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BACKGROUND

Association of VEGF gene polymorphisms (+405C/G, -460T/C, -1540C/A and -1512Ins18) with psoriasis in Turkish population.

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BACKGROUND

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  1. Association of VEGF gene polymorphisms (+405C/G, -460T/C, -1540C/A and -1512Ins18) withpsoriasis in Turkishpopulation 1Tuba Bozduman, 1İncilay Lay, 2Yıldız Kantarcı, 2Sibel Ersoy Evans, 3Sevilay KarahanHacettepe UniversityFaculty of Medicine, 1Department of MedicalBiochemistry, 2Department of Dermatology, 3Department of Biostatistics, Ankara, TURKEY

  2. BACKGROUND • Psoriasis is a chronic, recurrent, inflammatory andhyperproliferative skin disease that can be seen indifferent parts of the body with an unknown etiology. • Although the prevalence varies depending onethnicity, age, geographic location and environmental factors, it is between 0.2% to 4.8% inepidemiological studies.(ClinDermatol. 2007;25(6):535-46.) • Psoriasis is an ongoing lifelongdisease. • It has relapse and recovery periods and due to its affect to the quality of life,requiring life-longtherapy. • Recentyears, it is defined as a systemic disease, rather than limited to skin. • The biggest cause of treatment failure is that thepathophysiology is not fully understood.

  3. Histopathology • Endothelialcellproliferation (Angiogenesis) (Clindermatol 2007;25(6):524-8) • Süperficialperivascularlymphocyticinfiltrate in thedermis(ArchDermatolRes 1983;275:181-9) • Capillarydilation in thedermalpapillae • Edema, capillarycongestion, increasedpermeability in thedermalpapillae(T Klin J IntMedSci.2005;1:62-7) • Tortuouscapillary

  4. The inflammatory infiltrate in skin is thought to be carried withthe active role of microcirculation in psoriasis whichsuggeststhat the changes in the dermal vascularstructures are the early pathophysiological events. • Morphological and functional vascular changes occurat an early stage in psoriasis. • Neovascularization plays an important role in the pathogenesis ofpsoriasis and vascular endothelial growth factor (VEGF) is a key angiogenic factor in psoriasis.(Br J Dermatol. 1999; 141:1054-160, ArchDermatol.2002;138:791-96.) • It is shown in somestudiesthat VEGF levelsincreaseandthisincreasecorrelateswithdiseaseseverity. (InflammRes. 2002;51:563-67, J ExpMed. 1994;180(3):1141–46.) • Limited studieswithcontroversialresultswerefoundforthe role of VEGF gene polymorphisms in psoriasis.

  5. Theaim of thisstudywastoreveal the VEGF +405 C/G, -460 T/C, -1540 C/A and -1512Ins18 polymorphisms in psoriasissusceptibility of Turkishpopulation.

  6. METHODS • Fourpolymorphismsthathave a highdegree of linkagedisequilibriumwerechosenforthisstudy: VEGF +405 C/G, -460 T/C, -1540 C/A and -1512Ins18 • 100 patientswithpsoriasisand 100 ageandsexmatchedcontrolsweregenotypedusingPCR-RFLP. • Patientswereevaluatedwithclinictype (Type I- Type II), diseaseseverity (PASI), familyhistoryandrespondtotherapy. • Statisticalanalyseswereperformedwith IBM SPSS for Windows v21.0 andhaplotypeestimationwasconductedwithHaplotype Analysis versionv1.04

  7. RESULTS • Control andstudygroupswereselectedsimilar in ageandsex • Çalışmaya alınan hasta grubunun; PASI skoru, psöriazis tipi (Tip I-Tip Theageandsexdistribution of patientsandcontrols

  8. Characteristics of the psoriasis patients

  9. VEGF genotypedistribution - I VEGF (+405 C/G) polymorphism; • Homozygosity (GG) andheterozygosity (CG) in thepatientgroupweresignificantlyhigherthanthecontrolgroup (p<0,001). • Inthisregion, G allelfrequencywashigher in thepatientgroupand C allelfrequencywashigher in thecontrolgroup(p<0,001). • Forthispolymorphism, homozygosity (GG) increasesthe risk of diseaseby 9- fold(Oddsratio, OR: 9,40)andheterozygosity (CG) by 7-fold(Oddsratio, OR: 7,02) (p<0,001). VEGF (-1540 C/A) polymorphism; • Heterozygosity (CA) in thepatientgroupwassignificantlyhigherthanthecontrolgroup(p=0,002). • A allelfrequencywashigher in thepatientgroupand C allelfrequencywashigher in thecontrolgroup(p=0,002). • Heterozygosityincreasethe risk of psoriasisby 2.5-fold (Oddsratio, OR: 2.51) (p=0,004).

  10. VEGF genotypedistribution - II VEGF (-1512 -/+Ins18) polymorphism; • The presence of 18 basepairsinsertion in patientswashigherthanthecontrolsandthelack of 18 basepairsinsertionwereobservedhigher in thecontrolgroup (p<0,001). • 18 basepairsinsertionpolymorphismincreasethe risk of psoriasisby 4-fold (Oddsratio, OR:4,10) (p<0,001). VEGF (-460 T/C) polymorphism; • Thegenotypeand allele distributions of thispolymorphismdid not differsignificantly between the patients andcontrols.

  11. VEGF genotypedistribution in patientsandcontrols

  12. VEGF genotypedistribution in patientsandcontrols

  13. VEGF HaplotypeAnalysisHaplotypes (+405 C/G; -460 T/C; -1540 C/A; -1512 -/+Ins18) • VEGF (CTC-) haplotypewashigher in controlgroup (<0,001). • Themostcommonhaplotypewasfound as VEGF (+405 GG ) homozygous + (-1512 +Ins18) in patients (p<0.001). • Theothercommonhaplotypes in patientswere as follows: VEGF (+405 CG) heterozygous + (-1540 CA) heterozygous + (-1512 +Ins18) (p=0.013) VEGF (+405 CG) heterozygous + (-1512 +Ins18) (p=0.002) VEGF (+405 GG) homozygous + (-1540 CA) heterozygous (p=0.002) VEGF (+405 CG) heterozygous + (-1540 CA) heterozygous (p=0.002)

  14. Themostfrequenthaplotypes

  15. Correlationbetween VEGF genotypesandpsoriasisclinic No significantrelationshipwasfoundbetweenclinicaltypes (Type I- Type II) and VEGF genotypes.

  16. Correlationbetweenpsoriasisseverity (PASI) and VEGF genotypes No significantrelationshipwasfoundbetweendiseaseseverity (PASI) and VEGF genotype.

  17. Correlationbetweenfamilyhistoryand VEGF genotypes Homozygosity of VEGF (+405 GG ) wasfoundhigher in patientswithfamilyhistory.

  18. Correlationbetweenclinicalresponsetotreatmentand VEGF genotypes No significantrelationshipwasfoundbetweenresponsetotreatmentand VEGF genotype.

  19. DISCUSSIONandCONCLUSION • Thisstudyshowsthat VEGF gene polymorphismsarethe risk factorsforTurkishpopulation in psoriasis. - VEGF (+405 C/G) homozygosity (GG) andheterozygosity (CG); - VEGF (-1540 C/A) heterozygosity (CA); - VEGF (-1512 -/+Ins18) the presence of 18 basepairsinsertion increasethe risk of disease. • So far, there are only eight studies of VEGF polymorphism inpsoriasis in theliterature. Most of themsupportourfindingshowever, a fewstudieshaveconflictingresults. (J Dermatol Sci 2008;49:263–5; TissueAntigens 2008;72:458-63; J InvestDermatol 2004;122:209–15; J InvestDermatol. Dermatol 2006;126:453-9; ExpDermatol 2006;15:368–76.) • Fewconflictingresultsare probably caused by ethnicdiversity.

  20. Ourstudyalsoshowsthatsome VEGF haplotypesareassociatedwithpsoriasis in Turkishpopulation: - VEGF (+405 GG ) homozygous + (-1512 +Ins18) - VEGF (+405 CG) heterozygous + (-1540 CA) heterozygous + (-1512 +Ins18) -VEGF (+405 CG) heterozygous + (-1512 +Ins18) -VEGF (+405 GG) homozygous + (-1540 CA) heterozygous -VEGF (+405 CG) heterozygous + (-1540 CA) heterozygous • VEGF (CTC-) haplotypewashigher in controlgroup. • However, the level of plasma VEGFwere notsignificantlyassociatedwiththecommonhaplotypes. • Unidentification of the functional consequences of thosehaplotypes may be because of the small sample size in thehaplotypegroups and otherconfounding factors in patients. It is also possible thatother SNPs within VEGF gene might contribute to generegulation.

  21. Inourstudy, homozygosity (GG) of VEGF (+405 C/G ) wasfoundhigher in patientswithfamilyhistory. • Togetherwiththeresults of genotypedistributionandhaplotypeanalysis, this data showsthatthehomozygosity (GG) of VEGF (+405 C/G) polymorphismcould be a prognosticfactorforpsoriasissusceptibility in Turkishpopulation. • No significantrelationshipwasfoundbetween VEGF polymorphismsandclinicaltypes (type 1-type 2) ordiseaseseverity (PASI) orresponsetotreatment. • This could be due tothe subclassifications of patientandcontrolgroupsthatreducethesample size or to the actionof other, currently unknown, factors contributing to the psoriasisphenotype, severity and response to therapy.

  22. Ourresults strongly support the role of VEGFpolymorphisms in the pathogenesis ofpsoriasis however, further studies and large cohortsof patients are required to reach firm conclusions. Thankyou….

  23. References • Gudjonsson JE, Elder JT. Psoriasis: epidemiology. ClinDermatol. 2007;25(6):535-46. • Murphy M, Kerr P, Grants-Kels JM. Thehistopathologicspectrum of psoriasis. ClinDermatol 2007; 25(6):524-8 • Bos JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH.Immunocompetentcells in psoriasis. Insituimmunophenotypingbymonoclonalantibodies. ArchDermatolRes. 1983;275(3):181-9. • Akkaya VB, Ceyhan AM. Psoriyazisde tanı ve ayırıcı tanı. T Klin J IntMedSci. 2005;1:62-7. • Creamer D, Allen M, Jaggar R, Stevens R, Bicknell R, Barker J. Mediation of systemicvascularhyperpermeability in severe psoriasisbycirculatingvascularendothelialgrowthfactor.ArchDermatol.2002;138:791-796. • Nielson HJ, Christensen IJ, Svendsen MN, Hansen U, Werther K, Brünner N, Petersen LJ, Kristensen JK. Elevatedplasmalevels of vascularendothelialgrowthfactorandplasminogenactivator inhibitör-1 decreaseduringimprovement of psoriasis. InflammRes. 2002;51:563-567. • Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascularpermeabilityfactor/vascularendothelialgrowthfactoranditsreceptors in psoriasis. J ExpMed. 1994;180(3):1141–1146. • Wang Z, Liang W, Zhang B, Lv M, Wang J, ZhangL.Singlenucleotidepolymorphisms of VEGF gene andpsoriasis risk. J DermatolSci 2008;49:263-5. • J. Wongpiyabovorn, S. Yooyongsatit, K. Ruchusatsawat, Y. Avihingsanon & N. Hirankarn. Association of the CTG (-2578/-460/+405) haplotypewithinthevascularendothelialgrowthfactor gene withearly-onsetpsoriasis. TissueAntigens.2008;72(5):458-63. • Young HS, Summers AM, Bhushan M, Brenchley PE, Griffiths CE. Single-nucleotidepolymorphisms of vascularendothelialgrowthfactor in psoriasis of earlyonset. InvestDermatol.2004;122(1):209-15. • Young HS, Summers AM, Read IR et al. Interactionbetweengeneticcontrol of vascularendothelialgrowthfactorproductionandretinoidresponsiveness in psoriasis. J InvestDermatol. Dermatol 2006;126: 453-9.

  24. VEGF-A gene:Located on the short arm of chromosome 6 in the localization of 6p21.3 • +405: 5’UTR • -460, -1512,-1540: Promoter Calculation of the PASI score

  25. the age at onset of psoriasis before the age of 40 years (Type I, n =78) and those with the age at onset above 40 years (Type II, n = 22).

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