Human Molecular Genetics, 2000, Vol. 9, No. 10 1533-1542
© 2000 Oxford University Press
A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele
Department of Medical Genetics, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland, 1Department of Dermatology, Oulu University Central Hospital, 90401 Oulu, Finland, 2Finnish Red Cross Blood Transfusion Service, Department of Tissue Typing, 00310 Helsinki, Finland, 3Department of Dermatology, Helsinki University Central Hospital, 00250 Helsinki, Finland, 4Department of Dermatology, Central Hospital of Päijät-Häme, 15850 Lahti, Finland and 5Finnish Genome Center, University of Helsinki, 00014 Helsinki, Finland
Received 15 February 2000; Revised and Accepted 11 April 2000.
DDBJ/EMBL/GenBank accession no. AF216493.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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A susceptibility gene for psoriasis, a chronic skin disorder, resides in chromosome 6p near the HLA-C locus. Sequencing of the region has allowed the identification of a new gene, HCR. We found that HCR is highly polymorphic with at least 12 coding variants. An association study of the new HCR polymorphisms and the previously suggested susceptibility alleles HLA-Cw*0602 and corneodesmosin allele 5 (CD*5) with psoriasis revealed a specific HCR variant associated with psoriasis susceptibility. However, the HLA-Cw*0602 allele was rarer in controls and associated with a stronger relative risk. Association analysis did not support CD*5 as a psoriasis susceptibility allele in our sample of patients (n = 100) and population-matched controls (n = 93) from an isolated population. We found HCR to be overexpressed in keratinocytes of psoriatic lesions compared with paired samples of healthy skin. Our results suggest a potential role for HCR in the pathogenesis of psoriasis.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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Psoriasis is a chronic skin disorder characterized by keratinocyte hyperproliferation, angiogenesis and inflammatory leukocyte infiltrates (1). It shows familial clustering, and in recent years, several candidate loci for psoriasis have been proposed (PSORS1–5) (2–5). The oldest and still strongest evidence exists for a susceptibility locus in the HLA region (PSORS1, OMIM#177900); in the earlier studies for the HLA-A and HLA-B loci (6,7) and later for the HLA-C locus (8,9). By DNA-based genotyping, the HLA-Cw*0602 allele has been found in many populations to be the best marker for the major risk allele of psoriasis. The proportion of patients who are HLA-Cw*0602 positive (54–80%), is four to five times higher than in population-based controls (10–20%) (10,11). Also linkage results from genome-wide scans place a major psoriasis locus on chromosome 6p21.3 (12,13). Recently, the susceptibility region for psoriasis has been tentatively narrowed to an interval of a few hundred kilobases either centromeric or telomeric to HLA-C (14,15).
A typical feature of psoriasis is lymphocyte, macrophage and neutrophil infiltration in the skin lesions. The HLA class I antigens (HLA-A, -B, -C) have an important role in immune response as antigen presenting molecules to CD8+ T lymphocytes (16). Current knowledge of the pathogenesis of psoriasis suggests, however, that CD4+ T lymphocytes may have a more important role in the disease process than CD8+ cells (17). The class I antigens can also inhibit NK cell-mediated cytotoxicity through killer cell-inhibitory receptors (KIRs), but the significance of NK cells in psoriasis has remained contradictory (1,18). Therefore, the psoriasis susceptibility gene may not be HLA-C, but instead another gene in linkage disequilibrium (LD) with the HLA-C locus. Indeed, the corneodesmosin gene allele 5 (CD*5) has been found to be linked with psoriasis by the transmission disequilibrium test and CD has been suggested to be a prime functional candidate for the psoriasis susceptibility gene (19–21).
The HLA region has been completely sequenced, and most if not all of its genes have been predicted by sequence analysis (22). In the immediate neighborhood of HLA-C, there are only four known functional genes: HLA-B, OTF3, TCF19 and CD (Fig. 1). We determined the structure of a new gene predicted from the genomic sequence. This gene was first called Pg8 (for putative gene 8, a suggested tricohyalin homolog) (23) and more recently HCR (for 
-helix coiled coil rod homolog) (15) (GenBank accession no. AB029331). Due to its genomic position between HLA-C and CD and from preliminary data on its expression in keratinocytes, HCR must be considered as an interesting candidate for a psoriasis susceptibility gene.
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We screened the HCR gene for sequence variations and found that it is highly polymorphic with at least 12 coding variants. The HCR polymorphisms were analyzed together with HLA-Cw*0602 and CD*5 for association with psoriasis in patients and population-matched controls from a Finnish subisolate. We found a specific HCR variant associated with psoriasis susceptibility, whereas association analysis did not support CD*5 as a psoriasis susceptibility gene. We found HCR to be overexpressed in keratinocytes at psoriatic lesions. Our results suggest a potential role for HCR in the pathogenesis of psoriasis.
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RESULTS |
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Gene structure and expression pattern
We predicted the exon–intron structure of the HCR gene from the sequence of the genomic clone Y24c027 (GenBank accession no. AC004195) by using two different gene prediction programs, FGENES and GENSCAN. To verify the coding sequence, we designed primers specific for the predicted exons; these were then used in RT–PCR with keratinocyte RNA, and the amplified products sequenced. Compared with the verified cDNA sequence, FGENES had predicted the intragenic exon structure exactly right, whereas GENSCAN had merged exons 12 and 13 into one exon. The gene consists of 16 exons, varying in size from 46 to 304 bp (Fig. 2). The coding sequence of HCR was confirmed to be 2271 bp, encoding a protein of 757 amino acids (GenBank accession no. AF216493). HCR was shown to be expressed by RT–PCR at variable levels in all human tissues tested, most abundantly in heart, liver, skeletal muscle, kidney and pancreas, and more weakly in lung and placenta (Fig. 3).
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Detection of HCR polymorphisms
To detect sequence variations, we screened all exons in five psoriasis patients and one control by parallel SSCP analysis and direct sequencing of PCR products. Two patients were chosen among the HLA-Cw*0602-positive and three among the HLA-Cw*0602-negative to enrich for different variants. Altogether, 18 polymorphisms were found in the coding region distributed in eight exons (Table 1). All sequence variants were single nucleotide polymorphisms (SNPs). Eleven SNPs were predicted to cause an amino acid change, nine of them non-conservative, and one SNP introduced a stop codon. Exons 2 and 8 were the most polymorphic, with five and four SNPs, respectively. We did not screen introns systematically, but found seven non-coding SNPs in the small introns 3, 7, 10 and 12 that were included in amplicons containing flanking exons. The Mendelian segregation of each SNP was confirmed in 22 families.
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Patients and controls
Altogether, 142 psoriasis patients and 210 family members (total of 100 families) were recruited from the central-eastern part of Finland (the Kainuu province) during January 1996. In addition, we recruited 93 population-based controls. Sample collection was approved by the Ethical Review Boards of the Kainuu Central Hospital and the Department of Medical Genetics, University of Helsinki, and all samples were used with informed consent.
The clinical characteristics of the study subjects are shown in Table 2. The subgroup with familial psoriasis consists of patients (n = 71) who have at least one affected first-degree family member. Fifty-three of familial psoriasis patients had developed psoriasis before the age of 40 (type I psoriasis).
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Association analyses
All unrelated psoriasis patients (n = 100, one from each family) and 93 population-based controls were included in an association study. HLA-Cw*0602 was genotyped using the PCR–SSP method, and CD*5 using PCR and restriction digestion. HCR SNPs were screened using SSCP, direct sequencing or restriction digestion of PCR products.
Thirty-seven of the patients (37%) and eight of the controls (9%) were HLA-Cw*0602-positive (P = 0.0000031). Two HCR SNPs in exon 2 associated significantly with psoriasis (Table 3). Both SNPs changed an amino acid from tryptophan to arginine, and in all instances they occurred together; we call this the Arg–Arg allele (HCR*Arg–Arg). Forty-two percent of the patients (42/100) compared with 19% of the controls (18/93) had HCR*Arg–Arg, showing significant excess of HCR*Arg–Arg among patients (P = 0.00068, Table 4). Both HLA-Cw*0602 and HCR*Arg–Arg associations were even stronger among type I psoriasis patients (52 versus 9%, P = 0.00000015 and 61 versus 19%, P = 0.0000099, respectively).
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All the HLA-Cw*0602-positive patients (37/37) were also HCR*Arg–Arg positive. In the control group, HLA-Cw*0602 was also always found in association with HCR*Arg–Arg (8/8). Among the HLA-Cw*0602-negative patients, 8% (5/63) had HCR*Arg–Arg, which did not differ significantly from the proportion of HLA-Cw*0602-negative HCR*Arg–Arg-positive controls (10/85, 12%). These results suggested that HLA-Cw*0602 and HCR*Arg–Arg are in strong linkage disequilibrium among both patients and controls.
We next considered two CD SNPs that together form the allele CD*5 (+619 T, +1243 C) and that have been reported to associate with psoriasis (19–21). In our material, CD*5 was the major allele in both the patient and control groups. Eighty-six percent (86/100) of patients and 85% (79/93) of controls had CD*5 and thus we could not detect any disease association (Table 4). We did not observe any significant deviations from the Hardy–Weinberg equilibrium for HCR or CD gene.
Haplotype analysis
We genotyped all family members in 30 psoriasis families to study an eight-marker haplotype including HLA-Cw*0602, five HCR SNPs representing different exons (+269, +715, +1667, +2122, +2271) and two CD SNPs (+619, +1243). Two additional CD SNPs at +1215 and +1236 were genotyped to differentiate between the CD2 and CD3 haplotypes (21) in all HLA-Cw*0602-positive chromosomes. Sixty-nine eight-marker haplotypes could be determined unambiguously and 15 of the chromosomes were HLA-Cw*0602-positive. Altogether 17 different haplotypes were detected.
Among the HLA-Cw*0602-positive chromosomes, a single five-marker haplotype was seen for HCR (Table 5). All 13 HLA-Cw*0602-positive patient chromosomes had the same HCR susceptibility haplotype, but for the CD gene, the haplotype was broken into three different haplotypes. None of the HLA-Cw*0602-negative haplotypes associated with psoriasis by chi-squared analysis.
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Tissue in situ hybridization
We examined HCR expression in paired biopsies from psoriasis lesions and normal-looking skin from six psoriasis patients and from three unaffected individuals by in situ hybridization (Fig. 4). HCR expression appeared strong in keratinocytes of psoriatic lesions. The samples from healthy-appearing skin of psoriasis patients and from unaffected individuals remained negative even after 40 days of exposure. These results suggested upregulation of HCR in psoriatic keratinocytes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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PSORS1 at 6p21.3 has been the most consistently observed susceptibility locus for psoriasis in both linkage and association studies. Our data suggest that HCR (Pg8) has many characteristics of a psoriasis susceptibility gene located in the HLA region and, specifically, it emerges as a better candidate than CD. This conclusion is based on several lines of evidence.
The region of interest for a psoriasis susceptibility gene has been narrowed down to a few hundred kilobase interval around the HLA-C locus (14,15). The role of HLA-C as a causative gene in the pathogenesis of psoriasis is unclear. Of the non-HLA genes in the region, CD has been suggested to be involved in skin desquamation, making it a tempting candidate for a psoriasis susceptibility gene. CD was reported to carry an HLA-C-independent effect and CD*5 was suggested as a risk allele (19–21). HCR localizes in the most promising interval for a psoriasis susceptibility gene, between HLA-C and CD, but we are not aware of any studies assessing its role in psoriasis directly. The OTF3 and TCF19 genes, located very close to HCR, are most likely to have housekeeping functions and no polymorphism has been described in these genes so far (24).
We verified the structure of HCR and found that its amino acid sequence shows little homology with known proteins; the strongest homologies are with various myosins. The corresponding porcine gene in the MHC region has been cloned (GenBank accession no. AJ251914). The secondary structure of the HCR protein is predicted to consist mainly of -helical coils and it may be a nuclear protein with a leucine zipper motif. The predictions do not allow specific suggestions beyond speculations about the physiological role of HCR.
We found that HCR is highly polymorphic, including 11 predicted amino acid substitutions and one truncated variant. Of these variants one, named HCR*Arg–Arg, is associated with psoriasis [relative risk (RR) 2.1, 95% confidence interval (CI) 1.7–2.6, P = 0.00068]. It was present in all psoriasis-associated HLA-Cw*0602 chromosomes, but its frequency was higher than that of HLA-Cw*0602 among control chromosomes; thus HLA-Cw*0602 associated with psoriasis even more strongly (RR 4.3, 95% CI 3.1–5.0, P = 0.0000031). HCR*Arg–Arg was also detected in HLA-Cw*0602-negative chromosomes, suggesting that it might be an older variant than HLA-Cw*0602. The proposed different age of the two variants might explain the difference in the relative risk and strength of association. However, we cannot exclude the possibility that HCR*Arg–Arg together with HLA-Cw*0602 forms the risk allele. Further association studies of both genes in larger sets of psoriasis patients and controls from different populations are obviously needed to verify and refine these suggestions.
We found the previously suggested psoriasis susceptibility allele CD*5 at a high frequency (85–86%) among both psoriasis patients and controls. This observation argues strongly against CD*5 as a major psoriasis susceptibility allele, because the prevalence of psoriasis is 1–2% in the population studied; a strong effect of such a common variant should cause a much higher disease incidence. Furthermore, our haplotype analysis showed that a single susceptibility haplotype was intact across the HLA-C and HCR genes, but split into three haplotypes in CD. When intragenic SNP haplotypes for both HCR and CD were determined among HLA-Cw*0602-positive chromosomes, a single five-marker haplotype was detected for HCR, whereas three different four-marker haplotypes were present for CD, including non-CD*5 haplotypes. Thus, we conclude that HCR is a better candidate than CD for a psoriasis susceptibility gene by genetic association analysis.
HCR was expressed at high levels in the keratinocytes in psoriatic skin lesions whereas in paired samples from normal appearing skin it was barely detectable. At least one gene, amphiregulin, has been found to be overexpressed in psoriatic skin lesions, and transgenic mice with overexpression of amphiregulin in the skin develop lesions similar to psoriasis (25). It will be informative to study similarities and differences in the expression of both genes in the psoriatic process.
In conclusion, we have studied HCR, a new highly polymorphic gene near HLA-C, which by position, genetic association results and expression pattern in normal and psoriatic skin must be considered a candidate gene for psoriasis susceptibility. Its primary sequence suggests -helical rod structure but gives little additional insight to its physiological role. Further association and functional studies with HCR are highly warranted to find out its role in the pathogenesis of psoriasis.
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MATERIAL AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIAL AND METHODSREFERENCES |
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Gene structure
Exon–intron structure of the HCR (Pg8) gene was predicted from a genomic clone (GenBank accession no. AC004195) using two different gene prediction programs GENSCAN (http://ccr-081.mit.edu/GENSCAN.html ) and FGENES (http://dot.imgen.bcm.tmc.edu:9331/gene-finder/gf.html ). To amplify the HCR cDNA, RNA was extracted (RNeasy Mini Kit, Qiagen, Valencia, CA) from a primary keratinocyte cell line (54A III/IV) and RT–PCR [M-MLV Reverse Transcriptase, Promega (Madison, WI) and Random Hexamer primers, Research Genetics (Huntsville, AL)] was carried out using the manufacturer’s protocol. The coding regions of the HCR gene were identified from the cDNA by direct sequencing using the primer pairs: CCA CCT GGC TCT CAG ACA TT and GTG CAG CCT CTG AAC CTC TT (exons 1 and 2); AGC AGG CTG AGG TGA TCGT and CCC TTC AGC TGC TTA ACA GAG (exons 2–6); ATT CCC TGG AGC CTG AGT TT and CCT CCT GCT GGA TGA GGC (exons 6–11); GGT CAC AGA TGT GAG CCT TG and GCT GGA GCA TCT GTC AAG GT (exons 11–16). The primers were designed using the Primer3 program (26). A rough starting point for transcription was detected by PCR amplification using alternative forward primers designed to stepwise upstream and to find the site where no PCR product was obtained from cDNA. Genomic DNA was used as a positive control and all amplified products were sequenced. The end of transcription was detected by comparing several ESTs with the sequence obtained from keratinocyte cDNA and genomic DNA. The open reading frame was detected with the program DNAWorks.
PCR assays were carried out in a 50 µl volume containing 5 µl cDNA, 1x PCR buffer (10 mM Tris–HCl, 50 mM KCl, 0.1% Triton X-100), 440 µM dNTPs, 2.2 mM MgCl2, 1 µM primer mix and 2 U of DNA polymerase (DyNAzyme EXT, Finnzymes, Espoo, Finland). The samples were denatured for 3 min at 94°C, followed by 32 cycles each of 60 s at 94°C and 180 s at 68°C. Purification of the PCR products was performed using a gel extraction kit (Qiagen). Sequencing was performed by dye-terminator chemistry in both directions using an ABI 373A sequencer.
Patient and control samples
We informed people in Kainuu about the study through the local psoriasis patient organization, health care centers and the dermatological clinic of Kainuu Central Hospital. The Kainuu population represents a late settled region of Finland (27). At the end of the 16th century, Kainuu was inhabited by only a few hundred unrelated founders. The population remained small until rapid expansion occurred at the end of the 19th century, leading to the present population of ~100 000. Based on our genealogical study, 65% of the patients’ grandparents originated in Kainuu proper, and most of the remaining grandparents originated in the neighboring, often southern municipalities. Our sample set represents 5–10% of all psoriasis patients in the region.
Based on self-reported psoriasis, probands were selected for an interview and a clinical examination was performed by a senior dermatologist (R. Itkonen-Vatjus). The diagnosis was confirmed for 142 patients accepted into the study. To allow haplotyping, 210 unaffected family members were also recruited from 100 families. Both the probands and their family members donated blood samples and filled out a health questionnaire. All participants gave written, informed consent for access to their medical records to verify disease history, and the Ministry of Social and Health Affairs granted permission to access the patients’ medical records. As population-based controls, we used DNA samples from healthy individuals from the same recruitment area. DNA was extracted from venous blood using a standard non-enzymic method. The study protocol was approved by the Ethical Review Board of the Kainuu Central Hospital and the Department of Medical Genetics, University of Helsinki.
Screening for polymorphisms
Five psoriasis patients and one control sample were used for screening sequence variations with 12 different primer pairs covering all exons: CCC TCC CAC TTT CAA GCTC and TTC CAG TGA GGA AGG GTC AC (exon 1); CAC CTG CAC TAA CCT GTC TTTG and TTT CTA CCC CTG CAT TCA CC (exon 2); CTT CTT TCC GCA GCT GTC CT and TCC CTA AGT CTG CAC ACA GAT (exons 3 and 4); TAC AGA GGG GCT GCT TTC CT and GCT GAG GGT GAG GGG TCT (exon 5); AAA GAT GCC ACC TCC TTC CT and GAG GGA ATA CCG GGA GAA AA (exon 6); CTG CCC AGC TCT CTC TCCT and CTC CAT CCC TGA TAC CTG CT (exons 7 and 8); GGA TCA GTG ACT TGT GCC CT and GTG GCT CGC AGT TGT CCT AC (exon 9); TTT CTC CCT GCT TTT TCC CT and CTC ATC CTC TCC ACC CTC TG (exons 10 and 11); TCC TTT TAG GGG AGG CAG AG and AAG GCC CTA TCC ACC CTG (exons 12 and 13); TGC CTT GGC CTC TCT GTA GT and TCT GCC CTC CTG TCT CCT AC (exon 14); GCT CTA TCC GGG CTA GGT TT and CCC TTG TCC CTT TGT GCTT (exon 15); TGG TGC TCA TCT GCT GTC TT and CTT TCC CTC CAA CTG TCA GC (exon 16).
PCR assays were carried out in 50 µl vol containing 50 ng of genomic DNA, 1x PCR buffer (10 mM Tris–HCl, 50 mM KCl, 0.1% Triton X-100), 100 µM dNTPs, 1 mM MgCl2, 0.12 µM primer mix, 1% DMSO and 2 U of DNA polymerase (DyNAzyme II, Finnzymes). The samples were denatured for 5 min at 96°C, followed by 35–38 cycles each of 30 s at 96°C, 120 s at 57–64°C and 120 s at 72°C. Elongation was performed for 5 min at 72°C. Purified (PCR purification kit, Qiagen) PCR products were sequenced using an ABI 373A sequencer and dye-terminator chemistry.
Association analyses
DNA samples were genotyped for HLA-Cw*0602 using the Class I SSP ARMS–PCR method (28) and for the HCR sequence variations using SSCP, sequencing and restriction digestion. The primers and PCR protocols used were as described above. The six fully sequenced samples were used as references, but we also sequenced all variant band patterns observed in SSCP to confirm the polymorphisms. SSCP gel was prepared in a 50 ml volume containing 10–12.5 ml of 2x MDE gel solution (FMC BioProducts, Rockland, ME), 6 ml of 5x TBE, 100 µl of 10% APS and 40 µl of TEMED, and the samples were electrophoresed for 17–20 h at 2–4 W. In exon 8, the SNPs were identified using direct sequencing in 50 patients and 50 controls. In addition, seven polymorphisms were verified using altered restriction site recognizing enzymes. Digestions were performed in 20 µl reactions containing 10 µl of PCR product and 2.5 U of either PstI (+249), AvaII (+269), Tsp509I (+421), BsmFI (+715), MslI (+1667), SfaNI (+2122) or MwoI (+2271) and the appropriate buffer provided by the manufacturer (New England Biolabs, Beverly, MA).
The SNPs of CD*5 were amplified with primer pairs S5/S6 (+619) and S15/S16 (+1243) and analyzed with restriction site recognizing enzymes (MnlI for +619 and HphI for +1243) as described previously (29). The SNPs at +1215 and +1236 were detected by sequencing the primer pair S15/S16 product.
Statistical significance of the differences in the allele frequencies between patients and controls was calculated using the chi-square test. Relative risk was calculated using the formula [a/(a + c)]/[b/(b + d)], where a is the number of patients with the risk allele; c the number of patients without the risk allele; b and d are the equivalent values in the controls, respectively.
Haplotype classification
The haplotypes were constructed manually. For each family, the chromosome was classified as trait-associated if it occurred in any affected family member and as a control if it occurred only in unaffected family members. Each chromosome was counted only once per family.
Expression analyses
The tissue expression of the HCR gene was studied by PCR amplification (Human Multiple Tissue cDNA panel I, Clontech, Palo Alto, CA) using the primer pair GGT CAC AGA TGT GAG CCT TG and GCT GGA GCA TCT GTC AAG GT (exons 11–15). GAPDH was used as a housekeeping control gene and was amplified using the primer pair GAA GGT GAA GGT CGG AGT CA and CTT CTA CCA CTA CCC TAA AG (PE Biosystems, Foster City, CA). The PCR amplifications for both genes were performed in 50 µl reactions using 35 cycles.
Skin specimens for in situ hybridization were obtained from the Department of Dermatology, University of Helsinki. The following subgroups of histological sections were examined: three samples of normal skin from different parts of the body, paired biopsies from psoriasis plaques and normal looking skin from six psoriasis patients. For in situ hybridization, a probe was generated by PCR amplification of the keratinocyte cell line 54A III/IV by RT–PCR with random hexamer primers as described above as well as primers ATT TAG GTG ACA CTA TAC att ccc tgg agc ctg agt tt and TAA TAC GAC TCA CTA TAc ctc ctg ctg gat gag gc, introducing T7 and Sp6 RNA polymerase promoter sequences at opposite ends of the 628 bp gene-specific product. In vitro transcribed antisense and sense RNA probes were labeled with [35S]UTP. In situ hybridization was performed at 50°C overnight on formalin-fixed paraffin-embedded specimens using 4 x 104 c.p.m./ml of labeled probe with subsequent washing under stringent conditions, including treatment of RNase A (30,31). Following autoradiography for 20–40 days, the photographic emulsion was developed and the slides were stained with hematoxylin and eosin for microscopy.
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ACKNOWLEDGEMENTS |
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The authors wish to thank Ms Liisa Rajasalo and Ms Päivikki Pajunen and their staff in the Kainuu Central Hospital for their invaluable help in the recruitment of the patients. We also wish to thank Mr Vesa Ollikainen for his valuable advice concerning the statistical analysis. This study was supported by the Academy of Finland, the Sigrid Juselius Foundation and Helsinki University Research Funds.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +358 9 191 26538; Fax: +358 9 191 26789; Email: juha.kere@helsinki.fi
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REFERENCES |
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