www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
REVIEW
ARTICLE
Polymorphisms
in
chronic
rhinosinusitis
with
nasal
polyps
---
a
systematic
review
夽
Vanessa
Ramos
Pires
Dinarte
a,
Anemari
Ramos
Dinarte
dos
Santos
b,
Luiza
Ferreira
de
Araújo
c,
Mariah
Guieiro
Alves
dos
Reis
d,∗,
Edwin
Tamashiro
e,
Fabiana
Cardoso
Pereira
Valera
e,
Wilson
Araújo
da
Silva
Júnior
b,f,g,h,
Wilma
Terezinha
Anselmo-Lima
eaEscoladeMedicinadeMarília,DepartamentodeOtorrinolaringologia,DivisãodeOtorrinolaringologia,Marília,SP,Brazil bHemocentrodeRibeirãoPreto,CentroRegionaldeHemoterapia,LaboratóriodeGenéticaMoleculareBioinformática(LGMB),
RibeirãoPreto,SP,Brazil
cUniversidadedeSãoPaulo(USP),FaculdadedeMedicinadeRibeirãoPreto,DepartamentodeGenética,RibeirãoPreto,SP,Brazil dEscoladeMedicinadeMarília,DepartamentodeOtorrinolaringologia,Marília,SP,Brazil
eUniversidadedeSãoPaulo(USP),FaculdadedeMedicinadeRibeirãoPreto,DepartamentodeOftalmologia,
OtorrinolaringologiaeCirurgiadeCabec¸aePescoc¸o,RibeirãoPreto,SP,Brazil
fCentrosdePesquisa,Inovac¸ãoeDifusão/Fundac¸ãodeAmparoàPesquisadoEstadodeSãoPaulo(Cepid/Fapesp),Centrode
TerapiaCelular,DepartamentodeGenética,SãoPaulo,SP,Brazil
gHospitaldasClínicas,UniversidadedeSãoPaulo(HCFMRP/USP),FaculdadedeMedicinadeRibeirãoPreto,CenterforMedical
Genomics,RibeirãoPreto,SP,Brazil
hUniversidadedeSãoPaulo(USP),ListadosNúcleosdeApoioàPesquisa(NAPs),CenterforIntegrativeSystemsBiology(CISBi),
SãoPaulo,SP,Brazil
Received27September2016;accepted1March2017 Availableonline23March2017
KEYWORDS
Polymorphism; Rhinosinusitis; Polyps
Abstract
Introduction:Chronicrhinosinusitiswithnasalpolypsisamultifactorialdiseasewithacomplex pathophysiologyinvolvingmultiplegeneticandenvironmentalfactors.
Objective: Thepurpose ofthiswork reviewis tofocuson theimportance ofgenetic stud-iesinchronicrhinosinusitis withnasal polypsbesidestheseveralbarriersthatexists for its understanding.
Methods:A systematicreviewonstudies ofassociationbetween singlenucleotide polymor-phismsandchronicrhinosinusitiswithnasalpolypsbasedonaPubMed/MedlineandPeriódicos
夽 Pleasecitethisarticleas:DinarteVR,SantosAR,AraújoLF,ReisMG,TamashiroE,ValeraFC,etal.Polymorphismsinchronicrhinosinusitis
withnasalpolyps---asystematicreview.BrazJOtorhinolaryngol.2017;83:705---11.
∗Correspondingauthor.
E-mail:reismariahh@gmail.com(M.G.Reis).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.
http://dx.doi.org/10.1016/j.bjorl.2017.03.002
CAPESsearchofallarticlespublishedbetweenJanuary2005andJanuary2015wasmade.The searchwasguidedonstudiescontainingthetermspolymorphisms,rhinosinusitis,andpolyps.
Results:Two studiesfound anassociation ofMMP-9 and MMP-2 polymorphisms andchronic rhinosinusitiswithnasalpolyps,butnotinpatientswithrecurrentnasalpolyps.Otherstudies foundanassociationofnasalpolypswithMMP-9polymorphisms,butnotwithMMP-2ones.There isevidenceofanassociationofLTC4S,NOS2A,PTGDR,MET,COX-2,OSF-2,andLFpolymorphisms andtheriskofdevelopingnasalpolyps,especiallywhencombinedwithchronicallergicrhinitis andasthma.
Conclusion:Geneticstudiesonchronicrhinosinusitiswithnasalpolypsarepromisingandmay offerinsightsintoitspathophysiology,whichislikelyaffectedbymultiplegeneticfactors. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE
Polimorfismo; Rinossinusite; Pólipos
Polimorfismosnarinossinusitecrônicacompóliposnasais---umarevisãosistemática
Resumo
Introduc¸ão:A rinossinusitecrônicacompóliposnasaisé umadoenc¸a multifatorialcomuma fisiopatologiacomplexaenvolvendomúltiplosfatoresgenéticoseambientais.
Objetivo:Oobjetivodestetrabalhoéenfatizaraimportânciadosestudosgenéticosna rinossi-nusitecrônicacompóliposnasais,alémdasdiversasbarreirasexistentesparasuacompreensão.
Método: Realizou-seumarevisãosistemáticadeestudosdeassociac¸ãoentrepolimorfismosde nucleotídeo únicoerinossinusite crônicacompólipos nasais combase em umabusca feita nosbancosdedadosPubMed/MedlineePeriódicosCAPESdetodososartigospublicadosentre janeirode 2005 e janeirode 2015. A busca foi direcionadaà estudos contendo os termos polimorfismos,rinossinusiteepólipos.
Resultados: Doisestudosencontraramumaassociac¸ãoentreospolimorfismosMMP-9eMMP-2 erinossinusitecrônicacompólipos nasais,masnão em pacientescompólipos nasais recor-rentes.Outrosestudosencontraramumaassociac¸ãodepóliposnasaiscompolimorfismosMMP-9, masnãocomMMP-2.Existemevidênciasdeumaassociac¸ãodospolimorfismosLTC4S,NOS2A, PTGDR,MET,COX-2,OSF-2eLFeoriscodedesenvolverpóliposnasais,especialmentequando combinadoscomrinitealérgicacrônicaeasma.
Conclusão:Estudosgenéticossobre rinossinusitecrônicacompólipos nasaissãopromissores epodem oferecer conhecimentosobresua fisiopatologia,que éprovavelmenteafetadapor múltiplosfatoresgenéticos.
© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http://
creativecommons.org/licenses/by/4.0/).
Introduction
ThelastEuropeanPositionPaperonRhinosinusitisandNasal Polyps(EPOS2012)definedchronic rhinosinusitisas inflam-mationofthenoseandtheparanasalsinuses≥12weeksthat is characterizedby two or more symptoms,one of which shouldbeeither nasalblockage/congestion/obstructionor nasal discharge (anterior/posterior nasal drip) associated with facial pain/pressure or reduction/loss of smell. In children, cough should be included as a symptom. Addi-tionalsymptoms include endoscopic signs of Nasal Polyps (NP),and/ormucopurulentdischargeprimarilyfrommiddle meatus,and/oredema/mucosalobstructioninmiddle mea-tus. Computed Tomography (CT) changes includemucosal changeswithintheostiomeatalcomplexandorsinuses.1
According to a study performed within the Global AllergyandAsthmaEuropeanNetwork(GA2LEN),theoverall
prevalence of Chronic Rhinosinusitis (CRS) in Europe was 10.9%.2InSãoPaulo,Brazil,Pilanetal.(2012)founda preva-lence of 5.51%.3 Additionally, it was estimated that CRS affects 13%of the totalpopulation in the UnitedStates.4 These figures arewithin the estimated global prevalence of the condition, which affects 5%---15% of the general population.1
The socioeconomic burden of CRS is substantial and includesnotonlymedicalcosts(doctor’svisits,exams, med-ication),butalsocoststothesocietyandeconomy,including highmorbidity,workabsenteeism,andpooracademic per-formance(Fig.1).
Database search (2005–2015): 30 studies
identified
Inclusion and exclusion
criteria 24 studies excluded
6 studies selected
Figure1 Databasesearchandselectionofstudies.
Someguidelineshavealsoadvisedfurthercategorization of patient groups with CRSwNP into allergic fungal rhi-nosinusitis,Aspirin-ExacerbatedRespiratoryDisease(AERD), and/orCysticFibrosis(CF).6Infact,furthercategorization or subanalysis of cases into subphenotypes or endotypes couldhelpidentifythedifferentpathophysiological mecha-nismsofCRSandimprovetreatment.
CRSwNP is a complex, multifactorial disease that involves multiple genetic, immunological, environmental, and mucosal factors, but its etiology remains unclear. Many potential contributing factors have been identified, including allergic responses, impaired mucociliary clear-ance, immune dysfunction, impaired epithelial defense, microbes,andenvironmentalexposure.7Nevertheless, fur-ther research is needed todetermine therole of genetic factorsandtheirinteractionwiththesecontributingfactors inthepathophysiologyofCRSwNP.
The lack of suitable animal models, the difficulty in standardizingphenotypes,theneed forlargecase---control cohorts,andthehighcostsandsparsereplicationofstudies arethemainhurdlestoelucidatingthepathophysiologyof CRSwNP.
There isstrong evidencefor theimplicationof genetic factorsinthepathophysiologyofCRSwNP.TheCysticFibrosis TransmembraneConductanceRegulator(CFTR)gene,whose mutationsresultinCysticFibrosis(CF),hasbeen themost replicatedgeneassociatedwithCRS.Thereisahigh preva-lence of CRSwNP in CF carriers, but some studies have
suggestedthat CTFRmutations alsooccurin CRS patients withoutCF.8
Family studies indicate the existence of a hereditary factor in the pathogenesis of CRSwNP, but environmental factorsalsoplayasignificantroleintheoccurrenceofnasal polyps. For instance, studies of identical twins have not shownthatbothsiblingsalwaysdeveloppolyps.1
Methods
WeconductedaPubMed/MedlineandPeriodicCAPESsearch ofallEnglish-language articlespublishedbetweenJanuary 2005 and January 2015 with the search terms poly-morphisms, rhinosinusitis, and polyps. Studies that only evaluatedpatientswithaspirin-exacerbatedrespiratory dis-ease,cysticfibrosis,Epstein---Barrvirus,asthmaandstudies thatgroupedtogetherCRSpatientswithandwithoutnasal polypswereexcluded.Studiesthatonlyevaluatedpatients withCRSwNPwereincluded.
Ofthe30studiesidentified,sixcase---controlstudiesmet theinclusionandexclusioncriteriaandwereincludedinthis review.
Results
Inastudy conductedin Taiwan, Wangetal.(2008) inves-tigatedthe roleof 17 MatrixMetalloproteinase-2 (MMP-2) Single Nucleotide Polymorphisms (SNPs) in the develop-mentofCRSwNPusingthreemodelsofgeneticinheritance. Matrix Metalloproteinases (MMPs) are a family of zinc-and calcium-dependent endopeptidases that are impor-tant in upper airway remodeling. MMP-2 cleaves type IV collagen,themajorstructurecomponentofbasement mem-branes. The authors recruited 136 patients with CRSwNP and136 control subjects withchronic hypertrophic rhini-tis who underwent turbinectomy (Table 1). Of the 17 polymorphisms investigated, only rs857403 was associ-atedwithCRSwNP (p=0.03). However,the resultbecame non-significant after includingan additional 691 controls, indicatingthat the initialsignificance wasafalse-positive finding. The study also grouped the 17 SNPs into four haplotypeblocks,buthaplotypeanalysisdidnotyield sig-nificantresultsforanyblock(Table2).Thus,the17MMP-2 polymorphismswerenotsignificantlyassociatedwithnasal polyps.9
Inanothercase---controlstudy,Wangetal.(2010) inves-tigatedtheassociationbetweenMPP-9genepolymorphisms andthepresenceofnasalpolypsinpatientswithCRSwNP. In total, 203 patients with CRSwNP and 730 controls recruitedfromthe generalpopulationwereenrolled.One
Table1 BaselinecharacteristicsofstudysubjectsinastudythatinvestigatedtherelationshipbetweenMMP-2gene polymor-phismsandtheriskofnasalpolyps(NP).
N RecurrentNP Non-recurrentNP Meanageyears Men/women
Cases 136 26 110 42.5 96/40
Controls 136 --- --- 34.9 108/28
MMP,matrixmetalloproteinase.
Table2 Haplotypeanalysisofthefour haplotypeblocks formedby17MMP-2polymorphisms.
Block1 Block2 Block3 Block4
p-Value 0.26 0.58 0.44 0.53
MMP,matrixmetalloproteinase.
Source:AdaptedfromWangetal.(2008).9
functional promoter SNP (rs3918242) and three linked SNPs(rs2274756,rs3787268,andrs2664538)wereselected and genetic effects were evaluated using three models of inheritance. The results showed that three SNPs were associatedwiththedevelopmentofnasalpolyps.TheMPP-9 promoter SNP (rs3918242, i.e., −1562 C/T) yielded the mostsignificantresult(Table3).However,noneofthefour SNPs were associated with CRSwNP in recurrent patients (p=ns).Haplotypeanalysis,includingthefourSNPs,showed a positive association for haplotype TGGA (p=0.00045). Thus, the authors concluded that MPP-9 polymorphisms mayincrease therisk ofdeveloping CRSwNP,but maynot beassociatedwithitsreccurrence.10
In a more recent study, Wang et al. (2013) eval-uated the expression of MMP-2 and MMP-9 promoter polymorphismsbyimmunohistochemistry andtheir associ-ation with CRSwNP (Table 4). The hypothesis that MMPs are involved with NP formation is based on the role of MMPs in asthma and on the fact that asthma and nasal polypsshare similar presentationand histopathology find-ings. The authors recruited 30 patients with bilateral CRSwNP and no NP recurrence at 6 month follow-up and 32 patients who underwent revision surgery for NP. The controlgroup consisted of 31 patients with chronic rhini-tis and septum deviation. Two functional promoter SNPs were selected, one in the MMP-9 gene (rs3918242, i.e., −1562 C/T) and the other in the MMP-2gene (rs243865, i.e.,−1306 A/G). Even though MMP-9 andMMP-2 expres-sionwassignificantlyhigherinpatientswithrecurrentand non-recurrent NP than in controls, no significant differ-enceswereobservedbetweenrecurrentandnon-recurrent patients.The authorsconcluded that thepathogenesis of recurrentnasalpolypsmayinvolvemechanismsotherthan MMPs.11
BenitoPescadoretal.(2012)conductedacase---control study in Spain with241 patients with CRSwNP (with and without asthma) and 245 controls to determine whether polymorphisms in genes implicated in inflammatory
pathways (Leukotriene C4 Synthase [LTC4S], Cysteinyl Leukotriene Receptor 1 [CYSLTR1], Prostaglandin D2 Receptor [PTGDR], and Nitric Oxide Synthase[NOS2]) are associatedwithNP.Theauthorsfoundnosignificant associa-tionbetweensimpleNPandtheSNPsevaluated.However,a significantassociationwasobservedbetweenNPandspecific phenotypes(atopy,asthma,NonsteroidalAnti-Inflammatory Drug intolerance [NSAIDi],and aspirin triad). Specifically, significant associationswerefoundin the−444A>CLTC4S polymorphism in patients with NP and atopy (p=0.033) andNPandatopicasthma(p=0.012);andwhentheCCTTT nucleotide repeat in the NOS2A gene was present >14× in patientswithNPandasthma (p=0.034), NPandNSAIDi (p=0.009),andtheaspirintriad(p=0.005).Additionally,the PTGDRdiplotype(CCCT/CCC)wasmorefrequentinpatients withNP(p=0.043),NPandasthma(p=0.013),andwiththe aspirin triad (p=0.041) (Table 5). The authors concluded that nasal polyposis was associated with specific poly-morphisms only when combinedwith the aforementioned phenotypes.12
TheassociationofNPwithallergyandasthma wasalso evaluatedinaPolishpopulationbySitareketal.(2012).13 The study investigated the association of the −765 G/C polymorphism ofcyclooxygenase-2(COX-2) gene(rs20417) andthe−14C/Gpolymorphismoftransmembranetyrosine kinase receptor (MET) gene (rs78116323) with the risk to develop CRSwNP. The authors recruited195 patients with NP, 63 of whom had chronic allergic rhinitis and 65 had asthma,and200controlswithhearinglosscomplaintsand nonasalpathologies.Theauthorsfoundastrongassociation betweenthepolymorphismsevaluatedandanincreasedrisk ofdevelopingNPinthePolishpopulation,eveninpatients without asthma or allergy(Table6).Inaddition,a signifi-cantassociationwasalsoobservedforthe−765G/CCOX-2 polymorphisminpatientswithasthmaorallergy(Table6). The authorsconcludedthatCOX-2andMETgene polymor-phisms may play a significant role in the development of CRSwNP,whichmayalsodependonthepresenceofasthma orallergy.13
ThesamePolishresearchgroupalsoevaluatedthe asso-ciationofthe−33C/GpolymorphismofOsteoblastSpecific Factor-2 (OSF-2) gene and the 140 A/G polymorphism of Lactoferrin(LF)genewithNPinthesamepatientcohortas inSitareketal.(2012).13Theauthorsreportedthatthe140 A/GLF,and−33C/Gand−33G/GOSF-2genotypes,were associated withan increasedrisk of developing NP in the studypopulation.Inaddition,theassociationofthe−33G/G homozygoteandthe140A/Gheterozygotewithanincreased
Table3 MMP-9polymorphisms,underthreegeneticmodels,andtheirrelationshipswithnasalpolyposis.
p-Value
SNP(singlenucleotidepolymorphisms) Dominant Additive Recessive
rs2664538(exon6) 0.64 0.752 0.073
rs3787268 0.503 0.345 0.361
rs2274756(exon12) 0.034 0.02 0.134
rs3918242 0.023 0.012 0.097
MMP,Matrixmetalloproteinase.
Table4 ExpressionofMMP-9andMMP-2polymorphismsbyimmunohistochemistryinchronicrhinosinusitiswithnasalpolyps (CRSwNP)patientswithrecurrentandnon-recurrentNP.
RecurrentNP Non-recurrentNP Controls
ElevatedMMP-9(MMPpolymorphism)expression Yes Yes No
ElevatedMMP-2(MMP-2polymorphism)expression Yes No No
NP,nasalpolyps;MMP,matrixmetalloproteinase. Source:AdaptedfromWangetal.(2013).11
Table5 Associationbetween LTC4S,NOS2A,andPTGDRgenepolymorphismsandnasalpolyps(NP),NP andatopy,NP and asthma,aspirintriad,andnonsteroidalanti-inflammatorydrugintolerance(NSAIDi).
NP NP+atopy NP+asthma Aspirintriad NSAIDi
−444A>CLTC4S +(p=0.033) +(p=0.012)
NOS2AVNTR:CCTTT(>14×) +(p=0.034) +(p=0.005) +(p=0.009)
PTGDRCCCT/CCCC +(p=0.043) +(p=0.013) +(p=0.041)
LTC4S,leukotrieneC4synthase;NOS2A,nitricoxidesynthase;VNTR,variablenumbertandemrepeat;PTGDR,prostaglandinD2receptor. Source:AdaptedfromBenitoPescadoretal.(2012).12
Table6 Oddsratio(OR)and95%confidenceintervals(CI)fortheassociationbetweenCOX-2andMETgenepolymorphismsand nasalpolyps(NP)phenotypeswithandwithoutallergyorasthma.
−765G/CCOX-2 −14C/GMET
OR(95%CI) p-Value OR(95%CI) p-Value
NP(nasalpolyps) 7.79(4.88---12.4) <0.001 2.83(1.74---4.61) <0.001
Allergy 5.64(2.91---10.9) <0.001
Asthma 4.74(2.49---9.03) <0.001
Withoutallergy 7.25(4.38---12.1) <0.001 2.47(1.46---4.17) <0.001
Withoutasthma 7.61(4.47---12.6) <0.001 2.59(1.54---4.37) <0.001
COX-2,cyclooxygenase-2;MET,tyrosinekinasereceptor. Source:AdaptedfromSitareketal.(2012).13
Table7 Oddsratio(OR)and95%confidenceintervals(CI)fortheassociationsbetweenOSF-2(−33C/Gand−33G/G)andLF
polymorphismsandNPphenotypeswithandwithoutallergyorasthma.
−33C/GOSF-2 −33G/GOSF-2 140A/GLF
OR(95%CI) p-Value OR(95%CI) p-Value OR(95%CI) p-Value
NP 3.48
(2.19---5.52)
<0.001 16.45
(6.71---40.3)
<0.001 4.78
(3.07---7.24)
<0.001
Allergy 2.4
(1.23---4.69)
0.014 16.01
(5.77---44.41)
<0.001 3.22
(1.74---6.11)
<0.001
Asthma 2.4
(1.23---4.69)
0.014 17.9
(6.53---49.05)
<0.001 3.25
(1.75---6.04)
<0.001
Withoutallergy 3.72
(2.24---6.19)
<0.001 3.73
(2.24---6.19)
<0.001 3.89
(2.4---6.31)
<0.001
Withoutasthma 15.11
(5.91---38.6)
<0.001 14.07
(5.47---36.16)
<0.001 3.62
(2.45---5.34)
<0.001
riskof NPwasstrongerin patientswithallergyor asthma thanin patientswithout theseconditions (Table7).Thus, theLFandOSF-2genepolymorphismswereassociatedwith anincreasedriskofdevelopingNPandtheassociationmay alsodependonthepresenceofasthmaandchronicallergic rhinitis.14
Discussion
Mostgeneticstudies of CRSwNP have focused onthe role ofinnateimmunityinthepathophysiologyofCRS.1Mostof thesestudies are candidategene studies, which compare theallelefrequencies of SingleNucleotidePolymorphisms (SNPs) within genes that are suspected a priori of being involvedwiththediseaseamongpatientswithCRSand con-trols.However,associationstudiesusuallyhaveinadequate power, mostly due to highly heterogeneousstudy groups, andlimitedabilitytogeneratenovelinformation,once can-didategenesareselectedbasedonwhatissuspectedabout thedisease.7Conversely,Genome-WideAssociationStudies (GWAS) use a hypothesis-independent approach to exam-ine a number of polymorphisms across the entire human genome. However, GWAS of CRS are still lacking due to the high costs and large patient cohorts required.6 DNA pool-basedGWAS(pGWAS)thatreplaceindividualDNA geno-typingbypooledgenomicDNAareanalternativetoreduce costs.1
Intheir 2008study,Wangetal.failedtofindevidence for aroleof MMP-2genepolymorphisms inthe riskof NP inasmallpatientcohort.In2010,thesameresearchgroup showedthatMMP-9genepolymorphismsaffected the sus-ceptibilityofdevelopingNPinaChinesepopulation.Inthat study,thesample size wasmoderately adequate,but the three-monthfollow-upforNPrecurrencewasshort.Another limitationisthatcontrolsdidnotreceivefullnasal exami-nationtoruleoutNP.
InastudyevaluatingtheexpressionofMMP-2and MMP-9 in recurrent NP, Wang et al. (2013) showed that even thoughMMP-9andMMP-2expressionwassignificantlyhigher inpatientswithrecurrentandnon-recurrentNPthanin con-trols,nosignificantdifferenceswereobservedbetweenthe twoNP presentations. The authors suggested that mech-anismsother than MMPs maybe involved inrecurrent NP. Themainlimitationofthatstudywasthesmallsamplesize (patientsandcontrols), which couldnotexcludea typeII error.Thesix-monthfollow-upwasanothershortcomingof thatstudy,becauseNPmayrecurseveralyearsaftersurgery. Lastly,theauthorsrecognizedthatusingcontrolswithnasal pathologies(patientswithchronicrhinitisandseptum devi-ationwhounderwentrevisionsurgery)wasinadequate.
ThestudyconductedbyBenitoPescadoretal.(2012)in SpainexaminedpolymorphismswithintheLTC4S,CYSLTR1, PTGDR,andNOS2AgenesandtheirassociationwithNP.The authorsconcludedthatspecific polymorphismswere asso-ciated withthe development of NP when combined with allergyandasthmaphenotypes.
Theassociation ofNP,allergy,andasthma withspecific genepolymorphismswasalsoinvestigatedbySitareketal. (2012)in a Polishpopulation. The authorsfound that the −14 C/G MET and −765 G/C COX-2 polymorphisms are
associated withan increasedrisk of developing NP, which mayalsodependonthepresenceofallergyandasthma.
ThesamePolishresearchgroup14 foundapositive asso-ciation between the −33 C/G OSF-2 and 140 A/G LF polymorphismsandNP, andtheassociation wasalsolikely dependentonthepresenceofallergyandasthma.
Geneticstudiesarepromisingandmayofferinsightsinto the pathophysiology of CRS, but several factors may be responsiblefor theassociationsandshouldbeconsidered. Phenotyping of patients andcontrols must beaccurateto avoid comparisons of heterogeneous groups. Sample sizes mustbelargeenoughtoreducethepossibilitythatrandom associations are found between SNPs and CRS. Moreover, environmental factors that interact withthe genome and helptriggerdiseaseshouldalsobeinvestigated.15The iden-tified SNPmay not directly cause disease, but may be in linkagedisequilibrium(LD)withtheactual causalvariant. Alternatively, the associated SNP may be an expression quantitativetraitlocus(eQTL)affectingthetranscriptionof anothergeneinvolvedinthedisease.7Thus,thereplication ofstudiesreducesthepossibilityofrandomassociations.
Todate,CFTRhasbeenthemostreplicatedgene associ-atedwithCRS,butSNPsinIL1A,TNF(tumornecrosisfactor), and AOAH (acyloxyacyl hydrolase) genes have also been replicated. Several other polymorphisms associated with CRS have been published, but have notbeen replicated,1 including Human Leukocyte Antigen (HLA) alleles, espe-ciallyHLA-DRB1*04,genesofinnateimmunity(e.g.,IRAK4, nitric oxide synthase --- NOS, MET proto-oncogene, SER-PINA1),inflammatorymediators(e.g.,IL13,IL33,IL22RA1), andgenesinvolvedinarachidonicacidmetabolismand tis-sueremodeling(metalloproteinaseMMP9,TGFB1).7
Conclusion
Genetic studies of CRSwNP are promising and may offer insights into the pathophysiology of the disease,which is likely affected by multiple genetic factors. Nevertheless, thereareseveral barrierstounderstanding the pathophy-siologyofCRSwNP,includingthevariabilityinphenotyping, lackofcohortstudies,limitedresearchfunding,andlackof aclearunderstandingofhowgeneticandepigeneticchanges maytriggerthedisease.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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