Braz. j. . vol.83 número1

BrazJOtorhinolaryngol.2017;83(1):80---87

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Association

of

the

C47T

polymorphism

in

superoxide

dismutase

gene

2

with

noise-induced

hearing

loss:

a

meta-analysis

夽

Jing

Wang

,

Jun

Li

,

Kang

Peng

,

Zi-Ying

Fu

,

Jia

Tang

,

Ming-Jian

Yang

,

Qi-Cai

Chen

a_{CentralChinaNormalUniversity,SchoolofLifeSciencesandHubeiKeyLabofGeneticRegulationandIntegrativeBiology,}

Wuhan,China

b_{DaliUniversity,SchoolofBasicMedicine,Dali,China} c_{DaliUniversity,SchoolofClinicalMedicine,Dali,China}

Received28October2015;accepted25January2016 Availableonline19April2016

KEYWORDS

Superoxidedismutase gene2;

Polymorphism; Noise-induced hearingloss; Meta-analysis

Abstract

Introduction:Currently,thereislimitedinformationabouttherelationshipbetweenmanganese superoxidedismutase(sod2)c47tpolymorphismandsusceptibilitytonoise-inducedhearingloss (NIHL).

Objective:The aimofthismeta-analysiswastoclarify theassociationbetweenSOD2 C47T polymorphismandNIHL.

Methods:A search inPubMed and Web ofScience was performedto collect data.All full-text,English-writtenstudiescontainingsufficientandcomplete case-and-controldataabout the relationship betweenSOD2 C47T polymorphismand NIHL wereincluded. Three eligible studies,comprising1094subjects,wereidentified.pooledoddsratios(ORs)and95%confidence intervals(CI)werecalculatedtoevaluatethestrengthoftheassociationbetweenSOD2C47T polymorphismandNIHL.

Results:No significantassociation betweenC47T polymorphismand risk ofNIHL was found withthefollowingcombinations:Tvs.C(OR=0.83;95%CI=0.63---1.09);TTvs.CC(OR=0.49; 95%CI=0.22---1.09);CTvs.CC(OR=0.54; 95%CI=0.25---1.17);TTvs.CC+CT(OR=0.82;95% CI=0.50---1.32);CCvs.TT+TC(OR=0.49;95%CI=0.23---1.04).However,insubgroupanalysis,a significantassociationwasfoundforTTvs.CC+CT(OR=0.77;95%CI=0.42---1.41)intheChinese population.

夽 _{Pleasecitethisarticleas:WangJ,LiJ,PengK,FuZ-Y,TangJ,YangM-J,etal.AssociationoftheC47Tpolymorphisminsuperoxide}

dismutasegene2withnoise-inducedhearingloss:ameta-analysis.BrazJOtorhinolaryngol.2017;83:80---7.

∗_{Correspondingauthors.}

E-mails:wangjing1807@foxmail.com(J.Wang);chenqc@mail.ccnu.edu.cn(Q.Chen).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.

http://dx.doi.org/10.1016/j.bjorl.2016.01.008

Conclusion: Thepresentmeta-analysissuggeststhatSOD2C47Tpolymorphismissignificantly associatedwithincreasedriskofNIHLintheChinesepopulation.Furtherlargeandwell-designed studiesareneededtoconfirmthisassociation.

© 2016 Publishedby Elsevier Editora Ltda. onbehalf of Associac¸˜ao Brasileira de Otorrino-laringologiaeCirurgiaC´ervico-Facial.ThisisanopenaccessarticleundertheCCBYlicense (http://creativecommons.org/licenses/by/4.0/).

PALAVRAS-CHAVE

Genedasuperóxido dismutase2; Polimorfismo; Perdaauditiva induzidaporruído; Metanálise

Associac¸ãodopolimorfismoC47Tnogenedasuperóxidodismutase2comperda

auditivainduzidapeloruído:metanálise

Resumo

Introduc¸ão: Atualmente,sãolimitadasasinformac¸õesacercadarelac¸ãoentreopolimorfismo C47T desuperóxidodismutase2(SOD2) dependentedemanganês esuscetibilidadeàperda auditivainduzidapeloruído(PAIR).

Objetivo: Oobjetivodestametanálisefoiesclareceraassociac¸ãoentreopolimorfismoC47T deSOD2ePAIR.

Método: FoirealizadasbuscasnoPubMedeWebofScienceparacoletadedados.Foram incluí-dos todos os estudos noidioma inglês, contendo dados suficientes e completos de casose controlessobrearelac¸ãoentreopolimorfismoC47TdeSOD2ePAIR.Foramidentificadostrês estudos qualificados, abrangendo 1.094 indivíduos.Foramcalculadas as razõesdaschances (oddsratio,OR)acumuladaseintervalosdeconfianc¸a(IC) de95%paraquefosseavaliadaa potênciadaassociac¸ãoentreopolimorfismoC47TdeSOD2ePAIR.

Resultados: Nãofoiencontradaumaassociac¸ãosignificativaentreopolimorfismoC47TdeSOD2 eriscodePAIRcomasseguintescombinac¸ões:Tvs.C(OR=0,83,IC95%=0,63-1,09);TTvs.CC (OR=0,49,IC95%=0,22-1,09);CTvs.CC(OR=0,54,IC95%=0,25-1,17);TTvs.CC+CT(OR= 0,82,IC95%=0,50-1,32);CCvs.TT+TC(OR=0,49,IC95%=0,23-1,04).Contudo,naanálise desubgrupo,foiencontradaumaassociac¸ãosignificativaparaTTvs.CC+CT(OR=0,77,95% CI=0,42-1.41)napopulac¸ãochinesa.

Conclusão:A presente metanálise sugere que o polimorfismo C47T de SOD2 demonstra associac¸ãosignificativacommaiorriscodePAIRnapopulac¸ãochinesa.Hánecessidadedenovos estudosdegrandeportebemconcebidos,paraconfirmac¸ãodessaassociac¸ão.

© 2016Publicadopor ElsevierEditora Ltda.em nomede Associac¸˜ao Brasileira de Otorrino-laringologia eCirurgiaC´ervico-Facial.Este ´eumartigo Open Accesssob umalicenc¸a CCBY (http://creativecommons.org/licenses/by/4.0/).

Introduction

Noise-inducedhearingloss(NIHL),oneofthemostcommon occupational diseases, is a form of sensorineural hearing impairmentcausedbytheinteractionbetween environmen-tal factors (such as prolonged exposure to high levels of noise) and geneticfactors.1 _{According to statistical data,} aboutone-thirdofallcasesofhearinglosscanbeattributed tonoiseexposure,2_{and10%oftheworld’spopulationareat} riskofdevelopingNIHL.3

Currently,littleisknownaboutgenepolymorphismsthat may be involved in the susceptibility toNIHL. Ohlemiller etal.4 _{demonstrated thatnoise can damagethe cochlear} sensorial epitheliumby inducing the localrelease of free radicals.Consequently,genesinvolvedintheregulationof releasingoffreeradicalswereexamined,5_andmanganese superoxidedismutase(SOD2)wasidentified.6

SOD2 is a homotetramer located within the mitochon-drion and is an enzyme involved in the conversion of superoxideradicalstohydrogenperoxide.7_Amongthe poly-morphisms identified in the SOD2gene, C47T is themost widely studied. C47T is located at position 16 in the

mitochondrialtargetingsequenceandresultsinthe replace-ment of an alanine with valine (V16A).8,9 _{C47T has been} studiedinassociationwithseveraldiseases(heartdisease,10 diabetes,11 _{andnonalcoholicfattyliver disease[NAFLD])}12 whichincludeNIHL.13 _{Fortunatoetal.}6 _{previouslyshowed} thatSOD2polymorphismscouldpredisposetoNIHLby exert-ing variable local tissue antioxidant roles, whereas Wang et al.14 _{only showed a weak association between SOD2} polymorphisms and NIHL. The current individual studies providelimitedinformationanddonotproduceaconvincing conclusion.Therefore,inthisstudy,ameta-analysiswitha relativelylargesamplewasconductedinordertogeneratea morereliableconclusionregardingtherelationshipbetween SOD2C47TpolymorphismandNIHL.

Methods

Literaturesearch,selection,anddatacollection

82 WangJetal.

33 articles identified through database searching

16 articles assessed for eligibility

17 duplicated articles excluded

12 articles excluded through title/abstract screening: Not in english (n=5)

Review (n=1) Editorial comment (n=1) Unrelated topic (n=5)

1 article excluded through full text screening: Meeting abstract (n=1)

4 articles assessed for eligibility

3 articles Included In the study

Figure1 Flowchartofstudyinclusion.

terms were used: superoxide dismutase, SOD2, polymor-phism, polymorphisms, variation, variations, genotype, noiseinducedhearingloss,noise-inducedhearingloss,and NIHL.Studiesthatmetthefollowingcriteriawereincluded: (1) full-text, English-written studies; (2) complete case-and-control data about the relationship between SOD2 polymorphism and NIHL; (3) sufficient data to infer the results;and(4)controlgroupgenotypesinHardy---Weinberg Equilibrium(HWE).HWEwastestedbythechi-squaredtest, andwhen ap-valueof morethan 0.05 wasobserved,the controlgroupgenotypeswereconsistentwithHWE.

Inthisstudy,twoinvestigatorsindependentlycollected data from each eligiblearticle. The data comprised first author, year of the publication, origin country, ethnicity, numberofcases,andnumberof controls.Through check-ingbetweenthetwoinvestigators,afinalsetof datawas determined.

Qualityassessment

StudyqualitywasevaluatedbytheNewcastle-Ottawa Qual-ityAssessmentScaleforcase---controlstudies,15_inwhichthe qualityof theselectedtrialswasdeterminedonthebasis ofselectionofthestudygroups(0---4points),comparability ofthestudygroups(0---2points),andascertainmentofthe outcomeofinterest(0---3points).

Dataanalysis

TheassociationbetweenC47TpolymorphisminSOD2gene and NIHL susceptibility was estimated under all genetic models. Five comparison models for C47T polymorphism wereevaluated: an allelemodel(Tvs. C),a co-dominant model(TTvs.CCandCTvs.CC),adominantmodel(TT+CT vs.CC),andarecessivemodel(TTvs.CT+CC).

Forthemeta-analysis,pooledoddsratios(ORs)and95% confidence intervals (CIs) were calculated using a fixed effectsmodelorrandomeffectsmodel.Thechosenmodel was based on the results of a heterogeneity test, which employedapreviouslydescribed,I2_{teststatistics.}16_IfI2_was greaterthan50%,arandomeffectsmodelwasused accord-ingtotheDerSimonianandLairdmethod;otherwise,afixed effects model wasusedaccording tothe Mantel-Haenszel method.

PublicationbiaswastestedusingBegg’sfunnelplotand Egger’s test.17 _{If the funnel plot was asymmetrical and} Egger’s test reported a p-value lower than 0.05, a publi-cationbiaslikelyexisted.

AllofanalyseswereperformedusingStataversion12.0 software(Stata Corporation ---CollegeStation,TX, United States).

Results

Searchresultsandstudycharacteristics

The finalsearch,whichtookplaceonDecember31,2014, resultedintheretrievalof33articles.Themajorityofthe articleswereexcluded duetothe factthatthestudywas aboutanunrelatedtopic,thearticleswerenotinEnglish,or thearticlewasaduplicate,review,orcommentaryarticle, resultinginatotaloffourincluded articles.Aftera study which wasameetingabstractwasomitted,threearticles remained.Thus,threearticleswerefinallyincluded6,14,18_in thismeta-analysis,comprising1094subjects,407ofwhom hadNIHL. Thereview processis depictedinFig.1, which followspreviouslypublishedreportingrecommendations.19 Ofthestudies,twowereconductedinthePeople’sRepublic ofChinaandonewasfromItaly.Allthegenotypefrequencies incontrolpopulationswereinWHEagreement(Table1).

Table1 Characteristicsofincludedstudies.

Author Year Country Ethnicity Samplesize

(case/control)

Case (CC/CT/TT)

Control (CC/CT/TT)

pHWE

Fortunatoetal. 2004 Italy White 61/29 14/33/14 4a/19/6 0.08

Liuetal. 2010 China Chinese 201/202 8/55/138 3/38/161 0.66

Lietal. 2014 China Chinese 145/456 3/36/106 6/120/330 0.18

polymorphism

in

SOD2

with

hearing

loss:

a

meta-analysis

83

Table2 Qualityassessmentofincludedstudies.

Author Selection Comparability Exposure Summary

Isthecase definition adequate?

Representativeness ofthecases

Selection ofcontrols

Definition ofcontrols

Ethnicity Age Ascertainment

ofexposure

Samemethodof ascertainmentfor casesandcontrols

Non-response rate

Fortunatoetal. 4.1.3

Liuetal. 4.2.3

Lietal. 3.2.3

Table3 Subgroupanalysisbasedonethnicityforallgeneticmodels.

Ethnicity No.of studies

Samplesize (case/control)

Tvs.C TTvs.CC CTvs.CC TTvs.CC+CT TT+CTvs.CC

OR(95%CI) p OR(95%CI) p OR(95%CI) p OR(95%CI) p OR(95%CI) p

Chinese 2 346/658 0.82(0.61---1.10) 0.12 0.43(0.17---1.11) 0.48 0.57(0.21---1.54) 0.92 0.77(0.42---1.41)a _0.04b _{0.46(0.18---1.19) 0.58}

White 1 61/29 0.92(0.46---1.85) --- 0.67(0.15---2.89) --- 0.50(0.14---1.73) --- 1.14(0.39---3.36) --- 0.54(0.16---1.81) ---Overall 3 407/687 0.83(0.63---1.09) 0.28 0.49(0.22---1.09) 0.71 0.54(0.25---1.17) 0.98 0.82(0.50---1.32)a _{0.12 0.49(0.23---1.04) 0.85}

OR,oddsratio;CI,confidenceinterval.

p-Valueforheterogeneitytest;Ifp>0.1,ORswerecalculatedusingafixedeffectsmodel,otherwisetherandomeffectsmodelwasused. a _{ORswerecalculatedusingtherandomeffectsmodel.}

84 WangJetal.

Qualityassessmentoftheincludedstudies

TheNOSforassessingthequalityofcase---controlstudieswas showninTable2.Allofthestudieswereidentifiedas rela-tivelyhigh-qualitybecausethetotalscorewashigherthan7.

Overallandsubgroupmeta-analysisresults

O meta-analysis and subgroup meta-analysis were per-formed based on ethnicity. The detailed results of the meta-analysis are shown in Table 3. Regarding overall

Study

A

T vs. C

B

TT vs. CC

C

E

CT vs. CC

D

TT vs. CC+CT

CC vs. TT+TC

%

Weight ID

Study

ID OR (95% CI)

.406 1 2.46

0.92 (0.46, 1.84)

0.63 (0.41, 0.98)

1.02 (0.68, 1.53) 14.58

44.55

40.86

0.83 (0.63, 1.09) 100.00

%

Weight OR (95% CI)

0.67 (0.15, 2.89)

0.32 (0.08, 1.24)

0.64 (0.16, 2.61) 25.73

48.37

25.90

0.49 (0.22, 1.09) 100.00 Fortunato (2004) Liu (2010) Wang (2014) Overall (I-squared=21.8%, P=.279) Study % Weight

ID OR (95% CI)

.135 1 7.4 .298 1 3.36

0.50 (0.14, 1.73)

0.54 (0.14, 2.18)

0.60 (0.14, 2.52) 42.67

32.83

24.50

0.54 (0.25, 1.17) 100.00 Fortunato (2004) Liu (2010) Wang (2014) Overall (I-squared=0.0%, P=.981) Study % Weight

ID OR (95% CI)

0.54 (0.16, 1.81)

0.36 (0.10, 1.39)

0.63 (0.16, 2.56) 38.56

39.17

22.27

0.49 (0.23, 1.04) 100.00 Fortunato (2004)

Liu (2010)

Wang (2014)

.0951 1 10.5

Overall (I-squared=0.0%. P=.845)

Fortunato (2004)

Liu (2010)

Wang (2014)

.0836 1 12

Overall (I-squared=0.0%, P=.709) Study ID % Weight OR (95% CI)

1.14 (0.39, 3.36)

0.56 (0.35, 0.88)

1.04 (0.68, 1.58) 15.32

41.21

43.47

0.82 (0.50, 1.32) 100.00 Fortunato (2004)

Liu (2010)

Wang (2014)

Note: Weights are from random effect analysis

Overall (I-squared=53.6%, P=.116)

Figure2 Forestplotsregardingtheassociationbetweensuperoxidedismutase2(SOD2)C47Tpolymorphismandnoiseinduced hearingloss(NIHL)underallthegeneticmodelsusingfixedeffectsorrandomeffectsmodels.Allelemodel,Tvs.C(A);co-dominant model,TTvs.CC(B);CTvs.CC(C);recessivemodel,TTvs.CC+CT(D);dominantmodel,CCvs.TT+TC(E).CI,confidenceinterval; OR,oddsratio.

Begg’s funnel plot with pseudo 95% confidence limits Begg’s funnel plot with pseudo 95% confidence limits

A

B

1.5

1

.5

OR

0

2

1

0

OR

–1

0 .2

s.e. of: OR

Begg’s funnel plot with pseudo 95% confidence limits

Begg’s funnel plot with pseudo 95% confidence limits

Begg’s funnel plot with pseudo 95% confidence limits

C

CC vs. TT+TC

D

E

TT vs. CC+CT

2

1

0

OR

OR

OR

–1

2

1

0

–1

2

1

0

0 .2 .4 .6 .8

0 .2 .4 .6 .8

0 .2 .4 .6

s.e. of: OR

s.e. of: OR

.4 0 .2

s.e. of: OR

s.e. of: OR

.4 .6 .8

Figure3 Begg’sfunnelplotforthesuperoxidedismutase2(SOD2) C47Tpolymorphismandnoiseinducedhearingloss(NIHL). Allelemodel,Tvs.C(A);co-dominantmodel,TTvs.CC(B);CTvs.CC(C);recessivemodel,TTvs.CC+CT(D);dominantmodel, CCvs.TT+TC(E).logor,oddsratiologarithm;s.e.,standarderror.

Publicationbias

The results ofBegg’s funnel plot(Fig. 3and Table4) and Egger’s test (Table 4) showed nopublication bias for the

allele model (T vs. C, p=1.00), dominant model (CC vs. TT+TC,p=0.952),co-dominantmodel(TTvs.CC,p=0.306; CTvs. CC, p=0.215), or recessive model (TT vs. CC+CT, p=0.832).

Table4 PublicationbiasusingBegg’stestandEgger’stestunderforallgeneticmodels.

Tvs.C TTvs.CC CTvs.CC TTvs.CC+CT TT+CTvs.CC

Begg’stest 1.00 0.296 0.296 1.000 1.000

86 WangJetal.

Discussion

Reactiveoxygenspecies(ROS)playakeyroleinthe underly-ingmechanismsofcochleardamageinductionundervarious pathological conditions. Superoxide, which can form the highlytoxicperoxynitrite,isreadilygeneratedintheinner earfollowingacousticoverstimulation.20_{SODisanenzyme} involvedintheregulationofsuperoxidelevelsbyconverting superoxidetohydrogenperoxide.LocalizationofSOD2inthe cochleahasbeen reportedandabsenceof SOD2hasbeen shown toleadtoincreased hearingloss relatedto acous-tictrauma.14,18,21,22_{Inaddition,auditorydysfunctiondueto} noiseexposureisattenuatedbySOD2application. Further-more,transgenicmiceoverexpressingSOD2wereprotected againstaminoglycoside-inducedhearingloss, whichis also mediatedbyROS.23 _{Todate,severalstudieshaveexplored} therelationshipbetweentheSOD2C47Tpolymorphismand NIHLsusceptibility. Forexamples,Fortunato etal.6 previ-ously showed that SOD2 polymorphisms could predispose toNIHLbyexertingvariablelocaltissueantioxidantroles, whereas Wang et al.14 _{only showed a weak association} betweenSOD2polymorphismsandNIHL.However,the pro-tectiveeffectsofSOD2remaincontroversial.

Thepresentstudyanalyzedthedatafromthreestudies thatincluded a total of 407NIHL cases and687 controls. NosignificantassociationsbetweenC47Tpolymorphismand NIHLwereobservedinallmodels.However,whensubgroup analysis based on ethnicity was performed, a significant association was observed between the SOD2 C47T poly-morphism and NIHL in a recessive model (TT vs. CC+CT, OR=0.77, 95% CI=0.42---1.41) in the Chinese population. There was nosignificant association in any other genetic modelsintheChinesepopulation.Tothebestoftheauthor’s knowledge,thiswasthefirstmeta-analysisinvestigatingthe associationbetweentheSOD2C47TpolymorphismandNIHL susceptibility.

Moreover,fixed-effects or random-effects modelswere usedin the analysis of the studies based on heterogene-itytesting.Two studyexhibits asubstantialheterogeneity for the overall analysis. However, according to subgroup analysisbasedonethnicity,nosignificantheterogeneitywas observed.Therefore,furtherexplorationoftheriskfactors forthisconditionisneeded.

Thepresentstudyhassomelimitations.Forinstance,the samplesizeusedinthismeta-analysiswasinsufficient, espe-ciallyforthesubgroupanalysisbasedonethnicity.Moreover, therewasalack ofcase---controldataadjustment accord-ingtodetailedindividualinformation,suchasage,sex,and lifestyle.The third limitationis thatthe exact molecular basisoftheassociation betweenSOD2C47Tpolymorphism andNIHLriskisstillnotclearatpresentandrequiresfurther investigation.

Conclusion

Despite these limitations, the present meta-analysis sug-gested that SOD2 C47T polymorphism is significantly associatedwithanincreasedriskofNIHLintheChinese pop-ulation.Nevertheless,additional,largerandwell-designed studiesareneededtoconfirmthisassociation.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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