inaddition,three
becauseitreportedtheintermediatefollow-upresultsofHealth articles343739withfourreportsprovidedinformationonfatal
ProfessionalsFollow-upStudy.Thefinalmeta-analysisincluded stroke(pooledrelativerisk0.94(0.80to1.10);P=0.46;table
eightarticles,ofwhichfour3436-38examinedmenandwomen 3).Moreover,fourarticles38394142reportedresultsfordifferent
separately.ForthestudybyScraffordandcolleagues,34the typesofstroke,andthreearticles344142providedresultsforstroke
estimateoftheassociationbetweeneggconsumptionandstroke inthosewithdiabetes.Forthesestudies,thecombinedrelative
mortalityamongmenwasimprecisebecauseofsparsedata,and riskscomparingthehighestversuslowesteggintakewere0.75
thusforthisreportweincludedonlydataforwomen.Intotal, (0.57to0.99)forhemorrhagicstroke,0.91(0.82to1.01)for
ourmeta-analysisincludedeightarticleswith17independent ischemicstroke,and0.80(0.29to2.15)fortotalstrokeamong
reports. peoplewithdiabetes(table3;webappendix,tableD).
Study characteristics Subgroup analyses
Tables1⇓and2⇓showtheinformationextractedfromthe Subgroupanalyseswereconductedtoexaminethestabilityof
includedstudies,allofwhichhadprospectivecohortdesigns theprimaryresults(table3).Theassociationsbetweenegg
andparticipantswithnopriordiagnosesofcardiovascular consumptionandriskofcoronaryheartdiseaseandstrokewere
diseaseatbaseline.Themeta-analysisconsistedof263938 similarinsubgroupanalyses,whichweredefinedbysex,study
participantswith3081269personyearsoffollow-upfor location,numberofcasesorparticipants,durationoffollow-up,
coronaryheartdisease,and210404patientswith4148095 repeatedeggconsumptionmeasurements,studyquality,and
personyearsoffollow-upforstroke.Amongtheparticipants, whetherdietvariablesorcholesterollevelswerecontrolledfor
wedocumented5847casesofcoronaryheartdiseaseduring inmodels.Anincrementofoneeggconsumedperdaydidnot
follow-upperiodsrangingfromeightto20years,and7579 significantlyincreaseriskofcoronaryheartdiseaseorstroke
casesofstrokeduringafollow-uprangingfrom8.8to22years. inanyofthecategories.
Threecohorts373940wereamongAsians(Japan),andthe
others3436384142wereconductedintheUnitedStates.Egg Discussion
consumptionwasmeasuredbyfoodfrequencyquestionnaires
inallstudies.Fourstudies36384042usedrepeatedmeasurements Thismeta-analysisidentifiednosignificantassociationbetween
toupdatedietaryinformationtomoreaccuratelyreflectthe eggconsumptionandriskofcoronaryheartdiseaseorstroke.
dietaryintakesoverfollow-up.Resultsofstudyquality Higherintakeofeggs(uptooneeggperday)wasnotassociated
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withriskofcoronaryheartdiseaseorstroke.Similarresults cardiovasculardiseaserisk.Onestudyfoundthatparticipants
wereobtainedinsubgroupanalyses.However,amongdiabetic withhighlevelsofcholesterolinthebloodweremorelikelyto
participants,highereggconsumptionwasassociatedwitha reducetheireggconsumptionthanothers.40However,our
significantlyelevatedriskofcoronaryheartdisease.Onthe subgroupanalysisshowedthattheassociationbetweenegg
otherhand,highereggintakewasassociatedwithalowerrisk consumptionandcoronaryheartdiseasewassimilarinthe
ofhemorrhagicstroke.Thesesubgroupresultsshouldbe models,withorwithoutadjustmentforcholesterollevels.
interpretedwithcaution,becauseonlyafewstudiesfocusedon Recently,acrosssectionalstudyassessedthetotalplaquearea
diabeticparticipantsandparticularstrokesubtypes. inpatientsattendingCanadianvascularpreventionclinicsto
determinewhethertheatherosclerosisburdenwasrelatedto
Results in relation to other studies dietaryeggintake.54Thestudyfoundastrongpositive
Todate,themajorityofprospectivestudieshavefoundno associationbetweenthenumberofeggyolksandthedegreeof
significantassociationbetweeneggconsumptionandriskof atherosclerosismeasuredbyplaqueareas.However,thestudy
coronaryheartdiseaseorstroke.However,Burkeand didnotassessoradjustforotherdietaryorlifestylefactorsand
colleagues43analyzeddatafrom514WesternAustralian didnotexaminehardcardiovasculardiseaseendpoints.The
aborigineswithalmost14yearsoffollow-upandfoundthat crosssectionalnatureofthestudyalsolimitedcausal
riskofcoronaryheartdiseaseincreasedinparticipants interpretationofthedata.Therefore,theresultsfromthiscross
consumingeggsmorethantwiceperweek.Butthisstudywas sectionalanalysisshouldbeinterpretedwithcaution.55The
smallandanalyzedmultipledietaryandlifestyleexposures. findingsfromourmeta-analysesofprospectivecohortstudies
donotsupportapositiveassociationbetweeneggconsumption
Somestudieshavefoundaninverseassociationbetweenegg
andcardiovasculardiseaseoutcomesinthegeneralpopulation.
consumptionandstrokerisk.Forexample,ananalysisofthe
ThirdNationalHealthandNutritionExaminationSurvey Subgroupanalyseshavesuggestedapositiveassociation
1988-1994(NHANESIII)datasetfoundasignificantinverse betweeneggconsumptionandcoronaryheartdiseaseriskin
associationbetweenhighereggconsumptionandstroke diabeticpatients.Amongdiabeticpopulations,decreasedplasma
mortalityamongmen.34AcohortstudyfromJapanfoundthat levelsofapolipoproteinE,togetherwithincreasedlevelsof
increasedconsumptionofanimalproducts(includingeggs)was apolipoproteinC-IIIcouldleadtoabnormalcholesterol
associatedwithreducedriskoftotalandhemorrhagicstroke transport,whichmightincreasetheriskofcoronaryheart
death.39 disease.5657Theadverseeffectofeggconsumptionon
lipoproteinprofileandglycemiccontrolcouldcontributetothe
Weconsideredseveralpotentialreasonsforthelackofanoverall
elevatedriskofcoronaryheartdiseaseindiabeticpopulations.
associationbetweeneggconsumptionandcoronaryheartdisease
orstroke.Althoughdietarycholesterolinfluencesplasma Inaddition,insulinsensitivitycouldinfluenceHDLmetabolism
concentrationsofserumcholesterol,theeffectsarerelatively andcholesteroltransport.5859Riemensandcolleagues60found
small.10Inaddition,epidemiologicstudieshavefoundweakor thatpeoplewithlowerinsulinsensitivityhadincreasedlevels
littleassociationbetweendietarycholesterolintakeand ofplasmacholesterol,verylowdensitylipoproteincholesterol,
cardiovasculardiseaserisk.10Apartfromdietarycholesterol, andLDLcholesterol,comparedwiththosewithhigherinsulin
saturatedfatanddietarypatternsmightalsoinfluenceblood sensitivity.Activitiesofplasmalecithin,cholesterolacyl
cholesterollevels,44-46suggestingthatcompliancewithgeneral transferase,phospholipidtransferprotein,andhepaticlipase
dietaryrecommendationsinsteadofsimplyreducingegg werenegativelycorrelatedwithinsulinsensitivity,whichcould
consumptioncouldhaveagreatereffectontheriskof haveenhancedreversecholesteroltransport.60Thesefindings
cardiovasculardisease.Additionally,individualdifferencesin suggestabiologicalmechanismforpossibleadverseeffectsof
responsetodietarycholesterolvarygreatly,whichcouldaffect insulinresistanceonriskofcoronaryheartdiseaseindiabetic
theassociationbetweeneggconsumptionandriskofcoronary populationsthroughcholesterolmetabolism.Nonetheless,this
heartdiseaseandstroke.Moreover,severalstudieshaveshown subgroupfindingofapositiveassociationbetweenegg
thateggconsumptionfavorstheformationoflargerLDLand consumptionandcoronaryheartdiseaseriskwasbasedona
HDLparticles,whichmightenhanceprotectionagainst smallnumberofstudiesandthusneedstobereplicatedinfurther
atherosclerosis.4748 studies.
Otherthancholesterol,eggsareagoodsourceofothernutrients Severalprospectivecohortstudiesshowedthathemorrhagic
suchashighqualityproteinandvitaminD.IntheDiet,Obesity, strokehadaninverseassociationwithserumlevelsof
andGene(Diogenes)Project,increasedproteinconsumption cholesterol.61-64Inparticular,theresultofameta-analysis
togetherwithamodestreductioninglycemicindexwas including13cohortsfromChinaandJapanshowedthat
beneficialforweightcontrol.49Substitutingproteinfor decreasedcholesterolconcentrationsconferredanincreased
carbohydratealsopartlyresultedinlowerbloodpressure, riskofhemorrhagicstroke.65Ithasbeensuggestedthatlow
improvedlipidslevels,andconcomitantlyreduced cholesterollevelspromotenecrosisofmedialmusclecellsand
cardiovascularrisk.50HighervitaminDintakemighthave reduceplateletaggregability,whichcouldleadtoplasmatic
beneficialeffectsonthereductionofvisceraladiposetissue51 arterionecrosisandtheincidenceofhemorrhagicstroke.6667It
andothercardiovascularriskfactors52. isunclearwhethertheinverseassociationbetweenegg
consumptionandhemorrhagicstrokeismediatedthroughlow
Anotherpossibilityisthatlifestylefactorsassociatedwithegg
levelsofserumcholesterolorothermechanisms.Sincethis
consumptionmighthaveobscuredapositiveassociationbetween
subgroupfindingwasbasedonasmallnumberofstudies,the
eggconsumptionandriskofcoronaryheartdiseaseandstroke.
resultsshouldbeinterpretedwithcaution.
However,regulareggconsumptiontendstobeassociatedwith
unhealthylifestylefactorssuchassmokingandphysical
Strengths and limitations
inactivity.343653Higherconsumptionofeggsisalsolikelytobe
associatedwithincreasedconsumptionofredandprocessed Ourstudyhasseveralstrengths.Ourmeta-analysisincluded
meats.36Theseconfoundingfactorstendtoexaggeraterather prospectivecohortstudieswithlargesamplesizeandlong
thanmasktheassociationbetweeneggconsumptionand durationoffollow-up,whichsignificantlyincreasedthe
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statisticalpowertodetectpotentialassociations.Weinvestigated (NSFC81072291),andNationalBasicResearchProgram
adose-responserelationbetweeneggconsumptionandriskof (2009CB118803)ofChina.Thefundershadnoroleinstudydesign,
coronaryheartdiseaseandstroke,allowingustoexaminethe datacollectionandanalysis,decisiontopublish,orpreparationofthe
shapeofthispossibleassociation.Linearandnon-linearrelations manuscript.
werealsotestedtoquantifytheassociations.Inaddition,we Competinginterests:AllauthorshavecompletedtheICMJEuniform
usedmodelsadjustingformostestablishedriskfactorsanddid disclosureformatwww.icmje.org/coi_disclosure.pdf(availableon
stratifiedanalysestoexplorewhethersomefactorscouldexplain requestfromthecorrespondingauthor)anddeclare:nosupportfrom
theresults. anyorganizationforthesubmittedwork;nofinancialrelationshipswith
Severallimitationsofourstudyshouldalsobeacknowledged. anyorganizationsthatmighthaveaninterestinthesubmittedworkin
Firstly,errorsinmeasurementofeggintakeandotherdietary thepreviousthreeyears;andnootherrelationshipsoractivitiesthat
habitscouldhaveattenuatedindividualstudyresultsandledto couldappeartohaveinfluencedthesubmittedwork.
thenullassociationbetweeneggconsumptionandriskof Ethicalapproval:Ethicalapprovalnotneeded.
coronaryheartdiseaseandstroke.Allthestudiesinouranalysis
Datasharing:Noadditionaldataavailable.
assessedeggconsumptionusingfoodfrequencyquestionnaires,
severalofwhichhavebeenvalidatedwithreasonable
1 FordES,CapewellS.CoronaryheartdiseasemortalityamongyoungadultsintheU.S.
reproducibilityandvalidityofselfreportedeggintake.However, from1980through2002:concealedlevelingofmortalityrates.JAmCollCardiol
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Moreover,participantswithhighereggintakeconsumedmore
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withlowereggintake.3436Severalstudiesadjustedforthose cholesterolwithstatintherapyinpeopleatlowriskofvasculardisease:meta-analysisof
confoundingfactors.Toreducethisbias,weconducteda individualdatafrom27randomisedtrials.Lancet2012;380:581-90.
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stratifiedanalysisandfoundtheresultstoberobustindifferent safetyofmoreintensiveloweringofLDLcholesterol:ameta-analysisofdatafrom170,000
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8 BrielM,Ferreira-GonzalezI,YouJJ,KaranicolasPJ,AklEA,WuP,etal.Association
Secondly,duringthelongfollow-up,participantsmayhave betweenchangeinhighdensitylipoproteincholesterolandcardiovasculardisease
morbidityandmortality:systematicreviewandmeta-regressionanalysis.BMJ
changedtheirdiets.However,inourmeta-analysis,nearlyhalf
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theincludedstudiesupdatedthedietinformationfromfood 9 SnidermanAD,WilliamsK,ContoisJH,MonroeHM,McQueenMJ,deGraafJ,etal.A
frequencyquestionnaires.Stratifiedanalysisindicatedthatthe meta-analysisoflow-densitylipoproteincholesterol,non-high-densitylipoprotein
cholesterol,andapolipoproteinBasmarkersofcardiovascularrisk.CircCardiovascQual
associationsbetweeneggconsumptionandriskofcoronary Outcomes2011;4:337-45.
heartdiseaseandstrokeweresimilar,regardlessofwhether 10 KanterMM,Kris-EthertonPM,FernandezML,VickersKC,KatzDL.Exploringthefactors
thataffectbloodcholesterolandheartdiseaserisk:isdietarycholesterolasbadforyou
repeatedeggconsumptionmeasurementswereconsidered. ashistoryleadsustobelieve?AdvNutr2012;3:711-7.
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Thirdly,somestudiesconsideredtheintakeoffoodsinwhich
atriskofvasculardisease.CanJCardiol2010;26:e336-9.
eggwasthemainingredient.However,theresultssuggested 12 LichtensteinAH,AppelLJ,BrandsM,CarnethonM,DanielsS,FranchHA,etal.Summary
thattheamountofeggsestimatedinotherfoodswasrelatively ofAmericanHeartAssociationDietandLifestyleRecommendationsrevision2006.
ArteriosclerThrombVascBiol2006;26:2186-91.
smallandwasunlikelytoaffecttheaforementionedassociations. 13 LichtensteinAH,AppelLJ,BrandsM,CarnethonM,DanielsS,FranchHA,etal.Dietand
Finally,thestatisticalpowerwaslimitedinsubgroupanalyses lifestylerecommendationsrevision2006:ascientificstatementfromtheAmericanHeart
AssociationNutritionCommittee.Circulation2006;114:82-96.
ofdiabeticpatientsorsubtypesofstroke.
14 KraussRM,EckelRH,HowardB,AppelLJ,DanielsSR,DeckelbaumRJ,etal.AHA
DietaryGuidelines:revision2000:astatementforhealthcareprofessionalsfromthe
Conclusions NutritionCommitteeoftheAmericanHeartAssociation.Stroke2000;31:2751-66.
15 SongWO,KerverJM.NutritionalcontributionofeggstoAmericandiets.JAmCollNutr
2000;19(5suppl):556-62S.
Insummary,resultsfromourmeta-analysisdonotsupportthat
16 MutungiG,RatliffJ,PuglisiM,Torres-GonzalezM,VaishnavU,LeiteJO,etal.Dietary
highereggconsumptionisassociatedwithelevatedriskof cholesterolfromeggsincreasesplasmaHDLcholesterolinoverweightmenconsuming
acarbohydrate-restricteddiet.JNutr2008;138:272-6.
coronaryheartdiseaseandstroke.Subgroupanalysessuggest
17 DiAngelantonioE,SarwarN,PerryP,KaptogeS,RayKK,ThompsonA,etal.Major
apositiveassociationbetweenhighereggintakeandriskof lipids,apolipoproteins,andriskofvasculardisease.JAMA2009;302:1993-2000.
coronaryheartdiseaseindiabeticpatients,andaninverse 18 HuxleyRR,BarziF,LamTH,CzernichowS,FangX,WelbornT,etal.Isolatedlowlevels
ofhigh-densitylipoproteincholesterolareassociatedwithanincreasedriskofcoronary
associationbetweenhighereggconsumptionandincidenceof heartdisease:anindividualparticipantdatameta-analysisof23studiesintheAsia-Pacific
hemorrhagicstroke.Studieswithlargersamplesizesandlonger region.Circulation2011;124:2056-64.
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follow-uptimesarewarrantedtoconfirmthesesubgroupresults. bhcarticles.nsf/pages/Cholesterol_explained?open.
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meta-analyses.2011.www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
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Whatisalreadyknownonthistopic
Cardiovasculardiseaseaffectsmillionsofpeopleinbothdevelopedanddevelopingcountries
Asamajorsourceofdietarycholesterol,eggshavebeeninvestigatedbyseveralepidemiologicstudiesinrelationtoriskofcoronary
heartdiseaseandstroke
However,whethereggconsumptionincreasesthefutureriskofcoronaryheartdiseaseandstrokeremainsunclear
Whatthisstudyadds
Consumptionofuptooneeggperdaywasnotassociatedwithincreasedriskofcoronaryheartdiseaseorstroke
Subgroupanalysissuggestedthatconsumptionofuptooneeggperdaywasassociatedwithasignificantlyelevatedriskofcoronary
heartdiseaseindiabeticpopulations,andareducedriskofhemorrhagicstroke
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heartdisease.AmJClinNutr1982;36:617-25. HealthStudy.Circulation2008;117:512-6.
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Tables
Table1|Characteristicsofparticipantsandfollow-upinincludedstudiesofeggconsumptioninrelationtoriskofcoronaryheartdisease
andstroke
Ageat Meanlength
Publication Sexof baseline Noof offollow-up
Author year Studyname Country population (years) participants (years) Endpoints(Noofcases)
Huetal36 1999 HealthProfessionals USA Male 40-75 37851 8 Coronaryheartdisease(866)
Follow-upStudy
Huetal36 1999 Nurses’HealthStudy USA Female 34-59 80082 14 Coronaryheartdisease(939)
Sauvagetetal39 2003 Hiroshima/Nagasaki Japan Maleand 34-103 34807 16-17 Strokemortality(1259)
LifeSpanStudy female
Nakamuraetal37 2004 NIPPONDATA80 Japan Male 30+ 4077 14 Ischemicheartdisease
mortality(39),stroke
mortality(112)
Nakamuraetal37 2004 NIPPONDATA80 Japan Female 30+ 5186 14 Ischemicheartdisease
mortality(41),stroke
mortality(107)
Nakamuraetal40 2006 JapanPublicHealth Japan Maleand 40-69 90735 10.2 Coronaryheartdisease(462)
Center-based female
prospectivestudy
Qureshietal41 2007 NHANES-I USA Maleand 25-74 9734 20 Coronaryarterydisease
female (1584),stroke(655)
Djousseetal42 2008 Physicians’Health USA Male 40-85 21327 20 Myocardialinfarction(1550),
StudyI stroke(1342)
Scraffordetal34 2011 NHANESIII USA Male 17+ 6833 8.8 Coronaryheartdisease
mortality(198),stroke
mortality(63)
Scraffordetal34 2011 NHANESIII USA Female 17+ 8113 8.9 Coronaryheartdisease
mortality(168),stroke
mortality(74)
Bernsteinetal38 2012 HealthProfessionals USA Male 40-75 43150 22 Stroke(1397)
Follow-UpStudy
Bernsteinetal38 2012 Nurses’HealthStudy USA Female 30-55 84010 26 Stroke(2633)
NHANES-I=FirstNationalHealthandNutritionExaminationSurvey;NHANESIII=ThirdNationalHealthandNutritionExaminationSurvey;NIPPONDATA80=National
IntegratedProjectforProspectiveObservationofNon-communicableDiseaseanditsTrendsintheAged,1980.
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RESEARCH
Table2|Outcomesandcovariatesofincludedstudiesofeggconsumptioninrelationtoriskofcoronaryheartdiseaseandstroke
Study Endpoints Caseascertainment Dietarycategoryandrelativerisk(95%CI) Covariatesinfullyadjustedmodel
Huetal,199936 Coronaryheart Selfreporteddiagnosis <1egg/week,1.0(reference);1,1.06(0.88to1.27); Age,bodymassindex,twoyeartime
(men) disease orconfirmedbymedical 2-4,1.12(0.95to1.33);5-6,0.90(0.63to1.27);≥7, periods,smoking,parentalhistoryof
recordsorautopsy 1.08(0.79to1.48) myocardialinfarction,multivitamin
Huetal,199936 Coronaryheart Sameasabove <1egg/week,1.0(reference);1,0.82(0.67to1.00); supplementuse,alcoholconsumption,
menopausalstatusand
(women) disease 2-4,0.99(0.82to1.18);5-6,0.95(0.70to1.29);≥7,
postmenopausalhormoneuse
0.82(0.60to1.13)
(women),historyofhypertension,
physicalactivity,andtotalenergyintake
Sauvagetetal, Strokemortality Confirmedby Never,1.0(reference);≤1egg/week*,0.74(0.55to Age,sex,birthcohort,city,radiation
200339 nationwidefamily 1.00);2-4eggs/week,0.78(0.59to1.04);almostdaily, dose,bodymassindex,smoking,
registrationsystem 0.72(0.54to0.97) alcoholhabits,educationlevel,history
ofdiabetes,orhypertension
Nakamuraetal, Ischemicheart ConfirmedbyNational Ischemicheartdiseasemortality:seldom,1.18(0.26 Age,serumcreatinine,totalcholesterol,
200437(men) diseasemortality, VitalStatistics to5.42);1-2eggs/week,1.71(0.78to3.76);0.5 bloodglucose,bodymassindex,blood
strokemortality eggs/day,1.49(0.63to3.48);1egg/day,1.0 pressures,useofbloodpressure
(reference) loweringdrugs,smoking,andalcohol
Strokemortality:seldom,0.93(0.36to2.40);1-2 intake
eggs/week,1.09(0.69to1.72);0.5eggs/day,1.10
(0.68to1.76);1egg/day,1.0(reference);≥2eggs/day,
0.25(0.03to1.81)
Nakamuraetal, Ischemicheart Sameasabove Ischemicheartdiseasemortality:seldom,1.42(0.56
200437(women) diseasemortality, to3.62);1-2eggs/week,0.64(0.28to1.44);0.5
strokemortality eggs/day,0.78(0.35to1.82);1egg/day,1.0
(reference);≥2eggs/day,1.27(0.16to9.80)
Strokemortality:seldom,0.78(0.35to1.73);1-2
eggs/week,0.79(0.47to1.33);0.5eggs/day,1.46
(0.89to2.4);1egg/day,1.0(reference);≥2eggs/day,
1.22(0.29to5.17)
Nakamuraetal, Coronaryheart Confirmedbymedical <1egg/week*,1.19(0.86to1.64);1-2eggs/week, Age;sex;bodymassindex;
200640 disease records,letter, 1.00(0.77to1.30);3-4eggs/week,1.00(0.79to1.26); hypertension;diabetes;useof
telephoneordeath almostdaily,1.0(reference) cholesterolloweringdrugs;smoking;
certificate alcoholdrinking;whetherparticipants
intendedtoavoidcholesterolrichdiets;
consumptionfrequenciesofmeat,fish,
vegetables,andfruits;andcohorteffects
Qureshietal, Coronaryartery Confirmedbymedical Coronaryarterydisease:<1egg/week,1.0(reference); Age,sex,raceorethnicity,systolicblood
200741 disease,stroke recordsordeath 1-6,1.0(0.9to1.1);>6,1.1(0.9to1.3) pressure,diabetesmellitus,serum
certificate Stroke:<1egg/week,1.0(reference);1-6,0.9(0.7to cholesterol,smoking,bodymassindex,
1.0);>6,0.9(0.7to1.1) andeducationalstatus
Djousseetal, Myocardialinfarction, Confirmedby Myocardialinfarction:<1egg/week,1.0(reference); Age,bodymassindex,smoking,history
200842 stroke physiciansormedical 1,1.12(0.96to1.31);2-4,1.16(1.00to1.36);5-6, ofhypertension,vitaminintake,alcohol
records 1.18(0.93to1.49);≥7,0.90(0.72to1.14) consumption,vegetableconsumption,
Stroke:<1egg/week,1.0(reference);1,0.96(0.82to breakfastcereal,physicalactivity,
1.13);2-4,1.06(0.91to1.24);5-6,1.13(0.89to1.42); treatmentarm,atrialfibrillation,diabetes
≥7,0.99(0.80to1.23) mellitus,hypercholesterolemia,and
parentalhistoryofprematuremyocardial
infarction
Scraffordetal, Coronaryheart Notapplicable Coronaryheartdiseasemortality:<1egg/week,1.0 Age,energy,maritalstatus,educational
201134(men) diseasemortality, (reference);1-6,1.26(0.79to2.00);>6,1.13(0.61to status,raceorethnicity,smoking,body
strokemortality 2.11) massindex,waisttohipratio,diabetes,
Strokemortality:<1egg/week,1.0(reference);1-6, hypertension,anddietaryvariables
1.00(0.49to2.02);>6,0.27(0.10to0.73)
Scraffordetal, Coronaryheart Notapplicable Coronaryheartdiseasemortality:<1egg/week,1.0
201134(women) diseasemortality, (reference);1-6,1.12(0.66to1.89);>6,0.92(0.27to
strokemortality 3.11)
Strokemortality:<1egg/week,1.0(reference);1-6,
0.93(0.46to1.90);>6,1.03(0.25to4.22)
Bernsteinetal, Stroke Confirmedbymedical 0.14eggs/week†,1.0(reference);0.49,0.80(0.66to Age,timeperiod,bodymassindex,
201238(men) recordsorautopsy 0.97);1.19,0.88(0.73to1.05);3.01,0.80(0.66to smoking,physicalexercise,parental
report 0.96);5.53,0.84(0.68to1.04) historyofearlymyocardialinfarction,
menopausalstatusinwomen,
Bernsteinetal, Stroke Sameasabove 0.49eggs/week†,1.0(reference);1.26,0.90(0.80to
201238(women) 1.01);2.17,0.94(0.83to1.05);3.01,0.86(0.76to multivitaminuse,vitaminEsupplement
use,aspirinuseatleastonceperweek,
0.99);4.69,0.91(0.80to1.04)
totalenergy,cerealfiber,alcohol,trans
fat,fruitandvegetables,andother
proteinsources
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RESEARCH
Table2(continued)
Study Endpoints Caseascertainment Dietarycategoryandrelativerisk(95%CI) Covariatesinfullyadjustedmodel
*Unitofeggconsumptionwasassumed.
†Servingsperdayconvertedtoeggsconsumedperweek.
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RESEARCH
Table3|Stratifiedanalysesofrelativeriskofcoronaryheartdiseaseandstroke
Noofreports* Relativerisk(95%CI) Pforheterogeneity I2 Pfortest
Coronaryheartdisease
Totalcases 9 0.99(0.85to1.15) 0.97 0.0 0.88
Fatalcases 4 1.18(0.71to1.96) 0.91 0.0 0.53
Coronaryheartdiseasewith 5 1.54(1.14to2.09) 0.59 0.0 0.01
diabetes†
Subgroupanalysesfortotalcoronaryheartdisease
Sex
Male 4 1.06(0.89to1.25) 0.83 0.0 0.53
Female 3 0.99(0.83to1.20) 0.99 0.0 0.95
Studylocation
USA 6 1.01(0.90to1.13) 0.96 0.0 0.89
Asia 3 0.95(0.64to1.41) 0.76 0.0 0.79
Noofparticipants
>10000 4 0.97(0.81to1.15) 0.87 0.0 0.70
≤10000 5 1.14(0.83to1.56) 0.93 0.0 0.42
Noofcases
>500 4 1.00(0.89to1.13) 0.79 0.0 0.94
≤500 5 0.96(0.67to1.37) 0.93 0.0 0.83
Durationoffollow-up
>15years 2 1.02(0.89to1.16) 0.40 0.0 0.83
≤15years 7 0.98(0.81to1.19) 0.98 0.0 0.85
Repeatedeggconsumptionmeasurements
Yes 4 0.97(0.81to1.15) 0.87 0.0 0.70
No 5 1.14(0.83to1.56) 0.93 0.0 0.42
Studyquality
Score≥8 5 0.97(0.80to1.17) 0.93 0.0 0.74
Score<8 4 1.06(0.88to1.28) 0.81 0.0 0.55
Controllingforotherdietvariablesinmodels‡
Yes 6 0.97(0.82to1.15) 0.97 0.0 0.73
No 5 1.14(0.84to1.55) 0.92 0.0 0.40
Controllingforserumcholesterollevelsoruseofcholesterolloweringdrugsinmodels
Yes 5 0.97(0.75to1.26) 0.65 0.0 0.83
No 4 1.01(0.86to1.18) 0.97 0.0 0.94
Stroke
Totalstroke 8 0.91(0.81to1.02) 0.46 0.0 0.10
Fatalstroke 4 0.94(0.81to1.10) 0.47 0.0 0.46
Hemorrhagicstroke† 3 0.75(0.57to0.99) 0.21 36.8 0.04
Ischemicstroke† 4 0.91(0.82to1.01) 0.79 0.0 0.08
Strokewithdiabetes† 3 0.80(0.29to2.15) 0.09 58.9 0.65
Subgroupanalysesfortotalstroke
Sex
Male 4 0.89(0.77to1.03) <0.001 90.5 0.13
Female 4 0.91(0.77to1.07) 0.24 29.0 0.25
Studylocation
USA 5 0.90(0.79to1.03) 0.38 4.9 0.13
Asia 3 0.94(0.83to1.07) 0.28 20.6 0.34
Noofparticipants
>10000 4 0.90(0.80to1.02) 0.25 26.9 0.10
≤10000 4 0.97(0.75to1.27) 0.50 0.0 0.85
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