Table Of ContentGeneticsandMolecularBiology,32,1,32-36(2009)
Copyright©2009,SociedadeBrasileiradeGenética.PrintedinBrazil
www.sbg.org.br
ShortCommunication
Polymorphism of the catechol-O-methyltransferase gene
in Han Chinese patients with psoriasis vulgaris
LinGao1*,HongLi1*,KaiLi1*,ZhuShen1,LingLiu1,ChunyingLi1,ZhengdongZhang2andYufengLiu1
1DepartmentofDermatology,XijingHospital,FourthMilitaryMedicalUniversity,Shaanxi,China.
2DepartmentofMolecularGeneticToxicology,NanjingMedicalUniversity,Nanjing,China.
Abstract
Psoriasisvulgarisisdefinedbyaseriesoflinkedcellularchangesintheskin:hyperplasiaofepidermalkeratinocytes,
vascularhyperplasiaandectasia,andinfiltrationofTlymphocytes,neutrophilsandothertypesofleukocytesinthe
affectedskin.Catechol-O-methyltransferase(COMT)158polymorphismcanreducetheactivityoftheCOMTen-
zymethatmaytriggerdefectivedifferentiationofkeratinocytesinpsoriasis.Immunocytescandegradeandinactivate
catecholaminesviamonamineoxidase(MAO)andCOMTinthecells.WehypothesizedthattheCOMT-158G>A
polymorphism was associated with the risk of psoriasis vulgaris in Han Chinese people. In a hospital-based
case-control study, 524 patients with psoriasis vulgaris and 549 psoriasis-free controls were studied.COMT-158
G>ApolymorphismwasgenotypedusingthePCRsequence-specificprimer(PCR-SSP)technique.Wefoundno
statisticallysignificantassociationbetweentheCOMT-158alleleAandtheriskofpsoriasisvulgaris(p=0.739ad-
justedOR=1.03;95%CI=0.81-1.31).ThissuggeststhattheCOMT-158G>Apolymorphismmaynotcontributeto
the etiology of psoriasis vulgaris in the Han Chinese population.
Keywords:COMT,genepolymorphism,geneticsusceptibility,psoriasis.
Received:February21,2008;Accepted:June26,2008.
Psoriasisisacommonskindisordercharacterizedby 1998;BosandDeRie,1999).T-cellsaccumulateearlyin
the focal formation of inflamed, raised plaques that con- psoriaticplaques,andtheircytokinesinduceabnormalke-
stantly shed scales derived from excessive growth of epi- ratinocyteproliferation.Catecholamine(CA)canalsoreg-
thelial cells. The disease is defined by a series of linked ulateimmunefunctions.Asearlyasin1983,Bidartetal.
cellularchangesintheskin:hyperplasiaofepidermalkera- found that human T and B lymphocytes had catechol-
tinocytes,vascularhyperplasiaandectasiaandinfiltration O-methyltransferase (COMT) immunoreactivity. Later,
of T lymphocytes, neutrophils, and other types of leuko- Balsaetal.(1989)reportedthatmonoamineoxideactivity
cytes in the affected skin (Weinstein and Frost, 1968; Si- (MOA) was present in human blood lymphocytes and
monart and Heenen, 2007). The global incidence of the granulocytes.Treatmentoflymphocyteswithpargylinere-
diseaseis1%-3%(FarberandNall,1974).Psoriasisisclin- sultedinanincreaseofintracellularCAsandadecreaseof
icallydividedintotype1(onsetbefore40yearsofage)and intracellular CA metabolites in the lymphocytes (Kara-
type 2 (onset after 40 years of age) (Henseler and Chris- yiorgouetal.,1997;Marinoetal.,1999).CAmetabolites
tophers,1985;Ferrandizetal.,2002). can be detected in immune cells (Yamamoto et al., 1998;
Psoriasis is a T-cell mediated autoimmune process. Cosentino et al., 2000). These results imply that immu-
Activatedlymphocytes,otherimmuneaccessorycellsand nocytesnotonlysynthesizeCAs,butalsodegradeandinac-
lymphokines have been detected in psoriatic plaques tivate CAs via MAO and COMT in the cells. Previous
(DereureandGuilhou,2003;PiruzianandAbdeev,2006). studieshavefoundthatepidermalhomogenatesfromlesio-
Several studies have suggested that T cells play a crucial nal psoriatic skin express higher levels of COMT activity
role in the pathogenesis of psoriasis (Bos et al., 1983; than those from normal skin. This could be due to a high
Schlaaketal.,1994;Boehnckeetal.,1996;Wrone-Smith epidermalcellturnoverortoaninbornerrorintheactivity
andNickoloff,1996;Gilharetal.,1997;Yamamotoetal., oftheenzyme(Bamshadetal.,1970).
Althoughthepathogenesisofpsoriasisisstillunclear,
SendcorrespondencetoYufengLiu.DepartmentofDermatology
many studies suggest that the disease has an exceedingly
ofXijingHospital,FourthMilitaryMedicalUniversity,Xi’an710032
complex genetic basis (Liu et al., 2007). Dimon-Gadal et
Shaanxi, China. E-mail: [email protected].
*These authors contributed equally to this work. al.(2000)foundthatoxidativedamageoccurredbeforethe
Gaoetal. 33
appearance of typical psoriatic plaques, suggesting that MedicalUniversity,betweenAugustandDecember,2005.
suchdamageisindependentofandmaypresentearlierthan Allcasesweresurveyed,butonlyHanChinese(morethan
theinflammatoryinfiltration.Ithasbeenproposedthatoxi- 90% of the Chinese population) patients and control sub-
dativestressofnon-differentiatedkeratinocytestriggersthe jects were included in the analysis, because genotype fre-
formationofadefectivehornylayer(ShilovandSergienko, quenciescanvaryamongethnicgroups.Thepsoriasis-free
2000). controlsubjectswerepersonswhocametothehospitalfor
Catechol-O-methyltransferase(COMT)isanenzyme healthexaminationsanddidnothaveindividualorfamily
that catalyses the O-methylation of biologically active historiesofpsoriasis.Allcasesandcontrolswereexamined
toxiccatecholsandplaysanimportantroleinthemetabo- anddiagnosedbydermatologists.Weusedaquestionnaire
lismofdrugsandneurotransmitters(Tursenetal.,2002).In tocollectdemographicandotherinformation[stage,type,
humans, the COMT protein exists as two length variants, age of onset, psoriasis area and severity index (PASI)
soluble (S-COMT) and membrane-bound (MB-COMT), scores], and matched the controls to the cases by age
which are encoded by a single gene localized at chromo- ((cid:2)10years)andgender.Theresponseratesofpatientsand
some22q11.1-q11.2(Grossmanetal.,1992;Lundstromet controlsapproachedforparticipationwerebothover90%.
al.,1995;Karayiorgouetal.,1997).TheMB-COMTvari- Allsubjectssignedinformedconsentforms,anddo-
anthasanadditional50aminoacidsattheN-terminal,but nated5mLvenousblood,usedforgenomicDNAextrac-
isotherwiseidenticaltoS-COMT(Lundstrometal.,1991). tion. This research protocol was approved by the ethics
Asinglebase-pairchange(G>A)inexon4oftheCOMT reviewboardoftheFourthMilitaryMedicalUniversity.
gene, resulting in an amino acid change (Val > Met) at Venousbloodcollectedfromeachsubjectwasadded
codon158ofMB-COMTandcodon108ofS-COMT,re- totubescontaining50mmolEDTA/L,andgenomicDNA
duces the thermostability and the activity of the enzyme was isolated from 1 mL anti-coagulated peripheral blood
(Lotta et al., 1995; Lachman et al., 1996; Tursen et al., leukocytes using a DNA extraction kit (Taingen Biotech,
2002). The two alleles refer to COMT*H, the site-absent China).AfterDNAextraction,reactionswerecarriedoutin
(G;Val)allelethatencodesthethermostable,high-activity afinalvolumeof20(cid:3)Lcontaining100ngDNA,2.5mM
enzyme,andCOMT*L,thesite-present(A;Met)allelethat MgCl2,1.25unitsofTaqDNApolymerase,1(cid:3)Lofeach
encodesthethermolabile,low-activityenzyme.Theallelic primer, 250 (cid:3)L dNTPs mixture, and 1X PCR buffer. All
variant only affects the enzyme activity (Palmatier et al., PCR reaction reagents were purchased from Fermentas
1999).Acommonsingle-nucleotidepolymorphism(SNP) (Lithuania). Genotyping for the G/A polymorphism was
in codon 158 of the COMT gene (COMT-158 G > A, carried out using polymerase chain reaction with se-
rs4680)codesforasubstitutionofvaline(Val)bymethio- quence-specific primers (PCR-SSP). The following prim-
nine(Met),resultinginthereducedthermostabilityandac- erswereusedtoamplifythetargetfragments:forCOMT-A,
tivityoftheenzyme(Bertoccietal.,1991;Grossmanetal., 5’-TggTggATTTCgCTggCA-3’(forward)and5’-ACACC
1992;Lundstrometal.,1995;Karayiorgouetal.,1997). CATACAAgcaTTCATCAgTT-3’(reverse);forCOMT-G,
Erdaletal.(2004),basedonacase-controlanalysisof 5’-gCATgCACACCTTgTCCTTCAC-3’ (forward) and
aTurkishpopulation,observedthattheCOMT-158G>A 5’-TgAgCATAgAggCTAAgggACCAT-3’ (reverse). The
polymorphismwassignificantlyassociatedwithgenotype PCR conditions were as follows: preheating for 1 min at
COMT AA and psoriasis cases. They speculated that low 96°Ctoachieveahotstart,thenatouch-down(TD)proce-
enzymeactivitycouldbeunabletopreventtheformationof dureconsistingofdenaturationat96°Cfor20sandanneal-
toxic o-quinones in psoriatics, and this oxidative stress of ingat70°Cfor45sduringthefirstfivecycles,followedby
keratinocytescouldtriggerdefectivedifferentiationinpso- 21cyclesof96°Cfor25s,65°Cfor50s,and72°Cfor30s
riasis.NodifferenceshavebeenfoundinCOMTpolymor- each,then21cyclesat96°Cfor30s,55°Cfor60s,and
phism between psoriatics and control subjects, but the 72°Cfor90s,andafinalextensionat20°Cfor2min.
COMT-LL genotype was found significantly increased in The size of the amplified PCR products was 455 bp
thepsoriasispatients(Karayiorgouetal.,1997).COMTis fortheCOMT-158Galleleand322bpfortheCOMT-158A
importantinpreventingtheformationoftoxico-quinones allele. These products were analyzed by 2% agarose gel
during epidermal cell synthesis. Therefore, COMT also electrophoresis and visualized with 0.5 (cid:3)g/mL ethidium
playsanimportantregulatoryroleintheoxidativedamage bromide staining under an ultraviolet illuminator. Geno-
ofkeratinocytes.Immunocytescandegradeandinactivate typeswerescoredbytwoindependentindividuals,andany
CAsviaMAOandCOMTinthecells(Qiuetal.,2005). ambiguousgenotypeswererepeatedoromitted.PCRprod-
Basedonthisconcept,wegenotypedtheCOMT-158 uctswereidentifiedbysequencing.
A > G polymorphism in an ongoing hospital-based case- Chi-squaretestswereusedtoevaluatethedifferences
controlstudyofpsoriasisvulgarisinaHanChinesepopula- in the frequency distributions of selected demographic
tion.Thestudysampleconsistedof524patients,478with variables between the cases and controls, including each
type1and46withtype2psoriasisvulgaris,and549control alleleandgenotypeoftheCOMTpolymorphisms.Uncon-
subjectsrecruitedfromtheXijingHospital,FourthMilitary ditional univariate and multivariate logistic regression
34 COMTpolymorphismandpsoriasisrisk
analyseswereperformedtoobtainthecrudeandadjusted Table1-Frequencydistributionsofselectedvariablesinthepsoriasis
casesandpsoriasis-freecontrols.
odds ratios (ORs) for the risk of psoriasis and their 95%
confidenceintervals(CIs).Themultivariateadjustmentin-
Variables Cases(n=524) Controls(n=549) pa
cludedageandgendervariables.Two-tailedtestsofstatis-
n % n %
tical significance were performed with SAS software
(version8.2;SASInstitute,Inc.,Cary,NorthCarolina). Age(years) 0.232
Wefoundnosignificantdifferencesinageandgender (cid:4) 10 18 3.4 22 4.0
betweenthepsoriasispatientsandthecontrolgroup:mean 11-20 102 19.5 136 24.8
age was 32.1 (cid:2) 13.6 years in the psoriasis group and 21-30 138 26.3 140 25.5
31.5(cid:2)13.9yearsinthecontrolgroup(p=0.232),whilethe 31-40 133 25.4 114 20.8
genderdistributions(M:F)were54.8%:45.2%inthestudy
41-50 83 15.8 79 14.4
group and 50.5%:49.5% in the control group (p = 0.157)
>51 50 9.5 58 10.6
(Table1).
Gender 0.157
ThegenotypeandallelefrequenciesofCOMT158in
Male 287 54.8 277 50.5
the study and control groups are shown in Table 2. In the
controlgroup,thegenotypefrequenciesoftheCOMT158 Female 237 45.2 272 49.5
polymorphism were in agreement with the Hardy- aTwo-sided(cid:5)2testforthefrequencydistributionsofselectedvariablesbe-
Weinberg equilibrium (p = 0.168). No significant differ- tweenthecasesandcontrols.
ences were found between the psoriasis and control sub-
jectsregardingthefrequenciesofgenotypesGG,GA,and thefrequencyofthevariantcombinedgenotype(GA+AA)
AA (p = 0.759) (Table 2). Similarly, there was no signifi- was 45.5% in level 1 and 41.5% in level 2 psoriasis pa-
cantdifferencebetweenthetwogroupsregardingthefre- tients.Therewasnostatisticaldifferencebetweenthetwo
quenciesofalleleA(p=0.624). levelsofpsoriasisandthecontrols.
To consider the single nucleotide polymorphism in Based on previous research, we hypothesized that
codon 158 (G > A) of the COMT gene, which leads to a polymorphism COMT 158 (G > A) might be associated
valine-methioninesubstitutionresultinginthedifferencein with the risk of psoriasis vulgaris. Our study, however,
COMTactivity,weanalyzedtheassociationbetweencom- found no significant association between COMT 158
bined genotypes (GG, GA+AA) and the risk of psoriasis (G>A)andpsoriasisvulgaris,andalsonosignificantdif-
vulgaris.Weinvestigatedwhetherthedistributionsofcom- ferencebetweenCOMT158(G>A)anddifferenttypesof
binedgenotypes(GG,GA+AA)weredifferentamongtype psoriasis vulgaris. Our study included only statistical re-
1andtype2psoriasispatientsandcontrolsubjects.How- search, not functional investigation of the association be-
ever,asshowninTable3,thefrequencyofthevariantcom- tweentheCOMTpolymorphismandpsoriasisvulgaris,so
binedgenotype(GA+AA)wasnotstatisticallydifferentin this hypothesis needs to be tested by further functional
the type 1 psoriasis (43.5%) and type 2 psoriasis (47.8%) studies.
casescomparedtocontrols(43.0%). Inconclusion,wefoundnosignificantdifferencere-
The Psoriasis Area and Severity Index (PASI) is a garding the COMT-158 (G > A) polymorphism between
widelyusedmethodtocharacterizetheseverityofthedis- psoriasis vulgaris patients and control subjects in a Han
ease(deRieetal.,2004).Inourstudy,PASIwasusedto Chinese population. The difference between these results
classifythepsoriaticpatientsintotwodifferentlevels:level andthoseofErdaletal.(2004)maybeduetodifferencesin
1=PASI(cid:4)20;level2=PASI>20.AsshowninTable3, theethniccompositionofthepopulationsandinthenum-
Table2-GenotypeandallelefrequenciesofpolymorphismCOMTandassociationswithpsoriasisrisk.
Genotype Cases(N=524) Controls(N=549)a pb CrudeOR AdjustedOR
(95%CI) (95%CI)c
N % N %
GG 294 56.1 313 57.0 1.00 1.00
GA 201 38.4 211 38.4 0.759 1.02(0.79-1.31) 1.00(0.78-1.29)
AA 29 5.5 25 4.6 1.24(0.71-2.16) 1.23(0.70-2.15)
GA+AA 230 43.9 236 43.0 0.765 1.04(0.82-1.33) 1.02(0.80-1.31)
Aallele 0.247 0.237 0.624
aThegenotypefrequenciesobservedinthecontrolsubjectswereinagreementwiththeHardy-Weinbergequilibrium((cid:5)2=1.900,p=0.168).
bTwo-tailed(cid:5)2testforeithergenotypedistributionsorallelefrequenciesbetweenthecasesandcontrols.
cOddsratios(ORs)wereobtainedfromalogisticregressionmodelwithadjustmentforageandgender;95%confidenceinterval(CI).
Gaoetal. 35
Table3-AssociationandstratificationanalysesofthecombinedgenotypesofpolymorphismCOMTandriskofpsoriasis.
Variables N Combinedgenotypes(case/controla) CrudeOR AdjustedOR pc
(case/control) (95%CI) (95%CI)b
GG GA+AA
n % n %
Total 524/549 294/313 56.1/57.0 230/236 43.9/43.0 1.04(0.82-1.33) 1.02(0.80-1.31) 0.765
Onsetage
(cid:4)40 478/549 270/313 56.5/53.7 208/236 43.5/43.0 1.02(0.80-1.31) 1.03(0.80-1.32) 0.865
>40 46/549 24/313 52.2/57.0 22/236 47.8/43.0 1.22(0.67-2.22) 0.81(0.40-1.63) 0.525
PASI
(cid:4)20 317/549 173/294 54.6/53.7 144/254 45.5/46.4 1.11(0.84-1.47) 1.09(0.82-1.44) 0.468
>20 209/549 122/313 58.4/57.0 87/236 41.5/46.4 0.95(0.69-1.31) 0.94(0.68-1.30) 0.735
aTheobservedgenotypefrequenciesofthecontrolswereinagreementwiththeHardy-Weinbergequilibrium((cid:5)2=1.900,p=0.168).
bOddsratios(ORs)wereobtainedfromalogisticregressionmodelwithadjustmentforageandgender;95%confidenceinterval(CI).
cTwo-tailed(cid:5)2testforeithergenotypedistributionsorallelefrequenciesbetweencasesandcontrols.
berofinvestigatedsubjects.Ourfindingssuggestthatpoly- deRieMA,GoedkoopAYandBosJD(2004)Overviewofpsori-
morphismCOMT158maynotbeassociatedwiththerisk asis.DermatolTher17:341-349.
ofpsoriasisvulgaris.Largerpopulation-basedstudies,dif- DereureOandGuilhouJJ(2003)Epidemiologyandgeneticsof
psoriasis.AnnDermatolVenereol130:829-836.
ferentclinicalsubgroupsandstudiesamongdifferenteth-
Dimon-GadalS,GerbaudP,TherondP,GuibourdencheJ,Ander-
nicgroupsareneededtoconfirmthesefindings.
son WB, Evain-Brion D and Raynaud F (2000) Increased
oxidativedamagetofibroblastsinskinwithandwithoutle-
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