Ülkü da l md Ülkü dağı md - dr. falk pharmaœlkü dağlı md yüksek ihtisas hospital, ankara...

Epidemiology and Geneticsof Inflammatory Bowel

Disease in Turkey

Epidemiology Epidemiology andand GeneticsGeneticsof of InflammatoryInflammatory BowelBowel

DiseaseDisease in in TurkeyTurkey

Ülkü Dağlı MD Yüksek Ihtisas Hospital, Ankara -Turkey

Falk Symposium 159, İstanbul

Ülkü Dağlı MD Yüksek Ihtisas Hospital, Ankara -Turkey

Falk Symposium 159, İstanbul

• ANKARA:– Ankara University– Hacettepe Unıversity– Gazi Unıversity– Gülhane Unıversity– T.C. Yüksek İhtisas

Hospital• ANTALYA:

– Akdeniz Unıversity• DİYARBAKIR:

– Dicle Unıversity• EDİRNE:

– Trakya Unıversity• ESKİŞEHİR

– Osmangazi University• UŞAK:

– Uşak Ministry Hospital

• İSTANBUL:– American Hospital.– Haydarpaşa Numune

Hospital, – İstanbul Unıversity. – Marmara Unıversity.

• İZMİR:– Dokuz Eylül University– Ege Unıversity– Izmir Atatürk Hospital

• MERSİN:– Mersin University

• TRABZON– Karadeniz Teknik

University

•

Epidemiology of IBD in Epidemiology of IBD in TurkeyTurkey

•• NNo o populationpopulation--basedbased studystudy has beenhas beenperformedperformed

•• ToTo investigateinvestigate IBD IBD epidemiologyepidemiology,,IBD IBD SSocietyociety designeddesigned a a researchresearchprotocolprotocol basedbased on on hospitalhospital data data

Epidemiology of IBD in Epidemiology of IBD in TurkeyTurkey

•• 19 19 medicalmedical centerscenters involvedinvolved•• TheseThese centerscenters werewere includedincluded ifif

–– TheThe medicalmedical centercenter waswas a a universityuniversity hospitalhospitaloror gradegrade A A tertiarytertiary hospitalhospital

–– DiagnosticDiagnostic facilitiesfacilities forfor highhigh qualityqualityendoscopyendoscopy, , radiologyradiology andand pathologypathology werewereavailableavailable

•• A A standarstandardd protocolprotocol waswas adoptedadopted forfordata data collectioncollection andand analysisanalysis

MaterialMaterial andand MethodsMethods

•• AllAll previousprevious data of IBD data of IBD patientspatientswerewere recordedrecorded onon patientpatient formsformscreatedcreated in in thethe webwebsitesite of the IBD of the IBD Society Society ((www.ibhd.org.trwww.ibhd.org.tr)) fromfromSeptemberSeptember 1,1, 20042004 toto April 1, April 1, 2007 (2007 (whichwhich waswas thethe prevalenceprevalencedatedate))


•• IncidenceIncidence andand pprevalrevaleencence waswas calculatedcalculatedfromfrom 3 of 10 3 of 10 citiescities

•• InIn thesethese 3 3 citiescities, , allall gastroenterologygastroenterologyclinicsclinics participatedparticipated inin thethe studystudy–– Ankara,Ankara,İİzmir,zmir,Edirne Edirne

•• DemographicDemographic andand clinicalclinical data data presentedpresentedhereinherein areare takentaken fromfrom thethe recordsrecords of of allallpatientspatients fromfrom allall 10 10 citiescities

3

3

3

Participating cities

Material and Methods

Data included– Demographics– Smoking history– History of appendectomy and tonsillectomy– Family history of IBD– Disease location and behavior– Extraintestinal manifestation


• Statistical analysis was performedby SPSS

• Numeric variables were comparedby t-test,

• Nominal variables were compared bychi-square tests

• Significance was set as 0.05

ResultsResults

IBD IBD PatientsPatients•• UlcerativeUlcerative colitiscolitis 2938 2938

•• CrohnCrohn’’ss diseasedisease 975 975

•• IndeterminIndeterminateate 41 41 colitiscolitis

•• IBD 3954 IBD 3954

Ulcerative colitis74%

Crohn's disease

25%

ındetermine colitis

1%

PPrevalrevaleencence ratesrates44.7

39.7

25.4

36

30.233.3

19

25.5

10.4

2.45

7.7

05

1015202530354045

IBD UC CD

AnkaraEdirneİzmirTotal

36.025.57.7

860000031002189660

TotalIBDUCCD

39.733.32.4

7720001501269

EdirneIBDUCCD

25.4195

3769000959717190

İzmirIBDUCCD

44.730.210.4

445300019911346461

AnkaraIBDUCCD

Prevalence(105)

PopulationPatient number

PrPrevalevaleencence ratesrates

4.12.61.4

8600000353228125

TotalIBDUCCD

3.92.81

77200030228

EdirneIBDUCCD

3.32.11.1

37690001238142

İzmirIBDUCCD

4.52.81.7

445300020012575

AnkaraIBDUCCD

Incidence (105)PopulationPatient number

IncidenceIncidence ratesrates (2006)(2006)

3,3

30,2

52,8

78,593,9

79,8

0

20

40

60

80

100

IBD prevalence according to age (per 100000)

10-1920-2930-3940-4950-59Over 60

Mean age at diagnosisUC: 38.4 ± 13 and CD: 34.3 ± 13

0

50

100

150

200

250

300

<10 10-19 20-29 30-39 40-49 50-59 60 andupper

Age groups

UC

CD

AgeAge distributiondistribution

MaleMale toto FemaleFemale RatioRatio

1.271.272187 55.92187 55.917261726 44.144.1IBD

1.241.24540 55.4540 55.4435 44.6435 44.6Crohn’s disease

1.271.271647 56.11647 56.11291 43.91291 43.9Ulcerative colitis

Male/ FemaleMalen %

Femalen %

Patients

Risk Risk FactorsFactors

GeneticGenetic FactorsFactors InIn TurkishTurkishIBD IBD PatientsPatients

•• FamilyFamily historyhistory of IBDof IBD•• HLA HLA tissuetissue groupsgroups•• CARD15 / NOD 2 CARD15 / NOD 2

studiesstudies•• ProthromboticProthrombotic gene gene

mutationsmutations in IBDin IBD•• CytokineCytokine gene gene

mutationsmutations

FamilyFamily HistoryHistory

%4.3

%4.2

0

500

1000

1500

2000

2500

3000

UC CD

Family history (+)Family history (-)

TheThe distributiondistribution of HLAof HLA--DRB DRB allelesallelesin in ulcerativeulcerative colitiscolitis patientspatients in in TurkeyTurkey

•• A A positivepositive associationassociation withwith thetheHLAHLA--DRB1*1502 DRB1*1502 alleleallele

•• A A negativenegative associationassociation withwith thetheDRB1*13 DRB1*13 alleleallele

•• HLAHLA--DRB1*0701 DRB1*0701 waswas significantlysignificantlyincreasedincreased in in pANCApANCA positivepositive UC UC patientspatients comparedcompared withwith pANCApANCAnegativenegative patientspatients

Uyar FA, İmeryüz N, Saruhan Direskeneli, et al. Eur J Immunogenet 1998; 25: 293-6

GeneticGenetic FactorsFactors

•• TheThe mostmost importantimportant gene of gene of interestinterest totodatedate is is thethe CARD15/NOD2 gene CARD15/NOD2 gene polymorphismpolymorphism

•• TheyThey areare associatedassociated withwith–– thethe terminal terminal ileumileum locationlocation of CDof CD–– thethe stricturingstricturing phenotypephenotype andand–– thethe familialfamilial form of form of diseasedisease

GeneticGenetic FactorsFactors

•• ThereThere areare twotwo

studiesstudies that havethat have

investigatedinvestigated

CARD15/NOD2 in CARD15/NOD2 in

IBD in IBD in TurkeyTurkey

• Aims: to investigate polymorphismin the– NOD2/CARD15 – NOD1/CARD4– ICAM-1 genes

NOD2/CARD15, NOD1/CARD4, NOD2/CARD15, NOD1/CARD4, andand ICAMICAM--1 1 gene gene polymorphismspolymorphisms in in TurkishTurkish patientspatients withwithinflammatoryinflammatory bowelbowel diseasedisease

• The study group– 70 Crohn’s disease patients– 120 ulcerative colitis patients– 106 healthy controls

• Individuals were genotyped for the threevariants by RFLP-PCR technique

Özen SC, Daglı U, Kılıç MY, et al. J Gastroenterol 2006; 41: 304-310

GenotypeGenotype andand alleleallele distributionsdistributions of of NOD2/CARD15 NOD2/CARD15 genesgenes


NS1.400

000

200

68120106

CDUCControls

3020insc

NS2.10.81

100

122

68118104

CDUCControls

G908R

NS1.41.71.9

000

244

68116102

CDUCControls

R702W

PAllelefrequencies(%)

+/+-/+-/-Genotype

GenotypeGenotype andand alleleallele distributionsdistributions of of NOD1/CARD4NOD1/CARD4


NS00

0.9

001

000

70120105

CDUCControls

D372N

NS48.651.755.2

72014

548489

9163

CDUCControls

NOD1/CARD4E266K

PAllelefrequencies

(%)+/+-/+-/-

Genotype

GenotypeGenotype andand alleleallele distributionsdistributions of of ICAMICAM--1 1 genesgenes


NS42.139.234.4

543

498667

163036

CDUC

Controls

K469E

NS000

000

000

70120106

CDUC

Controls

ICAM-1 geneG241R

PAllelefrequencies

(%)+/+-/+-/-

Genotype

ResultsResults

•• TheThe threethree previouslypreviously describeddescribedCrohnCrohn’’ss diseasedisease predisposingpredisposingvariantsvariants of of thethe NOD2/CARD15 gene NOD2/CARD15 gene andand thethe polymorphismpolymorphism examinedexamined in in thethe NOD1/CARD4 NOD1/CARD4 andand ICAMICAM--1 1 genesgenes werewere not not foundfound toto be be associatedassociated withwith UC UC andand CDCD


DistributionDistribution of of commoncommonCARD15/NOD2 CARD15/NOD2 variantsvariants in in patientspatientswithwith CrohnCrohn’’ss diseasedisease fromfrom TurkeyTurkey

•• TheThe studystudy groupgroup–– 56 56 CrohnCrohn’’ss diseasedisease patientspatients–– 100 100 healthyhealthy controlscontrols

•• IndividualsIndividuals werewere genotypedgenotyped forfor thethethreethree variantsvariants byby RFLPRFLP--PCR PCR techniquetechnique

Uyar FA, Hamzaoğlu HÖ, Türe F, et al. Dig Dis Sci 2006; 51(4): 706-10

GenotypeGenotype andand alleleallele frequenciesfrequencies of of CARD15/NOD2 CARD15/NOD2 variantsvariants in CDin CD

Uyar FA, Hamzaoğlu HÖ, Türe F, et al. Dig Dis Sci 2006; 51(4): 706-10

NS1.81

00

22

5498

CDControls

3020insc

0.000280

10

70

48100

CDControls

G908R

NS0.90.5

00

11

5599

CDControls

R702W

PAllelefrequencies(%)

+/+-/+-/-Genotype

ProthromboticProthrombotic Gene Gene MutationsMutationsin IBDin IBD


• The prevalence of prothrombinG20210A gene and factor V Leidengene mutations was found to be statistically insignificant betweenCD patients and the control group

Törüner M, Erkan Ö, Soykan İ, et al. Turk J Gastroenterol 2004Hamzaoğlu H, Abacı N, Türe F, et al. Hepato-Gastroenterol 2005Yılmaz Ş, Bayan K, Tüzün Y, et al. J Thromb Thrombolysis 2006


• There was a statistical differencebetween the proportions of themutated allele frequencies of Beta-Fibrinogen-455G-A, MTHFR A1298C and ACE-I/D in IBD

Yılmaz Ş, Bayan K, Tüzün Y, et al. J Thromb Thrombolysis 2006

Aim: To examine the allelic polymorphisms thatmay determine the immune response level in•TNFα, •IL-1β, •IL-10 and•IL-1RN cytokine geneswhich have a role in the inflammatory pathway in IBD

CytokineCytokine gene gene polymorphismspolymorphisms in in TurkishTurkish patientspatients withwith inflammatoryinflammatorybowelbowel diseasedisease•• ResultsResults

–– No No significantsignificant differencesdifferences werewere foundfoundin in thethe alleleallele andand genotypegenotype frequenciesfrequenciesof of thethe polymorphismspolymorphisms in in TNFα, IL-1β, IL-10 and IL-1RN genes betweenpatients with UC and CD and healthycontrols

Celik Y, Dağlı Ü, Kılıç MY. Scand J Gastroenterol 2006; 41: 559-65

2.4

9.4

1.72.7

14.412.1 9.6

2.1

31.3

55.8

0

10

20

30

40

50

60

Appendec. Tonsillec. Measles amebiazis Smoking

UC

CD

P:0.00

P:0.001P:0.001

EnviromentalEnviromental Risk Risk FactorsFactors in in IBD in IBD in TurkeyTurkey

ClinicalClinicalCharacteristicsCharacteristics

DistributionDistribution of UC of UC patientspatientsaccordingaccording toto localizationlocalization

Left sided45%

Pancolitis26%

Proctitis29%

DistributionDistribution of CD of CD patientspatientsaccordingaccording toto localizationlocalization

Colon25%

Small bowel22%

Ileo colon34%

Ileo ceacum18%

Isolated upper GI1%

DistributionDistribution of CD of CD patientspatientsaccordingaccording toto diseasedisease typetype

Penetrating18%

Stricturing30%

Non-penet. non strict.

52%

ExtraintestinalExtraintestinal ManifestationsManifestations of IBDof IBD

1.37

5.27

3.13

1.14

2.91

86.2%

16 1.6

108 11.1

41 4.2

16 1.6

30 3.1

741 78.3

CDn %

40Genitourinary

155Musculoskeletal

91Hepatobiliary

33Eye complications

85Skin diseases

2534Absent

UCn

13.8 21.7

ExtraintestinalExtraintestinal ManifestationsManifestations of IBDof IBD

• The most common findings were– peripheral arthropathy and sacroiliitis in both groups,

– followed by cholecystopathy

ConclusionsConclusions

•• TheThe prevalprevaleencence of IBD in of IBD in TurkeyTurkey is is lowerlowerthanthan otherother EuropeanEuropean countrcountryy prevalprevaleencesncesbut is but is higherhigher thanthan data fromdata from AsianAsianpopulationspopulations

•• TheThe peakpeak ageage of IBD of IBD onsetonset in in TurkeyTurkey is is similarsimilar toto thatthat in both in both thethe easteast andand westwest–– TheThe majoritymajority of IBD of IBD cases cases areare diagnoseddiagnosed in in

middlemiddle--agedaged patientspatients,, withwith malemalepredominancepredominance

ConclusionsConclusions

•• TheThe mostmost commoncommon clinicalclinical form of form of UC is UC is leftleft--sidedsided colitiscolitis, , andand of of CD CD is is ileoileo--coloniccolonic formform

•• TheThe proportionproportion of of patientspatients havinghavingextraintestinalextraintestinal manifestationsmanifestations in in TurkeyTurkey is is alsoalso similarsimilar toto that of that of Western Western andand EasternEastern seriesseries

ConclusionsConclusions•• TheThe studiesstudies regarding regarding associatassociationion withwith

mutationsmutations of of thethe NOD2/CARD15 gene in NOD2/CARD15 gene in the the TurkishTurkish populationpopulation areare controversialcontroversial

•• A A largelarge populationpopulation--basedbased studystudy in in thisthisregard is neededregard is needed

•• AccordingAccording toto thethe resultresultss of of thethe geneticgeneticstudiesstudies available thus faravailable thus far, , geneticgeneticfactorsfactors maymay not be not be importantimportant risk risk factorsfactors in in susceptibilitysusceptibility toto IBD in IBD in thetheTurkishTurkish populationpopulation

ThanksThanks toto•ANKARA:

–Dr. Hülya Çetinkaya–Dr. Serap Aslan–Dr. Candan Tuncer–Dr. Ahmet Erdil–Dr. Aysel Ülker

•ANTALYA:– Dr.İnci Süleymanlar

•DİYARBAKIR:–Dr. Vedat Göral

•EDİRNE:–Dr. Ahmet Tezel

•ESKİŞEHİR–Dr. Ayşegül Özakyol

•UŞAK• Dr. Derya Akın

•İSTANBUL:–Dr. Nefise Barlas Ulusoy–Dr. Oya Övünç–Dr. Zeynel Mungan–Dr. Aykut Feryal Çelik–Dr. Nurdan Tözün–Dr. Hülya Över Hamzaoğlu

•İZMİR:-Dr. Hale Akbaylar–Dr. Necla Osmanoğlu–Dr. Belkıs Ünsal

•MERSİN:–Dr. Orhan Sezgin

•TRABZON–Dr. Orhan Özgür

Ülkü da l md Ülkü dağı md - dr. falk pharmaœlkü dağlı md yüksek ihtisas hospital, ankara...

Documents