Mesko e al. BMC Medical Genomics 2010, 3:15
h p://www.biomedcen al.com/1755-8794/3/15
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RESEARCH ARTICLE
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Resea ch a icle
Pe iphe al blood gene exp ession pa e ns
disc imina e among ch onic in lamma o y diseases
and heal hy con ols and iden i y no el a ge s
Be alan Mesko
†1
, Szila d Poliska1
†1,4
, And ea Szegedi
3
, Zol an Szekanecz
5
, Ka oly Pala ka
6
, Ma ia Papp
6
and
Laszlo Nagy*
1,2,4
Abs ac
Backg ound: Ch onic in lamma o y diseases including in lamma o y bowel disease (IBD; C ohn's disease and
ulce a i e coli is), pso iasis and heuma oid a h i is (RA) a lic millions o people wo ldwide, bu hei pa hogenesis is
s ill no well unde s ood.
I is also no well known i dis inc changes in gene exp ession cha ac e ize hese diseases and i hese pa e ns can
disc imina e be ween diseased and con ol pa ien s and/o s a i y he disease. The main ocus o ou wo k was he
iden i ica ion o no el ma ke s ha o e lap among he 3 diseases o disc imina e hem om each o he .
Me hods: Diseased (n = 13, n = 15 and n = 12 in IBD, pso iasis and RA espec i ely) and heal hy pa ien s (n = 18) we e
ec ui ed based on s ic inclusion and exclusion c i e ia; pe iphe al blood samples we e collec ed by clinicians (30 ml)
in Venous Blood Vacuum Collec ion Tubes con aining EDTA and pe iphe al blood mononuclea cells we e sepa a ed by
Ficoll g adien cen i uga ion. RNA was ex ac ed using T izol eagen . Gene exp ession da a was ob ained using
TaqMan Low Densi y A ay (TLDA) con aining 96 genes ha we e selec ed by an algo i hm and he s a is ical analyses
we e pe o med in P ism by using non-pa ame ic Mann-Whi ney U es (P- alues < 0.05).
Resul s: He e we show ha using a panel o 96 disease associa ed genes and measu ing mRNA exp ession le els in
pe iphe al blood de i ed mononuclea cells; we could iden i y disease-speci ic gene panels ha sepa a e each disease
om heal hy con ols. In addi ion, a panel o i e genes such as ADM, AQP9, CXCL2, IL10 and NAMPT disc imina es
be ween all samples om pa ien s wi h ch onic in lamma ion and heal hy con ols. We also ound genes ha s a i y
he diseases and sepa a e di e en sub ypes o di e en s a es o p ognosis in each condi ion.
Conclusions: These indings and he iden i ica ion o i e uni e sal ma ke s o ch onic in lamma ion sugges ha
hese diseases ha e a common backg ound in pa homechanism, bu s ill can be sepa a ed by pe iphe al blood gene
exp ession. Impo an ly, he iden i ied genes can be associa ed wi h o e lapping biological p ocesses including
changed in lamma o y esponse. Gene panels based on such ma ke s can play a majo ole in he de elopmen o
pe sonalized medicine, in moni o ing disease p og ession and can lead o he iden i ica ion o new po en ial d ug
a ge s in ch onic in lamma ion.
Backg ound
Ch onic in lamma o y diseases such as in lamma o y
bowel disease (IBD; including C ohn's disease - CD and
ulce a i e coli is - UC), pso iasis and heuma oid a h i is
(RA) exis as a subs an ial bu den in social and economic
e ms wo ldwide. Despi e he impo ance o hese dis-
eases, i is s ill no clea i cha ac e is ic gene exp ession
signa u es can disc imina e his g oup o diseases om
heal hy con ols, he a ious diseases om each o he o
whe he i is possible o s a i y he diseases based on
gene exp ession changes.
These ch onic condi ions ha e common ea u es such
as he au oimmune o igin, he equen co-mo bidi y and
* Co espondence: [email protected]
1 Depa men o Biochemis y and Molecula Biology, Uni e si y o Deb ecen,
Deb ecen, Hunga y
† Con ibu ed equally
Full lis o au ho in o ma ion is a ailable a he end o he a icle
Mesko e al. BMC Medical Genomics 2010, 3:15
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a ew genes such as IL10, IL23R, SLC22A4 and SLC22A5
ha ha e been iden i ied as con ibu o s o hei gene ic
backg ound [Table 1]. Howe e hei p e alence and he
issues a ec ed a e clea ly di e en .
RA is a sys emic au oimmune diso de , wi h a p e a-
lence be ween 0.5-1.0% [1], ha causes in lamma ion and
issue damage in join s and endon shea hs. Pso iasis
which is a ch onic diso de o he skin and join s whe e
he pso ia ic plaques a e a eas o in lamma ion and
excessi e skin p oduc ion, a ec s app oxima ely 2% o
he popula ion only in he USA [2]. 1-2% o Wes e n pop-
ula ions su e om IBD [3] in which he common ea-
u es a e he in lamma ion o he in es ines and he
au oimmune o igin.
Global and selec i e gene exp ession analyses ha e
al eady been pe o med in o de o ga he hin s on he
mechanisms o hese medical condi ions by using human
biopsy samples such as colon issue in IBD [4]; skin issue
in pso iasis [5] and syno ial issue biopsy in RA [6]. How-
e e pe iphe al blood is a mo e accessible sou ce o cells
and may be easie o use o sc eening p ocesses. Fu he -
mo e as ci cula ing pe iphe al blood mononuclea cells
(PBMCs) a e key cells o in lamma ion, i may also e lec
disease mechanisms.
In addi ion s udies o gene exp ession p o iling o
PMBCs may p o ide a mo e cos e ec i e and less in a-
si e al e na i e o biopsy o in asi e measu emen s [7].
Examples o he clinical implica ions o his app oach
include he analysis o human b eas cance p og ession
[8] and PBMC p o iles in RA, sys emic lupus e y hema o-
sus, ype I diabe es and mul iple scle osis [9].
I appea s he e o e ha gene exp ession p o iling om
PBMCs is a alida ed ool o disco e y and also may be
used o explo e he pa hogene ic backg ound o hese
medical condi ions [10-12]. Howe e compa a i e s udies
on he exis ence o dis inc and o e lapping gene exp es-
sion pa e ns a e lacking. We sough o ill his gap by ca -
ying ou a compa a i e analysis o pe iphe al gene
exp ession pa e ns o a panel con aining 96 genes in a -
ious ch onic in lamma o y diseases and heal hy con ols.
Me hods
Pa ien ec ui men
The Resea ch E hics Commi ee o Uni e si y o Deb e-
cen Medical and Heal h Science Cen e app o ed he
Table 1: Known SNP - disease associa ions
Gene IBD Pso iasis Rheuma oid a h i is
ADAM33 NA s512625 PMID: 18560587 NA
IL10 s3024505 PMID: 18836448 NA s1800896 PMID: 18615156
IL13 NA s1800925 PMID: 19554022 NA
IL23R s2201841 PMID: 18338763 s11209026 PMID: 18369459 NA
IL4 s2243250 PMID: 18064451 NA NA
IL8 NA NA PMID: 18799095
PADI4 NA NA s2240340 PMID: 12833157
PTGS2 s20432 PMID: 16273614 NA s5275 PMID: 18381795
PTPN22 NA s1217414 PMID: 18341666 s2476601 PMID: 18466513
SLC22A4 s3792876 PMID: 17476680 s11568506 PMID: 18614543 s3792876 PMID: 15107849
SLC22A5 s3792876 PMID: 17476680 s2631367 PMID: 16255050 s2631367 PMID: 15107849
Known associa ions be ween single nucleo ide polymo phisms and ch onic in lamma o y diseases a e shown in he able wi h SNP ID and
PMID numbe e e ing o he publica ion ha documen s he associa ion. NA means he e is no documen ed associa ion on SNP le el. Bold
cells mean we could de ec he associa ion in ou s udy be ween ha speci ic disease and heal hy con ols.
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clinical p o ocol and he s udy ha we e in compliance
wi h he Helsinki Decla a ion. Signed in o med consen
was ob ained om all heal hy and diseased indi iduals
who p o ided blood sample. Inclusion and exclusion c i-
e ia we e de eloped using he bes e idence cu en ly
a ailable. Online supplemen is p o ided o addi ional
in o ma ion abou inclusion and exclusion c i e ia [Addi-
ional File 1: Figu e S2].
The s udy included 13 pa ien s wi h IBD; 15 wi h pso i-
asis and 12 wi h RA, all o whom had ac i e disease and
we e medica ion- ee a he ime o blood d aw [Table 2].
Blood was also ob ained om a g oup o heal hy con ol
indi iduals (18 pa ien s) ha did no show signi ican di -
e ences compa ed o he diseased g oups ega ding age.
A e he subjec s as ed o e nigh o 12 hou s, all o he
blood samples we e ob ained locally be ween 8:00 AM
and 9:00 AM; and we e p ocessed wi hin one hou a e
sample collec ion.
Pe iphe al blood mononuclea cell collec ion and RNA
p ocessing
Venous pe iphe al blood samples we e collec ed by clini-
cians (30 ml) in Venous Blood Vacuum Collec ion Tubes
con aining EDTA (BD Vacu aine K2E). PBMCs we e
sepa a ed by Ficoll g adien cen i uga ion.
To al RNA was ex ac ed om PBMCs using T izol
eagen (In i ogen), acco ding o he manu ac u e 's
p o ocol. RNA quali y and quan i y we e checked on
NanoD op and Agilen Bioanalyse 2100 (Agilen Tech-
nologies).
TaqMan mRNA analysis by RT-QPCR
Gene exp ession da a was ob ained using TaqMan Low
Densi y A ay (TLDA) (Applied Biosys ems) which is a
384-well mic o luidic ca d ha enables o pe o m 384
simul aneous eal- ime PCR uns and which has been
used o gene exp ession p o iling in se e al s udies
[13,14]. This low- o medium- h oughpu mic o luidic
ca d allows o 2 samples o be un in pa allel agains 96
TaqMan® Gene Exp ession Assay a ge s ha a e p e-
loaded in o each o he wells on he ca d. cDNA was gen-
e a ed wi h High Capaci y cDNA Re e se T ansc ip ion
Ki acco ding o manu ac u e 's p o ocol. 2 mic og ams
o RNA we e used pe sample in he RT-PCR uns. 400 ng
(4 μl) cDNA was used in each sample. 196 μl nuclease-
ee wa e and 200 μl 2× TaqMan Uni e sal PCR Mas e
Mix (Applied Biosys ems) we e added o he Real-Time
Quan i a i e PCR measu emen s. This mix u e was hen
equally di ided o e ou sample-loading po s o he
TLDA, each connec ed o one se o he 96 genes o in e -
es . The a ays we e cen i uged once (1', 1300 RPM on
oom empe a u e) o equally dis ibu e he sample o e
he wells. Subsequen ly, he ca d was sealed o p e en an
exchange be ween wells. RT-QPCR ampli ica ion was
pe o med using an Applied Biosys ems P ism 7900HT
sequence de ec ion sys em wi h he ollowing he mal
Table 2: Pa ien pa ame e s
Disease S a us Con ol IBD Pso iasis Rheuma oid
a h i is
n18131512
Sex (male/ emale) 8/10 4/9 5/10 2/10
Age (yea s) 40.07 ± 21.3 27.92 ± 8.49 30.53 ± 9.3 45.83 ± 18.24
Clinical sub ype NA CD/UC 8/4 A h i is posi i e/
nega i e 4/11
Bone e osion
posi i e/nega i e
4/8
CDAI UCDAI PASI DAS28
Clinical se e i y NA 270.4 ± 67.18 8 ± 1.2 27.47 ± 9.62 6.12 ± 1.05
124-365 6-9 15-48 4.07-7.56
De ini ion o abb e ia ions: IBD = In lamma o y bowel disease, CD = C ohn's Disease, CDAI = C ohn's Disease Ac i i y Index, UC = Ulce a i e
coli is, UC DAI = Ulce a i e Coli is Disease Ac i i y Index, PASI = Pso iasis A ea Se e i y Index, DAS28 = Disease Ac i i y Sco e 28, NA = non
a ailable. Da a a e p esen ed as mean ± SD; also ange in Clinical Se e i y.
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cycle condi ions: 2 min a 50°C and 10 min a 94.5°C, ol-
lowed by 40 cycles o 30 s a 97°C and 1 min a 59.7°C.
Gene Lis Selec ion P ocess
A da abase con aining 400 genes which a e associa ed
wi h he 3 ch onic in lamma o y diseases and in lamma-
ion was cons uc ed by using he da a de i ed om he
Human Genome Na iga o ha lis s all he genes ela ed
o a speci ic disease and he e idence he ela ion is based
on; he cu en medical li e a u e and in e na ional da a-
bases (e.g. OMIM, En ez Gene). Genes we e also
selec ed om genome-wide associa ion s udies as well as
mic oa ay analyses ocusing on skin biopsy in pso iasis,
colon biopsy in IBD and syno ial luid in RA. (Figu e 1)
In he second s ep, genes we e pu in o de by using a
sco e lis ha was based on he numbe o publica ions
men ioning he disease-gene associa ion, ela ion o
o he diseases and expec ed exp ession in PBMC acco d-
ing o p e ious s udies and ou pilo expe imen in which
we analyzed selec ed genes in PBMC samples h ough
indi idual RT-QPCR assays. This selec ion p ocess
esul ed in 150 genes.
In he hi d s ep, genes ha did no show exp ession
(missing signal in QPCR measu emen s) in he pilo
s udy we e emo ed, leading o a inal lis o 96 genes
Addi ional File 1: Figu e S1.
S a is ical Analyses
Rela i e gene exp ession le els o each gene we e calcu-
la ed by compa a i e C me hod and esul s we e no mal-
ized o glyce aldehyde-3-phospha e dehyd ogenase
(GAPDH) exp ession o each sample. S a is ical analyses
o he no malized gene exp ession da a we e pe o med
in P ism (G aphPad). Due o he ac ha ou da a did no
ollow no mal dis ibu ions, he gene exp ession in
g oups wi h di e en numbe s o samples was compa ed
sepa a ely using he non-pa ame ic Mann-Whi ney U
es . P- alues < 0.05 we e conside ed o be s a is ically
signi ican . This me hod ha does no include co ec ion
o mul iple compa isons is widely used in he analysis o
TLDA da a [15,13] and is explained in de ails in [16].
Gene in e ac ions we e analyzed by using he Di ec
In e ac ions and Biological P ocesses unc ions o Gene-
Sp ing GX (Agilen Technologies).
P incipal componen analysis (PCA), a s anda d, non-
pa ame ic ool ha educes a complex da a se o a lowe
dimension, was used in o de o e eal he in e nal s uc-
u e o he da a se s and o p ojec he di e ences
be ween diseased and heal hy g oups based on each se o
signi ican ly changing genes.
Resul s
Iden i ica ion o gene panels disc imina ing ch onic
in lamma o y disease pa ien s om heal hy con ols
A panel o 96 genes has been selec ed by he algo i hm
depic ed on Figu e 1. Pa ien s we e ec ui ed and PBMC
gene exp ession was de e mined as desc ibed in Ma e i-
als and Me hods. When we compa ed he gene exp es-
sion esul s we ha e ound 53 genes ha show signi ican
di e ences be ween diseased and heal hy samples. Fi s ,
we looked a he gene panels ha di e en ia e each dis-
ease om he se o con ol samples. Al oge he 25 genes
show signi ican di e ences be ween IBD; 16 genes
be ween pso iasis; 33 genes be ween RA and con ols
(Figu e 2a-c). P incipal componen analysis o hese gene
se s also sepa a es he di e en g oups o samples. In
o de o ge hin s o he complex ansc ip ional basis o
in lamma o y diseases and o ind po en ial a ge s ha
migh play a ole in he pa hogenesis o he condi ions,
he in e ac ion among mul iple genes needs o be
e ealed. Gene in e ac ion analyses highligh ed IFNG,
IL4, IL10, MMP9 and TIMP1 in IBD; IL10, IL13 and
PTGS2 in pso iasis; IL8, IL10 and PTGS2 in RA. These
genes had he mos di ec in e ac ions ha migh e eal
hei key ole in he pa hogene ic backg ound o he dis-
eases. Gene in e ac ion analysis on each se o genes is
p o ided in he supplemen ma e ial Addi ional File 1:
Figu e S3-5.
Gene se s showing o e lapping o di e en ial exp ession
In o de o analyze he gene exp ession pa e ns o hese
condi ions, i s we c ea ed a Venn diag am highligh ing
hose genes ha di e en ia e be ween a disease and he
se o con ol samples (Figu e 3a).
Figu e 1 Flowcha o gene selec ion p ocess. A low cha o he
gene selec ion p ocess shows he s eps h ough which we chose he
inal 96 genes ou o he da abase con aining 400 genes.
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Pe o ming Gene In e ac ion Analysis esul ed in he
iden i ica ion o a ne wo k ha highligh s he genes wi h
he mos in e ac ions such as CCL5, IFNG, IL4, IL8, IL10,
IL13, MMP9, PTGS2 and TIMP1 (Figu e 3b) clea ly
showing ha no only indi idual genes bu en i e ne -
wo ks a e impac ed and hence can be iden i ied.
Al hough he e a e genes ha showed disease speci ic
signa u es, all o hese genes showing signi ican di e -
ences be ween diseased and heal hy samples o m a ne -
wo k which migh ep esen he common backg ound o
he pa hogenesis o his ype o in lamma ion.
As he nex s ep in ou analysis all he signi ican ly
changing genes we e assigned o unc ional ca ego ies
ha we e c ea ed based on EASE, he Exp ession Analy-
sis Sys ema ic Explo e ha p o ides s a is ical me hods
o disco e ing biological hemes wi hin gene lis s [17].
Genes we e g ouped in o in lamma o y esponse; cell
g ow h and main enance; p o eolysis; me abolism and
unclassi ied (including genes in unique ca ego ies o
genes wi hou ca ego ies) ca ego ies wi h 21, 11, 7, 9 and
7 genes espec i ely. In o de o illus a e he simila i ies
in he pa hogene ic backg ound o hese diseases, he
unc ional ca ego ies, he numbe o genes and he dis-
ease gene panels a e isualized. I shows ha he e a e
simila numbe o genes in he same unc ional ca ego ies
in each o he diseases, hough he numbe o unique
genes (11 in IBD, 6 in pso iasis and 21 in RA) sepa a ing
only a disease om he con ol g oup is also high (Figu e
4).
Diseases sub ype s a i ica ion by di e en ially exp essed
genes
We also sough o iden i y po en ial ma ke s ha di e -
en ia e be ween dis inc sub ypes o s a es o p ognosis in
each o he h ee diseases o s a i y he disease based on
gene exp ession pa e ns (Figu e 5). Analyses o indi id-
ual genes a e p o ided in he supplemen ma e ial Addi-
ional File 1: Figu e S7-9.
Figu e 2 Fold changes o genes di e en ia ing be ween diseased and con ol samples. Fold change alues o genes, showing s a is ically sig-
ni ican (Mann-Whi ney U es ) di e en ial exp ession be ween diseased and con ol pa ien s, we e gene a ed om RT-QPCR measu emen s and ep-
esen he di e ence o he means o he diseased and con ol g oups. P incipal componen analysis was pe o med and sepa a es he wo g oups o
samples. 2a ep esen s he IBD, 2b he pso iasis and 2c he RA gene panel.

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Rega ding IBD, ADAM10, CUGBP1, CUGBP2, DUSP1,
ETS2, FOS, IL6, IL18 and PGRMC1 show signi ican ly
highe exp ession le els in pa ien s wi h CD compa ed o
pa ien s wi h UC (Figu e 5a).
In pso iasis, CCL4, GZMK and KLRF1 show signi i-
can ly highe , while ADM, ANXA3, IL4, MMP9 and
OLR1 show signi ican ly lowe exp ession le els in
pa ien s wi h a h i is nega i e pso iasis compa ed o
pa ien s wi h symp oms o a h i is (Figu e 5b).
HBB and PADI4 show lowe ; GZMK shows highe
exp ession in RA pa ien s wi h bone e osions con i med
wi h Magne ic Resonance Imaging compa ed o hose
wi hou such symp oms (Figu e 5c).
Pe iphe al blood de i ed uni e sal ma ke s o ch onic
in lamma ion
Impo an ly, we ha e iden i ied i e genes, ADM, AQP9,
CXCL2, IL10 and NAMPT ha show signi ican di e -
ences in exp ession le els be ween all he h ee condi-
ions and con ol samples (Figu e 6). These genes migh
be conside ed uni e sal ma ke s o ch onic in lamma ion
in PBMCs. Rega ding pa hway analysis ha ea u es he
biological p ocesses he genes a e associa ed wi h; IL10
has he highes numbe o ela ed biological p ocesses
(o e 20) including lymphocy e, T and B cell p oli e a-
ion, in e leukin p oduc ion and mac ophage ac i a ion.
ADM is ela ed o 10 p ocesses such as ac i a ion o
MAPK-ac i i y and in e leukin-6 p oduc ion; while
AQP9, CXCL2 and NAMPT a e only associa ed wi h a
single p ocess, u ea anspo , in e leukin-18 p oduc ion
and neu ophil apop osis, espec i ely (Figu e 7).
We also de e mined he numbe o diseased pa ien s
wi h gene exp ession le els abo e he ange o he mean +
SD o 2 SD o con ol samples. Addi ional File 1: Figu e
S6.
Discussion
I is o c i ical impo ance o iden i y new bioma ke s and
hin s o mechanisms o disease s a es and disease p o-
g ession in illnesses a ec ing la ge popula ions such as
ch onic in lamma o y diseases in o de o pe sonalize
ea men and accu a ely moni o disease p og ession.
Me hods based on genomic app oaches and amongs
hem global gene exp ession p o iles play an inc easing
ole in such e o s.
The pa homechanism o hese ch onic in lamma o y
diseases has been examined a di e en le els including
cell cul u es, animal models and clinical samples. Impo -
an ly, as he molecula signa u e o disease ac oss issues
is o e all mo e p ominen han he signa u e o issue
exp ession ac oss diseases [18], he e is good eason o
belie e one can de ec disease-speci ic gene exp ession
signa u es in PBMC samples which a e easy- o-access.
The e ha e been s udies analyzing he gene exp ession
pa e ns o hese diseases in PBMC samples which led o
he iden i ica ion o genes, which we also ound o be sig-
ni ican ly di e en be ween disease and con ol pa ien s.
Examples include PTGS2 in pso iasis [10]; PTPN22 in
RA [19] and GZMK in IBD [12]. O he g oups compa ed
Figu e 3 Genes sepa a ing ch onic in lamma o y diseases om con ols. (a) Venn diag am shows all o hose genes ha show signi ican di e -
ences be ween each disease g oup and con ol samples. Each se con ains genes ha sepa a e con ol samples only om he pa icula disease o
diseases. Unde lined genes we e down- egula ed compa ed o heal hy con ols. (b) Gene in e ac ion analysis in GeneSp ing GX in Di ec In e ac ions
mode highligh s 28 genes ha ha e di ec in e ac ions wi h each o he while 25 genes ha e no di ec in e ac ions. Genes wi h he highes numbe
o in e ac ions a e shown in ex ended size. Cyclooxygenase 2 enzyme is loca ed in he middle o his pa hway ne wo k. The genes ha showed sig-
ni ican di e ences be ween one o he diseased g oups and heal hy con ols ha e colo codes in which blue ep esen s RA, g een ep esen s IBD and
ed codes o pso iasis- ela ed genes.
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Figu e 4 Func ional ca ego iza ion o signi ican ly changing genes. We ound 53 genes ha show signi ican ly di e ences be ween ch onic in-
lamma o y diseases and con ol samples. These genes we e g ouped in o unc ional ca ego ies made by EASE. Genes we e g ouped in he ca ego y
ha had he highes ele ance acco ding o he EASE so wa e. Colo s ep esen disease g oups. The size o he diag ams co ela es wi h he numbe
o genes in each se . O e lapping se s o genes a e shown as o e lapping diag ams.
Figu e 5 Co ela ion be ween gene exp ession le els and clinical pa ame e s. No malized mRNA le els o genes showing signi ican di e ences
be ween pa ien s wi h (a) C ohn's disease and Ulce a i e coli is; (b) pso iasis pa ien s wi h and wi hou a h i is; (c) RA pa ien s wi h and wi hou MR-
con i med bone e osion we e gene a ed om RT-QPCR measu emen s and ep esen he means o he exp ession le els o he diseased and con ol
g oups.
Mesko e al. BMC Medical Genomics 2010, 3:15
h p://www.biomedcen al.com/1755-8794/3/15
Page 8 o 13
di e en ch onic diso de s o each o he s such as ju enile
a h i is and spondyloa h opa hy [20] o pso ia ic
a h i is, RA and spondyloa h opa hy [21], bu such an
ex ended numbe o genes ha e no ye been ound in
pe iphe al blood. Impo an ly he gene exp ession p o-
iles o RA, IBD and pso iasis ha e no been compa ed
p e iously. We ied o ill his gap wi h ou s udy and
iden i y ma ke s o ch onic in lamma ion ha o e lap
among he 3 condi ions and also ones ha disc imina e
hem om each o he .
I should be no ed hough gene exp ession analyses o
hese diseases p o ide li le insigh in o he pa homecha-
nisms o he disease simply because i is impossible o
so ou wha is cause and wha is consequence. Howe e
i can s ill p o ide hin s o clues abou he po en ial pa h-
ways a ec ed. The e o e such da ase s, al hough indi-
ec ly, can o m he basis o mo e mechanis ic s udies.
This is why we ha e ca ied ou and p esen ed he gene
in e ac ion analyses o he genes iden i ied and linked o
he di e en diseases. Signi ican ly he exis ence o o e -
lapping gene se s sugges s ha he e a e common pa h-
ways impac ed among he s udied diseases. A common
cha ac e is ic o all diseases is an al e ed in lamma o y
esponse.
In addi ion, gene ic associa ion s udies ha e al eady
iden i ied SNPs linked o hese diseases. A compa ison o
ou da ase o hese can p o ide u he suppo o hose
indings [Table 1].
Se e al o he now iden i ied di e en ially exp essed
genes ha e been linked o he s udied diseases al hough
ei he a a di e en le el o di e en model. Rega ding
he IBD gene panel, OLR1/LOX1 [22] and CCR1 [23]
bo h ha e immune esponse unc ion and a e exp essed
in human in es inal cells. The homophilic liga ion o
Figu e 6 Pe iphe al blood de i ed uni e sal ma ke s o ch onic in lamma ion. No malized mRNA le els o genes (wi h SD) showing signi ican
di e ences be ween all he samples o ch onic in lamma o y diseases and heal hy con ols we e gene a ed om RT-QPCR measu emen s.
Mesko e al. BMC Medical Genomics 2010, 3:15
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CEACAM1, which is a cell-su ace molecule, on T cells
leads o he inhibi ion o a ange o T-cell unc ions he e-
o e i migh be a new po en ial he apeu ic a ge in he
ea men o IBD [24]. MMP9, a gela inase, ha showed a
7- old up- egula ion in diseased samples in ou s udy is
an impo an media o o issue inju y in coli is and is up-
egula ed in spu um samples o CD pa ien s [25]. Ga g e
al. sugges ed ha de eloping s a egies o block MMP-9
ac i i y in he gu migh be o bene i o IBD [26]. TIMP1
is a na u al inhibi o o ma ix me allop o einases
(MMPs) and migh be conside ed a po en ial d ug a ge .
The DNA me hyla ion o IFNG ha egula es immune
esponse was analyzed wi hin he mucosal compa men
in bo h no mal and IBD popula ions [27]. PTGS2/COX2
is ela ed o IBD exp ession le el in colon biopsy [28].
ABCA1, BASP1, GZMK, HBB, SEC14L1, THEM2 and
TNFAIP6 ha e ne e been associa ed wi h IBD; he e o e
u he analyses should be ca ied ou .
In he pso iasis panel, CCR1 ha plays a ole in in lam-
ma o y esponse is associa ed wi h pso iasis ia he anal-
ysis o skin lesion samples [29]. Koczan e al. iden i ied
pai s o genes such as PTGS2/COX2 and NR1D2 which
allowed an accu acy o disease s age p edic ion o 86%,
based on gene exp ession pa e ns [10]. ADORA2B,
IFRD1, ITGA2B, MAP4K1, PADI4, PDE4A, SEC14L1
and TREM1 ha e no documen ed associa ion wi h pso i-
asis ye . The e o e hese a e candida es o u he SNP/
gene ic associa ion o mechanis ic s udies.
Rega ding he signi ican ly changing genes in RA sam-
ples, IL8 is ela ed o RA based on exp ession [30]. Van
De Voo e al. demons a ed ha he exp ession o
ADAM10 is s ongly enhanced in RA syno ia [31]. CCL4
was exp essed in PBMC [30] and CCL5 showed high
se um le els [32]. Kehlen e al. ound up- egula ion o
TNFAIP6 in ib oblas -like syno iocy es o pa ien s wi h
RA [33]. HMGB1 [34] and PLCB1 [35] only showed di -
Figu e 7 Pa hway analysis o uni e sal ma ke s o ch onic in lamma ion. Pa hway analysis was ca ied ou wi h GeneSp ing GX Biological P o-
cesses mode ha e ealed all he biological p ocesses he genes a e ela ed o. Ci cles ep esen he 5 genes; del oids ep esen biological p ocesses.