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The Region of 150 kb Telometic to HLA-C Is Associated with Psoriasis in the Jewish Population

2005; Elsevier BV; Volume: 125; Issue: 5 Linguagem: Inglês

10.1111/j.0022-202x.2005.23892.x

ISSN

1523-1747

Autores

Jesús Martínez‐Borra, Chaim Brautbar, Segundo González, Claes D. Enk, Antonio López‐Vázquez, Carlos López‐Larrea,

Tópico(s)

T-cell and B-cell Immunology

Resumo

The HLA-Cw*0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case–control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw*0602 nor the allele CDSN*TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1_4_4 (OR=2.6, 95% CI=1.4–4.7, pc=0.018) the octamer transcription factor (OTF)-3 gene (OR=2.6, 95% CI=1.6–4.3, pc=0.0001) and the α-helix coiled-coil rod homologue (HCR) gene (OR=2.5, 95% CI=1.3–4.5, pc=0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene. The HLA-Cw*0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case–control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw*0602 nor the allele CDSN*TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1_4_4 (OR=2.6, 95% CI=1.4–4.7, pc=0.018) the octamer transcription factor (OTF)-3 gene (OR=2.6, 95% CI=1.6–4.3, pc=0.0001) and the α-helix coiled-coil rod homologue (HCR) gene (OR=2.5, 95% CI=1.3–4.5, pc=0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene. corneodesmosin α-helix coiled-coil rod homologue psoriasis vulgaris single-nucleotide polymorphism Psoriasis vulgaris (PV) is a common inflammatory chronic disease characterized by keratinocyte hyperproliferation, and recruitment of T lymphocytes and mononuclear cells in the affected skin. The causes of psoriasis are still unknown, but there is clear evidence, from association, twin and family studies of a strong heritable component of the disease (Faber et al., 1974Faber E.M. Nall L. Watson W. Natural history of psoriasis in 61 twin pairs.Arch Immunol Rev. 1974; 109: 207-211Google Scholar; Bandrup et al., 1978Bandrup F. Hauge M. Henningse J. Eriksen B. Psoriasis in unselected series of twins.Arch Dermatol. 1978; 114: 874-878Crossref PubMed Scopus (92) Google Scholar). Although eight psoriasis susceptibility loci (designated PSORS1–7 and PSORS9) and a further 11 undesignated loci have been identified by genome-wide screening, linkage and association analysis have defined that MHC is the major genetic determinant related to psoriasis susceptibility (Capon et al., 2002Capon F. Munro M. Barker J. Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene.J Invest Dermatol. 2002; 118: 745-771Crossref PubMed Scopus (136) Google Scholar). Within the MHC complex, the allele HLA-Cw*0602 (Cw6) is the strongest association found in psoriasis (Brenner et al., 1978Brenner W. Gschnait F. Mayr R.W. HLAs B13, B17, B37 and Cw6 in psoriasis vulgaris: Association with age of onset.Arch Dermatol Res. 1978; 262: 337-339Crossref PubMed Scopus (74) Google Scholar). The possibility, however, exists that HLA-C is not the PSORS1 (the psoriasis gene in the MHC). Thus, not all psoriatic patients carry HLA-Cw6, especially in the case of most oriental populations, where many affected individuals carry HLA-Cw7. On the other hand, not all HLA-Cw6 psoriasis-associated haplotypes appear to confer equal risk of psoriasis in different populations (reviewed inElder et al., 2001Elder J.T. Nair R.P. Henseler T. et al.The genetics of psoriasis 2001.Arch Dermatol. 2001; 137: 1447-1454Crossref PubMed Google Scholar). Consequently, several case–control studies of genes located around the HLA-C locus have been performed to determine the association of such with PV. Significant associations have been observed between psoriasis and several genes located telomeric to HLA-C (Figure 1), namely the octamer-binding transcription factor-3 (OTF3) gene (González et al., 2000González S. Martínez-Borra J. Sanchez del Rio J. Santos-Juanes J. Lopez-Vazquez A. Blanco-Gelaz M. Lopez-Larrea C. The OTF3 gene polymorphism confers susceptibility to psoriasis independent of the association of HLA-Cw*0602.J Invest Dermatol. 2000; 115: 824-828Crossref PubMed Scopus (63) Google Scholar), the α-helix coiled-coil rod homologue (HCR) gene (Asumalahti et al., 2000Asumalahti K. Laitinen T. Itkonen-Vatjus R. et al.A candidate gene for psoriasis near HLA-C, HCR (PG8), is highly polymorphic with a disease-associated susceptibility allele.Hum Mol Genet. 2000; 9: 1533-1542Crossref PubMed Scopus (118) Google Scholar; O'Brien et al., 2001O'Brien K.P. Holm S.J. Nilsson S. et al.The HCR gene on 6p21 is unlikely to be a psoriasis susceptibility gene.J Invest Dermatol. 2001; 116: 750-754Crossref PubMed Scopus (0) Google Scholar) and the cornodesmosin (CDSN) gene (Allen et al., 1999Allen M.H. Veal C. Faassen A. Powis S.H. Vaughan R.W. Trembath R.C. Barker J.N.W.N. A non-HLA gene within the MHC in psoriasis.Lancet. 1999; 353: 1589-1590Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar; Jenisch et al., 1999Jenisch S. Koch S. Henseler T. et al.Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris.Tissue Antigens. 1999; 54: 439-449Crossref PubMed Scopus (73) Google Scholar; Tazi Ahnini et al., 1999Tazi Ahnini R. Camp N.J. Cork M.J. Mee J.B. Keohane S.G. Duff G.W. di Giovine F.S. Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.Hum Mol Genet. 1999; 8: 1135-1140Crossref PubMed Scopus (116) Google Scholar). Comparisons of different populations with different HLA profiles could be of value in identifying the genes involved in PV. Very limited information exists about the association of genes and polymorphic markers around HLA-C with psoriasis in the Jewish population. Interestingly, previous studies have shown that PV is not associated with HLA-Cw6 in this population, but is associated with the alanine in position 73 (Ala73), which is present in Cw6, Cw7 and some other alleles of HLA-C (Roitberg-Tambur et al., 1994Roitberg-Tambur A. Friedmann A. Tzfoni E.E. et al.Do specific pockets of HLA-C molecules predispose Jewish patients to psoriasis vulgaris.J Am Acad Dermatol. 1994; 31: 964-968Abstract Full Text PDF PubMed Scopus (44) Google Scholar). The Jewish population have a Caucasoid genetic profile, but differences have been found in allelic and HLA haplotypic frequencies (González-Roces et al., 1994González-Roces S. Brautbat C. Peña M. et al.Molecular analysis of HLA-B27 haplotypes in Caucasoids.Hum Immunol. 1994; 41: 127-134Crossref PubMed Scopus (29) Google Scholar; Roitberg-Tambur et al., 1995Roitberg-Tambur A. Witt C.S. Friedmann A. et al.Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews.Tissue Antigens. 1995; 46: 104-110Crossref PubMed Scopus (89) Google Scholar; Martínez-Laso et al., 1996Martínez-Laso J. Gazit E. Gomez-Casado E. et al.HLA-DR and DQ polymorphism in Ashkenazi and non-Ashkenazi Jews: Comparison with other Mediterraneans.Tissue Antigens. 1996; 47: 63-71Crossref PubMed Scopus (65) Google Scholar; Cox et al., 1999Cox S.T. Marsh S.G.E. Scott I. et al.HLA-A, -B, -C polymorphism in a UK Ashkenazi Jewish potential bone marrow donor population.Tissue Antigens. 1999; 53: 41-50Crossref PubMed Scopus (27) Google Scholar). Thus, the study of this population could help to identify the causative gene of this disease in the HLA region. In the present study we performed an association analysis of several polymorphic markers and genes spanning a region from HLA-B, to the CDSN gene, located 147 kb telomeric to HLA-C, in order to map the locus for susceptibility to psoriasis in the Jewish population. A total of 59 unrelated Israeli Jewish patients with PV and 79 unaffected population-matched controls were genotyped for HLA-B, HLA-C, three polymorphisms of CDSN, the polymorphism+251 of HCR (Asumalahti et al., 2000Asumalahti K. Laitinen T. Itkonen-Vatjus R. et al.A candidate gene for psoriasis near HLA-C, HCR (PG8), is highly polymorphic with a disease-associated susceptibility allele.Hum Mol Genet. 2000; 9: 1533-1542Crossref PubMed Scopus (118) Google Scholar), the HindIII polymorphism of OTF3, the microsatellite C1_4_4, and two non-coding SNPs close to HLA-C (Table I and Figure 1).Table IAllele frequencies of several polymorphic markers and genes located around HLA-C in healthy controls and patients with psoriasis in the Jewish populationMarkerAlleleControls (n=79)Patients (n=59)SNP7A53 (33.5%)51 (43.2%)G105 (66.5%)67 (56.8%)SNP9C53 (33.5%)51 (43.2%)T105 (66.5%)67 (56.8%)HLA-BB137 (4.4%)8 (6.7%)B144 (2.5%)10 (8.4%)B14022 (1.2%)10 (8.4%)B14012 (1.2%)–B573 (1.9%)3 (2.5%)HLA-CCw619 (12%)23 (19.5%)Cw727 (17%)23 (19.5%)Cw89 (5.7%)12 (10.1%)Ala73124 (78.4%)107 (90.6%)C1_4_438424 (15.2%)38 (32.2%)aOR=2.6, 95% CI=1.4–4.7, pc=0.018.OTF3OTF3-B50 (31.6%)65 (55.1%)bOR=2.6, 95% CI=1.6–4.3, pc=0.0001.OTF3-A108 (68.4%)53 (44.9%)HCR+251T22 (13.9%)34 (28.8%)cOR=2.5, 95% CI=1.3–4.5, pc=0.004.C136 (86.1%)84 (71.2%)CDSN619T128 (81%)94 (79.6%)1236T103 (65.2%)82 (69.5%)1243C98 (62%)80 (67.8%)CDSN*TTC43 (27.2%)44 (37.3%)The p-value has not been corrected by the number of locus studied.CSDN, corneodesmosin.a OR=2.6, 95% CI=1.4–4.7, pc=0.018.b OR=2.6, 95% CI=1.6–4.3, pc=0.0001.c OR=2.5, 95% CI=1.3–4.5, pc=0.004. Open table in a new tab The p-value has not been corrected by the number of locus studied. CSDN, corneodesmosin. No significant differences of HLA-B were found between PV patients and controls. In particular, no significant association of B13 and B57 alleles with disease susceptibility was found. A considerable incidence of the HLA-B14 in PV patients (8.4%vs 2.5%, p=0.051) was found. We performed a high resolution typing of the B14 individuals we found that all except two controls were B*1402 (B65) (OR=7.1, 95% CI=1.5–33.2, p=0.01). The significance of the association, however, was lost after correction. The allele HLA-Cw6 was increased in patients although not significantly (p=0.12). The Ala 73 was also studied. Although this polymorphism was increased in patients (90%vs 78%) it was not significantly associated with the disease. The analysis of SNP7 and SNP9, located at 7 and 4 kb centromeric to HLA-C, revealed that they were not associated with PV. The alleles SNP7A and SNP9C, which have been shown to be associated with PV in Caucasians (Veal et al., 2002Veal C.D. Capon F. Allen M.H. et al.Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.Am J Hum Genet. 2002; 71: 554-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar), are in disequilibrium with HLA-C since 34 out of 39 Cw6-positive individuals were positive for SNP7A and SNP9C. In order to address whether the susceptibility gene of psoriasis was located telomeric to HLA-C, the region between the CDSN gene and HLA-C was studied. Three SNP at positions 619, 1236, and 1243 of this gene that define the allele TTC, which has been found to be associated with psoriasis in several studies, were analyzed. We found that the frequency of the allele TTC was increased in patients although not significantly (p=0.09) (Table I). The HCR+251 polymorphism was also analyzed. A greater incidence of+251T allele in PV patients was detected (28%vs 13%, OR=2.5, 95% CI=1.3–4.5, pc=0.004). An association of the HindIII polymorphism of the OTF3 gene with PV was found. The frequency of the allele OTF3-B (HindIII) was 55% in patients and 31% in the controls (OR=2.6, 95% CI=1.6–4.3, pc=0.0001). In addition an association was also found between the allele 384 of the C1_4_4 microsatellite. The frequency of this allele was 32% in patients and only 15% in controls (OR=2.6, 95% CI=1.4–4.7, pc=0.018). The estimation of haplotypes was performed with the PHASE program (Table II). No haplotypic differences were found between patients and controls carrying the psoriasis associated alleles, although the haplotype B65-Cw8, described byJenisch et al., 1997Jenisch S. Nair R.P. Henseler T. Elder J.T. Marxen B. Krönke M. Westphal E. Association of type I psoriasis with the Cw*0802-DRB1*0102-DQB1*0501 haplotype in North-American multiplex families.in: Charron D. Genetic diversity of HLA. EDK Medical and Scientific, Paris1997: 712-715Google Scholar as associated with psoriasis, was increased in patients, although not significantly (OR=7.8, 95%=1.6–37, p=0.004, pc>0.3).Table IIDistribution of several HLA-B-Cw-CDSN haplotypes carrying the disease-associated alleles found in this study (indicated in bold) in both patients and controlsHaplotypesControls (n=79)Patients (n=59)OR (95% CI)B7-Cw7-C1_4_4(384)-OTF3B-251T-CDSN*TGC–1–B8-Cw7- C1_4_4(384)-OTF3B-251T-CDSN*TGC–1–B13-Cw6- C1_4_4(384)-OTF3B-251T-CDSN*TTC581.3 (0.7–7.5)B13-Cw7- C1_4_4(384)-OTF3B-251T-CDSN*TGC310.43 (0.04–4.3)B37-Cw6- C1_4_4(384)-OTF3B-251T-CDSN*TTC134.1 (0.4–41)B49-Cw7- C1_4_4(384)-OTF3B-251T-CDSN*TTC–3–B50-Cw6- C1_4_4(384)-OTF3B-251T-CDSN*TTC123.3 (0.2–30.9)B57-Cw6- C1_4_4(384)-OTF3B-251T-CDSN*TTC123.3 (0.2–30.9)B57-Cw7- C1_4_4(384)-OTF3B-251T-CDSN*TTT111.3 (0.8–21.9)B1402-Cw8- C1_4_4(384)-OTF3B-251C-CDSN*CTC2107.8 (1.6–37)ap=0.004, pc>0.3.CSDN, corneodesmosin.a p=0.004, pc>0.3. Open table in a new tab CSDN, corneodesmosin. These data suggest that the susceptibility region to psoriasis is located telomeric to HLA-C, between this gene and CDSN gene, in the Jewish population. The region of 150 kb between HLA-C and the CDSN gene has been intensely studied in order to identify the psoriasis susceptibility locus in the HLA (referred to as PSORS1). Although the allele Cw6 shows the strongest association with psoriasis in the HLA, evidence exists that the HLA-C gene itself may not be the primary locus responsible for psoriasis. Thus, there are many psoriatic patients that do not carry the Cw6 allele. This could be due to two reasons: to the locus heterogeneity and to the existence of several HLA-C alleles that predispose to disease. The locus heterogeneity means that several susceptibility genes located in different chromosomes could be involved in the disease in different patients and, therefore, Cw6 could be responsible for the disease in only a proportion of the patients. This does not, however, explain why different psoriatic HLA-Cw6-bearing haplotypes (B57-Cw6, B13-Cw6 and B37-Cw6) appear to confer different risk for psoriasis (Jenisch et al., 1998Jenisch S. Henseler T. Nair R.P. et al.Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: Strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.Am J Hum Genet. 1998; 63: 191-199Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Moreover, a Cw6-negative HLA-B/C haplotype (B65-Cw8) has been described that segregates with psoriasis (Jenisch et al., 1997Jenisch S. Nair R.P. Henseler T. Elder J.T. Marxen B. Krönke M. Westphal E. Association of type I psoriasis with the Cw*0802-DRB1*0102-DQB1*0501 haplotype in North-American multiplex families.in: Charron D. Genetic diversity of HLA. EDK Medical and Scientific, Paris1997: 712-715Google Scholar). Interestingly, this haplotype corresponds to the B*1402-Cw8 haplotype which is seen to be increased in the patients of our study. A second explanation would be that besides Cw6, other variants within the coding sequence of the HLA-C, which define specific antigen-binding pockets, could confer disease susceptibility. Thus, some case–control studies have reported a significant association of a specific amino acid residue of HLA-C (Ala-73) with psoriasis (Asahina et al., 1991Asahina A. Akazaki S. Nakanawa H. Kuwara S. Tokunaga K. Ishibashi Y. Juji T. Specific nucleotide sequence of HLA-C is strongly associated with psoriasis vulgaris.J Dermatol. 1991; 97: 254-258Google Scholar; Roitberg-Tambur et al., 1994Roitberg-Tambur A. Friedmann A. Tzfoni E.E. et al.Do specific pockets of HLA-C molecules predispose Jewish patients to psoriasis vulgaris.J Am Acad Dermatol. 1994; 31: 964-968Abstract Full Text PDF PubMed Scopus (44) Google Scholar; Mallon et al., 1997Mallon E. Bunce M. Wojnarowska F. Welsh K. HLA-Cw*0602 is a susceptibility factor in Type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics.J Invest Dermatol. 1997; 109: 183-186Crossref PubMed Scopus (81) Google Scholar); however, association of Ala-73 with psoriasis was not found in our study. It has been suggested that the disease polymorphism could lie within the regulatory region of the HLA-C; however, neither SNP7 nor SNP9 were associated with the disease. These polymorphisms have been described to be associated to a greater degree with psoriasis than Cw6 (Veal et al., 2002Veal C.D. Capon F. Allen M.H. et al.Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.Am J Hum Genet. 2002; 71: 554-564Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Due to this strong association and the proximity with HLA-C, it is to be expected that these polymorphisms would be in disequilibrium with the disease-associated alleles of HLA-C. The main evidence, however, provided by our study that the PSORS1 gene is located telomeric to HLA-C is the fact that the markers and genes telomeric to it, such as the microsatellite C1_4_4 and the OTF3 and HCR genes were found to be associated with the disease although the HLA-C itself does not achieve significance with the size of the sample studied. We have also found these loci to be associated with psoriasis in the Spanish population (González et al., 2000González S. Martínez-Borra J. Sanchez del Rio J. Santos-Juanes J. Lopez-Vazquez A. Blanco-Gelaz M. Lopez-Larrea C. The OTF3 gene polymorphism confers susceptibility to psoriasis independent of the association of HLA-Cw*0602.J Invest Dermatol. 2000; 115: 824-828Crossref PubMed Scopus (63) Google Scholar; Martínez-Borra et al., 2003Martínez-Borra J. Gonzalez S. Santos-Juanes J. et al.Psoriasis vulgaris and psoriatic arthritis share a 100 kb susceptibility region telomeric to HLA-C.Rheumatology. 2003; 42: 1089-1092Crossref PubMed Scopus (17) Google Scholar). Moreover, the HCR gene has been described to be strongly associated with the disease in several populations. The analysis of the haplotypes found in this study show a greater incidence of the haplotypes carrying the alleles C1_4_4(384), OTF3-B and HCR+251T in patients. The allele HCR+251T, however, is not always present in these haplotypes. Thus, the haplotype B65-Cw8, which carries the allele 384 of the microsatellite C1_4_4 and the allele OTF3-B, does not carry HCR+251T. This allele HCR+251T, however, is present in the haplotypes classically associated with psoriasis as B13-Cw6 and B57-Cw6. Although the B65-Cw8-C1_4_4(384)-OTF3B-251C-CDSN*CTC haplotype was found in 10 cases as opposed to only two controls, the sample size was too small to reach statistical significance after correction for multiple testing. As mentioned earlier, this haplotype segregates with psoriasis in some pedigrees (Jenisch et al., 1997Jenisch S. Nair R.P. Henseler T. Elder J.T. Marxen B. Krönke M. Westphal E. Association of type I psoriasis with the Cw*0802-DRB1*0102-DQB1*0501 haplotype in North-American multiplex families.in: Charron D. Genetic diversity of HLA. EDK Medical and Scientific, Paris1997: 712-715Google Scholar). Utilizing some of the same samples,Nair et al., 2000Nair R.P. Stuart P. Henseler T. et al.Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.Am J Hum Genet. 2000; 66: 1833-1834Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar previously reported overtransmission of this haplotype to psoriatic offspring. This result, however, could not be replicated in another larger sample (Cluster 17 collaboration, 2005Cluster 17 collaboration Fine mapping of the psoriasis susceptibility gene PSORS1: A reassessment of risk associated with a putative risk haploype lacking HLA-Cw6.J Invest Dermatol. 2005; 124: 921-930Crossref PubMed Scopus (17) Google Scholar), and association between psoriasis and this haplotype could not be verified in Sardinian psoriatics (Orru et al., 2005Orru S. Giuressi E. Carcassi C. Casula M. Contu L. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosing gene (CDSN).Am J Hum Genet. 2005; 76: 164-171Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Whether these differences reflect different gene-gene or gene-environment interactions in different populations, population-specific genetic variations on the same ancestral haplotype, or simply statistical fluctuation due to small sample size, remains to be determined. As for CDSN, this gene is associated with the disease in several populations, especially the allele CDSN*TTC (Tazi Ahnini et al., 1999Tazi Ahnini R. Camp N.J. Cork M.J. Mee J.B. Keohane S.G. Duff G.W. di Giovine F.S. Novel genetic association between the corneodesmosin (MHC S) gene and susceptibility to psoriasis.Hum Mol Genet. 1999; 8: 1135-1140Crossref PubMed Scopus (116) Google Scholar; Capon et al., 2003Capon F. Toal I.K. Evans J.C. et al.Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility.J Med Genet. 2003; 40: 447-452Crossref PubMed Scopus (36) Google Scholar); however, we have not found the association of this gene with PV in the Jewish population, although an association could be found in a larger sample. The allele CDSN*TTC was present in several haplotypes carrying the alleles associated with psoriasis, which explains their higher incidence in patients. The lack of this allele in other haplotypes, particularly in B65-Cw8, however, could explain the lack of association of this allele with the disease found in our study. In summary, our study of the Jewish population suggests that a major psoriasis susceptibility gene resides in a region of 150 kb between HLA-C and the CDSN gene and suggests that HLA-Cw6 itself may not be the causal variant. The role(s) of the remaining genes located in this region remain to be established, and the possibility exists that other unidentified genes located in this region could be responsible for the disease. Thus, several open reading frames have been found in this region (Capon et al., 2002Capon F. Munro M. Barker J. Trembath R. Searching for the major histocompatibility complex psoriasis susceptibility gene.J Invest Dermatol. 2002; 118: 745-771Crossref PubMed Scopus (136) Google Scholar). Linkage disequilibrium is generally maintained in the region telomeric to HLA-C, which hampers the confirmation of the gene primarily associated with psoriasis. This disequilibrium appears to have been broken in the Jewish population, which supports the conclusion, reported in other studies, that HLA-C is not the psoriasis gene (Oka et al., 1999Oka A. Tamiya G. Tomizawa M. et al.Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene.Hum Mol Genet. 1999; 8: 2165-2170Crossref PubMed Scopus (149) Google Scholar; Nair et al., 2000Nair R.P. Stuart P. Henseler T. et al.Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.Am J Hum Genet. 2000; 66: 1833-1834Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Thus, the study of different populations will allow us to reduce the boundaries of the minimal PSORS1 region. Note. While this manuscript was under review, a fine mapping study of the PSORS1 interval was published (Orru et al., 2005Orru S. Giuressi E. Carcassi C. Casula M. Contu L. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosing gene (CDSN).Am J Hum Genet. 2005; 76: 164-171Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Typing 17 markers spanning a 525 kb interval surrounding HLA-C, a minimal susceptibility region of 70 kb around CDSN was obtained. This fragment, which partially overlaps with the region defined by us, excludes HLA-C. Fifty-nine unrelated Jewish patients (39 male and 20 female) with early-onset chronic plaque psoriasis (type I) without any other extra-epithelial manifestation of psoriasis were included in the study. The mean age at onset of type I psoriasis was 27.4±13.9 y. Randomly matched healthy controls (79 individuals) from the same ethnic background as the patients were also analyzed. All patients gave written informed consent before enrolling in the study. The study was carried out with the approval of the ethics committee of our hospital and conducted according to the Declaration of Helsinki. HLA-C and HLA-B were typed using the polymerase chain reaction with sequence-specific primers (PCR-SSP) (Bunce et al., 1995Bunce M. Fanning G.C. Welsh K.I. Comprehensive, serologically equivalent DNA typing for HLA-B by PCR using sequence-specific primers (PCR-SSP).Tissue Antigens. 1995; 45: 81-90Crossref PubMed Scopus (129) Google Scholar,Bunce et al., 1996Bunce M. Barnardo M.C.N.M. Procter J. et al.High resolution HLA-C typing by PCR-SSP: Identification of allelic frequencies and linkage disequilibria in 604 unrelated random UK Caucasoids and a comparison with serology.Tissue Antigens. 1996; 48: 680-691Crossref PubMed Scopus (91) Google Scholar). High resolution typing of the B*14 allele was performed with the RELI-SSO typing kit (Dynal Biotech, Oslo, Norway). The Ala73 of HLA-C was analyzed by PCR as described byMallon et al., 1997Mallon E. Bunce M. Wojnarowska F. Welsh K. HLA-Cw*0602 is a susceptibility factor in Type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics.J Invest Dermatol. 1997; 109: 183-186Crossref PubMed Scopus (81) Google Scholar. The polymorphism of the OTF3 gene was analysed by PCR-restriction fragment length polymorphism (RFLP) as described previously (González et al., 2000González S. Martínez-Borra J. Sanchez del Rio J. Santos-Juanes J. Lopez-Vazquez A. Blanco-Gelaz M. Lopez-Larrea C. The OTF3 gene polymorphism confers susceptibility to psoriasis independent of the association of HLA-Cw*0602.J Invest Dermatol. 2000; 115: 824-828Crossref PubMed Scopus (63) Google Scholar). The SNP7, SNP9 and the polymorphisms of the HCR and CDSN genes were analysed by the amplification refractory mutation system (ARMS) (Newton et al., 1989Newton C.R. Graham A. Heptinstall L.E. et al.Analysis of any point mutation in DNA. The amplifications refractory mutation system (ARMS).Nucleic Acids Res. 1989; 17: 2503-2516Crossref PubMed Scopus (2013) Google Scholar) using the primers described in Table S1. Download .doc (.04 MB) Help with doc files Table S1Nucleotide sequences of the PCR primer pairs used for identification of the polymorphisms studied The microsatellite C1_4_4 was studied as inTamiya et al., 1998Tamiya G. Ota M. Katsuyama Y. et al.Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region.Tissue Antigens. 1998; 51: 337-346Crossref PubMed Scopus (68) Google Scholar. Fourteen alleles were detected and were named on the basis of the length of the amplified fragment. Allelic frequencies were calculated and the significance of the association was determined using the χ2 test with Yate's correction or alternatively the Fisher's exact test when the number of expected observations was less then five. The OR was calculated using the cross-product ratio. Exact 95% confidence intervals were obtained. The p values were corrected (pc) by multiplying these by the number of comparisons at every locus. Haplotypes were predicted from population data using the PHASE 2.1 program (Stephens et al., 2001Stephens M. Smith N.J. Donnelly P. A new statistical method for haplotype reconstruction from population data.Am J Hum Genet. 2001; 68: 978-989Abstract Full Text Full Text PDF PubMed Scopus (6191) Google Scholar). This work was partially support by Spanish Ministry of Education grant SAF 2004-02669 and by “Fondo de Investigation Sanitaria” grant FIS PI03-0067. Jesús Martínez-Borra is supported in part by Spanish Post-MIR program from “Fondo de Investigación Sanitaria”. We wish to thank David H. Wallace and James Traherne for critical revision of the manuscript.

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