research article the region centromeric to hla-c is a key...

Research ArticleThe Region Centromeric to HLA-C Is a Key Region forUnderstanding the Phenotypic Variability of Psoriatic Arthritis

Rubeacuten Queiro1 Patricia Tejoacuten1 Sara Alonso1 Pablo Coto2 Carlos Loacutepez-Larrea3

Jesuacutes Martiacutenez-Borra3 and Segundo Gonzaacutelez4

1 Rheumatology Department Hospital Universitario Central de Asturias (HUCA) CCelestino Villamil SN 33006 Oviedo Spain2Dermatology Department HUCA CCelestino Villamil SN 33006 Oviedo Spain3 Immunology Department Histocompatibility Unit HUCA CCelestino Villamil SN 33006 Oviedo Spain4Department of Functional Biology IUOPA University of Oviedo CCelestino Villamil SN 33006 Oviedo Spain

Correspondence should be addressed to Ruben Queiro rubenque7yahooes

Received 24 October 2013 Accepted 10 December 2013 Published 30 January 2014

Academic Editors M Schmitt-Egenolf and A Zalewska

Copyright copy 2014 Ruben Queiro et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

With the aim of clarifying the role of several polymorphisms around the HLA-C locus in the clinical expression of PsA thedistribution of several polymorphic markers and genes located around the HLA-C locus was analyzed in a well-established cohortof 110 patients with PsA 50 patients with psoriasis alone and 110 healthy controls The frequency of these genes was also analyzedby PsA articular models based on three main subgroups oligoarthritis polyarthritis and spondylitis Distal interphalangeal joint(DIP) involvement was associated with the presence of MICB-CA20 (OR 60 95 CI 158ndash2269 119875 = 0005) HLA-DRBlowast07 wasassociated with oligoarticular forms of PsA (OR 41 95 CI 18ndash93 119875 = 00007) The spondylitic forms overexpressed the antigenHLA-Blowast27 (OR 57 95 CI 24ndash136 119875 = 00001) MICA-A51 showed association with polyarthritis (OR 37 95 CI 15ndash88119875 = 0006) Genes telomeric to HLA-C were overexpressed in psoriasis but not in PsA subphenotypes This study shows thatthe region centromeric to HLA-C is a key region that expresses not only disease risk genes but also genes that help explain thephenotypic variability of PsA

1 Introduction

Psoriatic arthritis (PsA) is a complex disease in which envi-ronmental host and random factors interact resulting in dis-ease in genetically susceptible individuals [1] This conditionis associated with significant morbidity and mortality and isestimated to result in a cost to healthcare systems equivalentto that of rheumatoid arthritis [2] Hence the identificationof the etiological factors would be an important advancebecause it may suggest therapeutic targets for the develop-ment of specific drugs and help establish the prognosis ofpatients

Linkage and association analyses have shown that themajor histocompatibility complex (MHC) is the majorgenetic determinant related to psoriasis susceptibilityWithinthe MHC HLA-Clowast06 is the allele that shows the strongestassociation with psoriasis [3 4] Other HLA class I allelesassociated with the disease (ie B13 B47 and B57) are

due to linkage disequilibrium with HLA-Clowast06 [3 4] Theassociation ofHLAwith PsA ismore complex than that foundin psoriasis Although HLA-Clowast06 Blowast13 and Blowast57 have alsobeen associated with PsA the association ismuchweaker andseems to be related to psoriasis rather than arthritis [3 4]Centromeric to HLA-C a susceptibility gene (MICA) hasbeen associated with arthritis risk independently of Clowast06though other authors have not confirmed this finding [5 6]Other nearby genes that are in linkage disequilibrium withHLA class I or MICA could determine susceptibility to PsAor further increase the risk of developing the disease Forinstance HLA-Blowast38 and Blowast39 are associated with peripheralpolyarthritis whereas HLA-Blowast27 is associated with spinalinvolvement [3 4 7] HLA class II antigens have also beenassociated with psoriasis and PsA Thus associations havebeen described between HLA-DRBlowast07 and psoriasis andbetween DRBlowast04 and PsA although these associations havenot been confirmed in all populations studied [3 4 7]

Hindawi Publishing CorporationISRN DermatologyVolume 2014 Article ID 570178 5 pageshttpdxdoiorg1011552014570178

2 ISRN Dermatology

HLA-DR MICB HLA-B

TNFA MICA

HLA-C OTF3 CDSN

HCR

C1 4 4

C1 2 5

Figure 1 Map of theMHC region Polymorphisms in microsatellite C1 4 4 octamer transcription factor 3 gene (OTF3) a-helix coiled-coilrod homologue (HCR) corneodesmosin gene (CDSN) HLA-C microsatellite C1 2 5 HLA-B MICA MICB TNFA and HLA-DRB1 wereanalyzed in this study

Furthermore HLA-DR17 (corresponding to HLA-DRBlowast03)has been recently linked to psoriatic enthesopathy [8] How-ever it is not clear whether these alleles may be associatedwith a specific phenotype of some PsA patients rather thanthe development of the disease since genetic studies in PsAare complicated by the clinical heterogeneity of the diseaseConsequently stratification of patients by clinical subset maybe useful in reducing the heterogeneity of the disease inMHCassociation studies and may help to identify true geneticand prognostic markers of the disease In the present reportwe analyzed polymorphisms of several genes centromericand telomeric to HLA-C (Figure 1) to assess the potentialrelationship between them and the presence of differentarticular subphenotypes in a well-established cohort of PsApatients

2 Patients and Methods

21 Patients One hundred and ten consecutive patients whomet the classification criteria for psoriatic arthritis (CASPAR)[9] were consecutively selected from those attending therheumatology outpatient clinic of a tertiary care institutionThere were 55 men and 55 women with a mean age of 49 plusmn12 years The mean disease duration for psoriasis was 19 plusmn10 years and 13 plusmn 8 years for arthritis Psoriasis precededarthritis in 75 of cases and a family history of psoriasiswas recorded in 42 of patients Patients were initiallyclassified according to the Moll and Wright model [10] andthereafter according to the predominant articular patternseen in the last 5 years of followup In accordance with themain clinical and radiographic features of the last 5 yearsof disease evolution 42 patients showed an oligoarticularpattern (swollen joint countmdashSJCmdashle4) 30 had polyarthritis(SJC ge 5) and 38 had predominant axial disease (radio-graphic sacroiliitis plus inflammatory back pain irrespectiveof the presence of peripheral synovitis) The involvement ofdistal interphalangeal joints (DIP) as well as the ldquomutilansformsrdquo was recorded as typical features of PsA but not asindependent models of the disease

This study was performed in accordance with the Decla-ration of Helsinki All patients and controls gave their writteninformed consent before participating in the studyThe studywas conducted after approval by the ethics committee of ourhospital

22 HLA Typing HLA-C was typed using the polymerasechain reaction with sequence-specific primers (PCR-SSP)Polymorphisms of the octamer transcription factor 3 gene

(OTF3) the corneodesmosin gene (CDSN) and the a-helixcoiled-coil rod homologue (HCR) gene were analyzed as pre-viously described [11] MicrosatellitesC1 2 5 andC1 4 4wereamplified using the PCR primers reported by Tamiya et al[12] HLA-B typing was performed using the Dynal RELISSOHLA-B test following manufacturerrsquos instructionsHLA-DRB1 alleles were typed and subtyped using a polymerasechain reaction with specific primers (PCR-SSP) For theanalysis of microsatellite repeat polymorphism in the MICAgene PCR was performed out using primers labeled atthe 51015840 end with the fluorescent reagent Cy5 as previouslydescribed [11] ForMICB typing a dinucleotidemicrosatellitepolymorphism in the first intron was analyzed by PCR andTNF-120572 polymorphisms at positions minus238 and minus308 weretyped by PCR as previously described [11]

All previous typing was also performed in 50 patientssuffering psoriasis alone as well as in a control population of110 randomly selected ethnically and geographically matchedblood donors

23 Statistical Analysis Differences between the frequenciesof these allelic markers in patients and controls and differ-ences found depending on the articular patterns previouslydescribed were assessed using a Chi-square test with Yatesrsquoscorrection and Studentrsquos t-test The odds ratio (OR) wascalculated by the cross-product ratio and 95 confidenceintervals by the Cornfield method The extent of linkagedisequilibrium between the two loci is expressed as theobserved disequilibrium value (120582119904) that is a proportionof the theoretical maximum disequilibrium value (120582max)achievable for this combination of alleles The 120582119904 values werecalculated using the following formula 120582119904 = 120582120582max = Pab minus(Pa sdot Pb)Pa sdot (1 minus Pb)

3 Results

HLA-Clowast06 was increased in both populations whereasMICA-A9 was increased only in arthritic patients (Table 1)Patients suffering psoriasis alone showed a higher frequencyof HLA-Clowast06 C1 4 4 microsatellite OTFHind3 gen andHCR gen However genes centromeric to HLA-C were notoverexpressed in psoriatic patients (Table 1)

The analysis of the distribution of these markers accord-ing to the articular patterns defined in the study disclosedsignificant associations between the forms with DIP involve-ment and MICB-CA20 Of a total of 50 patients with DIPinvolvement 12 had this allele compared to only 3 of 60without this type of articular involvement (24 versus 5

ISRN Dermatology 3

Table 1 Major polymorphic variants found in this study in patients with psoriasis (PsO) and psoriatic arthritis (PsA)

Marker PsO 119899 = 50 Controls 119899 = 110 119875 values PsA 119899 = 110 Controls 119899 = 110 119875 valuesHLA-Clowast06 25 (50) 19 (17) lt000001a 62 (564) 19 (17) lt000001e

MICA-A9 15 (30) 33 (30) NS 66 (60) 33 (30) lt000001f

MICA-A51 18 (36) 44 (40) NS 38 (345) 44 (40) NSMICB-CA20 5 (10) 9 (81) NS 15 (136) 9 (81) NSHLA-DRB1lowast07 15 (30) 33 (30) NS 43 (391) 33 (30) NSHLA-Blowast27 5 (10) 8 (73) NS 36 (327) 8 (73) 0001g

C1 4 4 (384) 28 (56) 25 (23) 00001b 60 (545) 25 (23) 00001h

OTF3 Hind3 42 (84) 66 (60) 00033c 73 (664) 66 (60) NSHCR (Pg8) 31 (62) 28 (255) lt000001d 37 (336) 28 (255) NSaOR 48 (23ndash101)bOR 43 (21ndash88)cOR 35 (15ndash801)dOR 48 (23ndash97)eOR 618 (332ndash1151)fOR 35 (20ndash612)gOR 59 (26ndash134)hOR 43 (22ndash84)There was linkage disequilibrium between HLA-Clowast06 and C1 4 4 (120582119904 = 06)

Table 2 Distribution of the main genetic markers according to the articular patterns defined in the study Psoriatic arthritis population 110

Marker Oligoarthritis 119899 = 42 () Polyarthritis 119899 = 30 () Axial disease 119899 = 38 () 119875 valuesHLA-Clowast06 22 (524) 12 (40) 18 (474) NSMICA-A9 27 (643) 17 (567) 22 (579) NSHLA-DRB1lowast07 25 (595) 4 (133) 14 (368) 119875 lt 00007

lowast

HLA-DRB1lowast04 5 (12) 4 (133) 5 (131) NSHLA-B27 10 (238) 4 (133) 22 (579) 119875 lt 00001

lowastlowast

TNF-238A 6 (143) 5 (167) 8 (21) NSTNF-238G 34 (81) 25 (833) 29 (763) NSTNF-308A 12 (286) 9 (30) 12 (316) NSTNF-308G 28 (667) 21 (70) 25 (658) NSMICA-A51 9 (214) 17 (567) 12 (316) 119875 lt 0006

lowastlowastlowast

lowastOR 41 (18ndash93) lowastlowastOR 57 (24ndash136) lowastlowastlowastOR 37 (15ndash88) NS nonsignificant Note significant 119875 values represent intergroup comparisons

OR 60 95 CI 158ndash2269 119875 = 0005) HLA-DRBlowast07 wasoverexpressed in patients with oligoarticular forms (595) ascompared to polyarticular (133) and axial forms (368)OR 61 95 CI 2ndash17 119875 = 00007 The axial formsoverexpressed the antigen HLA-Blowast27 (579 versus 238 inoligoarthritis and 133 in polyarthritis) OR 57 95 CI24ndash136 119875 = 00001 MICA-A51 showed association withpolyarthritis (567) but not with oligoarthritis (214) norwith axial forms of PsA (316) OR 37 95 CI 15ndash88 119875 =0006 (Table 2) Genes located telomeric to HLA-C did notcontribute to the differentiation PsA into articular subtypes

4 Discussion

Characterization of the exact MHC gene or genes involvedin susceptibility to psoriasis and psoriatic arthritis has beencontroversial This is due to the high density of polymorphicgenes located in this region the extensive ranges of poly-morphism and the preservation ofHLA haplotypes [13] For

the same reasons to date it has been difficult to link thevarious joint patterns of PsA to specific genes in this regionMany of the associations betweenMHC genes and joint formsof PsA invoked in the past are better explained by the knownphenomenon of linkage disequilibrium between these andHLA-Clowast06 or by a specific association with the phenotypiccharacteristics of the disease [3 4 7]

In this study the analysis of a wideMHC sector disclosedthat several genetic variants of this region contribute to boththe risk of disease and the differentiation of the variousarticular subphenotypes of the disease As awhole our resultspoint to the region telomeric to HLA-C as being importantfor psoriasis development whereas the centromeric regionseems to play a key role in susceptibility and disease expres-sion in PsA

In the present report the region centromeric to HLA-C not only has been confirmed as a key arthritogenicregion (MICA-A9) but also appears to contribute to thevaried joint phenotype expression of PsA (HLA-DRB1lowast07

4 ISRN Dermatology

HLA-Blowast27 MICB-CA20 and MICA-A51) The associationof MICA-A51 with polyarthritis and of MICB-CA20 withDIP involvement has not been highlighted before ThereforeMICA andMICB regions appear as two of the most relevantregions among those centromeric to HLA-C to explain PsAarticular phenotype variabilityThough the role ofMICA andMICB polymorphisms in the pathogenesis of PsA has yet tobe elucidated the potential involvement of these genes in therisk and expression of the disease makes the role of innateimmunity significant in the pathogenesis thereof [14 15]MICA is a polymorphic gene capable of activating NK andT cells via NKG2D Deregulation of MICA expression hasbeen implicated in the pathogenesis of rheumatoid arthritisand other T cell-mediated autoimmune diseases therefore itshould not be surprising that these genes have a role in thepathogenesis of PsA [14 15] Some of our findings supportthose of the previous literature such as the relationshipbetween HLA-B27 and spondylitic variants of PsA or ofHLA-DR7 with less serious forms of the disease [16 17] Therole of MICA genes in PsA susceptibility remains howevercontroversial since some investigations have corroborated itbut others not [6 18] The potential relationship betweenHLA-B27 and DIP involvement invoked in the past hasnot been consistent (we could not show it here) howeverthe potential link between DIP involvement and a genesuch as MICB fits more easily with the current pathogenicmodel of the entheso-synovial organ of the disease wherefactors related to innate immunity outweigh those of adaptiveimmunity [19]

5 Conclusion

This study confirms previous association of HLA-Clowast06 andMICA-9 with PsA susceptibility however it also suggests acomplex interaction between genes located centromeric toHLA-C and the phenotypic characteristics of the disease thatcould be relevant to the prognosis and treatment of thiscondition

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This work was supported by the Spanish Grants of Fondo deInvestigaciones Sanitarias (Institute Carlos III) PI1201280

References

[1] D D Gladman C Antoni P Mease D O Clegg and O NashldquoPsoriatic arthritis epidemiology clinical features course andoutcomerdquoAnnals of the Rheumatic Diseases vol 64 supplement2 pp ii14ndashii17 2005

[2] A Zink K Thiele D Huscher et al ldquoHealthcare and burdenof disease in psoriatic arthritis A comparison with rheumatoidarthritis and ankylosing spondylitisrdquo Journal of Rheumatologyvol 33 no 1 pp 86ndash90 2006

[3] M Castelino and A Barton ldquoGenetic susceptibility factors forpsoriatic arthritisrdquo Current Opinion in Rheumatology vol 22no 2 pp 152ndash156 2010

[4] D D Gladman V T Farewell F Pellett C Schentag and PRahman ldquoHLA is a candidate region for psoriatic arthritisevidence for excessive HLA sharing in sibling pairsrdquo HumanImmunology vol 64 no 9 pp 887ndash889 2003

[5] S Gonzalez J Martınez-Borra J C Torre Alonso et al ldquoTheMICA-A9 triplet repeat polymorphism in the trasmembraneregion confers additional susceptibility to develop psoriaticarthritis and it is independent of the association of Cwlowast0602in psoriasisrdquo Arthritis amp Rheumatology vol 42 pp 1010ndash10161999

[6] R Pollock V Chandran J Barrett et al ldquoDifferential majorhistocompatibility complex class I chain-related A allele asso-ciations with skin and joint manifestations of psoriatic diseaserdquoTissue Antigens vol 77 no 6 pp 554ndash561 2011

[7] R Queiro-Silva J C Torre-Alonso T Tinture-Eguren andI Lopez-Lagunas ldquoThe effect of HLA-DR antigens on thesusceptibility to and clinical expression of psoriatic arthritisrdquoScandinavian Journal of Rheumatology vol 33 no 5 pp 318ndash322 2004

[8] R Queiro S Gonzalez M Alperi et al ldquoHLA-DR17 is associ-ated with enthesitis in psoriatic arthritisrdquo Joint Bone Spine vol78 no 4 pp 428ndash429 2011

[9] W Taylor D Gladman P Helliwell A Marchesoni P Measeand H Mielants ldquoClassification criteria for psoriatic arthritisdevelopment of new criteria from a large international studyrdquoArthritis amp Rheumatism vol 54 no 8 pp 2665ndash2673 2006

[10] J M H Moll and V Wright ldquoPsoriatic arthritisrdquo Seminars inArthritis and Rheumatism vol 3 no 1 pp 55ndash78 1973

[11] S Gonzalez J Martınez-Borra A Lopez-Vazquez S Garcıa-Fernandez J C Torre-Alonso and C Lopez-Larrea ldquoMICArather thanMICB TNFA or HLA-DRB1 is associated with sus-ceptibility to psoriatic arthritisrdquo The Journal of Rheumatologyvol 29 pp 973ndash978 2002

[12] G Tamiya M Ota Y Katsuyama et al ldquoTwenty-six newpolymorphic microsatellite markers around the HLA-B -C and-E loci in the human MHC class I regionrdquo Tissue Antigens vol51 no 4 part 1 pp 337ndash346 1998

[13] J A Traherne ldquoHumanMHCarchitecture and evolution impli-cations for disease association studiesrdquo International Journal ofImmunogenetics vol 35 no 3 pp 179ndash192 2008

[14] C Lopez-Larrea B Suarez-Alvarez A Lopez-Soto A Lopez-Vazquez and S Gonzalez ldquoThe NKG2D receptor sensingstressed cellsrdquo Trends in Molecular Medicine vol 14 pp 179ndash189 2008

[15] S Gonzalez V Groh and T Spies ldquoImmunobiology of humanNKG2D and its ligandsrdquo Current Topics in Microbiology andImmunology vol 298 pp 121ndash138 2006

[16] R Queiro C Sarasqueta J Belzunegui C Gonzalez MFigueroa and J C Torre-Alonso ldquoPsoriatic spondyloarthropa-thy a comparative study between HLA-B27 positive and HLA-B27 negative diseaserdquo Seminars in Arthritis and Rheumatismvol 31 no 6 pp 413ndash418 2002

[17] P Y P C Ho A Barton J Worthington W Thomson AJ Silman and I N Bruce ldquoHLA-Cw6 and HLA-DRB1lowast07together are associated with less severe joint disease in psoriaticarthritisrdquo Annals of the Rheumatic Diseases vol 66 no 6 pp807ndash811 2007

ISRN Dermatology 5

[18] AMameli A Cauli E Taccari et al ldquoAssociation ofMICA alle-les with psoriatic arthritis and its clinical forms A multicenterItalian studyrdquo Clinical and Experimental Rheumatology vol 26no 4 pp 649ndash652 2008

[19] DMcGonagle R J U Lories A L Tan andM Benjamin ldquoTheconcept of a ldquosynovio-entheseal complexrdquo and its implicationsfor understanding joint inflammation and damage in psoriaticarthritis and beyondrdquoArthritis ampRheumatism vol 56 no 8 pp2482ndash2491 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


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OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Dermatology

HLA-DR MICB HLA-B

TNFA MICA

HLA-C OTF3 CDSN

HCR

C1 4 4

C1 2 5

Figure 1 Map of theMHC region Polymorphisms in microsatellite C1 4 4 octamer transcription factor 3 gene (OTF3) a-helix coiled-coilrod homologue (HCR) corneodesmosin gene (CDSN) HLA-C microsatellite C1 2 5 HLA-B MICA MICB TNFA and HLA-DRB1 wereanalyzed in this study

Furthermore HLA-DR17 (corresponding to HLA-DRBlowast03)has been recently linked to psoriatic enthesopathy [8] How-ever it is not clear whether these alleles may be associatedwith a specific phenotype of some PsA patients rather thanthe development of the disease since genetic studies in PsAare complicated by the clinical heterogeneity of the diseaseConsequently stratification of patients by clinical subset maybe useful in reducing the heterogeneity of the disease inMHCassociation studies and may help to identify true geneticand prognostic markers of the disease In the present reportwe analyzed polymorphisms of several genes centromericand telomeric to HLA-C (Figure 1) to assess the potentialrelationship between them and the presence of differentarticular subphenotypes in a well-established cohort of PsApatients

2 Patients and Methods

21 Patients One hundred and ten consecutive patients whomet the classification criteria for psoriatic arthritis (CASPAR)[9] were consecutively selected from those attending therheumatology outpatient clinic of a tertiary care institutionThere were 55 men and 55 women with a mean age of 49 plusmn12 years The mean disease duration for psoriasis was 19 plusmn10 years and 13 plusmn 8 years for arthritis Psoriasis precededarthritis in 75 of cases and a family history of psoriasiswas recorded in 42 of patients Patients were initiallyclassified according to the Moll and Wright model [10] andthereafter according to the predominant articular patternseen in the last 5 years of followup In accordance with themain clinical and radiographic features of the last 5 yearsof disease evolution 42 patients showed an oligoarticularpattern (swollen joint countmdashSJCmdashle4) 30 had polyarthritis(SJC ge 5) and 38 had predominant axial disease (radio-graphic sacroiliitis plus inflammatory back pain irrespectiveof the presence of peripheral synovitis) The involvement ofdistal interphalangeal joints (DIP) as well as the ldquomutilansformsrdquo was recorded as typical features of PsA but not asindependent models of the disease

This study was performed in accordance with the Decla-ration of Helsinki All patients and controls gave their writteninformed consent before participating in the studyThe studywas conducted after approval by the ethics committee of ourhospital

22 HLA Typing HLA-C was typed using the polymerasechain reaction with sequence-specific primers (PCR-SSP)Polymorphisms of the octamer transcription factor 3 gene

(OTF3) the corneodesmosin gene (CDSN) and the a-helixcoiled-coil rod homologue (HCR) gene were analyzed as pre-viously described [11] MicrosatellitesC1 2 5 andC1 4 4wereamplified using the PCR primers reported by Tamiya et al[12] HLA-B typing was performed using the Dynal RELISSOHLA-B test following manufacturerrsquos instructionsHLA-DRB1 alleles were typed and subtyped using a polymerasechain reaction with specific primers (PCR-SSP) For theanalysis of microsatellite repeat polymorphism in the MICAgene PCR was performed out using primers labeled atthe 51015840 end with the fluorescent reagent Cy5 as previouslydescribed [11] ForMICB typing a dinucleotidemicrosatellitepolymorphism in the first intron was analyzed by PCR andTNF-120572 polymorphisms at positions minus238 and minus308 weretyped by PCR as previously described [11]

All previous typing was also performed in 50 patientssuffering psoriasis alone as well as in a control population of110 randomly selected ethnically and geographically matchedblood donors

23 Statistical Analysis Differences between the frequenciesof these allelic markers in patients and controls and differ-ences found depending on the articular patterns previouslydescribed were assessed using a Chi-square test with Yatesrsquoscorrection and Studentrsquos t-test The odds ratio (OR) wascalculated by the cross-product ratio and 95 confidenceintervals by the Cornfield method The extent of linkagedisequilibrium between the two loci is expressed as theobserved disequilibrium value (120582119904) that is a proportionof the theoretical maximum disequilibrium value (120582max)achievable for this combination of alleles The 120582119904 values werecalculated using the following formula 120582119904 = 120582120582max = Pab minus(Pa sdot Pb)Pa sdot (1 minus Pb)

3 Results

HLA-Clowast06 was increased in both populations whereasMICA-A9 was increased only in arthritic patients (Table 1)Patients suffering psoriasis alone showed a higher frequencyof HLA-Clowast06 C1 4 4 microsatellite OTFHind3 gen andHCR gen However genes centromeric to HLA-C were notoverexpressed in psoriatic patients (Table 1)

The analysis of the distribution of these markers accord-ing to the articular patterns defined in the study disclosedsignificant associations between the forms with DIP involve-ment and MICB-CA20 Of a total of 50 patients with DIPinvolvement 12 had this allele compared to only 3 of 60without this type of articular involvement (24 versus 5

ISRN Dermatology 3



MICA-A9 15 (30) 33 (30) NS 66 (60) 33 (30) lt000001f


C1 4 4 (384) 28 (56) 25 (23) 00001b 60 (545) 25 (23) 00001h




lowast


lowastlowast


lowastlowastlowast



4 Discussion





4 ISRN Dermatology


5 Conclusion




Acknowledgment


References


















ISRN Dermatology 5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Dermatology 3



MICA-A9 15 (30) 33 (30) NS 66 (60) 33 (30) lt000001f


C1 4 4 (384) 28 (56) 25 (23) 00001b 60 (545) 25 (23) 00001h




lowast


lowastlowast


lowastlowastlowast



4 Discussion





4 ISRN Dermatology


5 Conclusion




Acknowledgment


References


















ISRN Dermatology 5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















4 ISRN Dermatology


5 Conclusion




Acknowledgment


References


















ISRN Dermatology 5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















ISRN Dermatology 5








of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















research article the region centromeric to hla-c is a key...

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