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The Association of Psoriasis with Human Leukocyte Antigens in Korean Population and the Influence of Age of Onset and Sex

2000; Elsevier BV; Volume: 114; Issue: 2 Linguagem: Inglês

10.1046/j.1523-1747.2000.00863.x

ISSN

1523-1747

Autores

Tai‐Gyu Kim, Ho Jae Han, Hyejung Lee, Jai Il Youn, Tae‐Yoon Kim,

Tópico(s)

Cytokine Signaling Pathways and Interactions

Resumo

To identify HLA markers that may contribute to the genetic susceptibility of Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The distribution of HLA markers and the associated haplotypes were analyzed according to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis (relative risk = 36.0, p < 10−8, Pc < 8 × 10−7). The frequencies of A1 (relative risk = 17.0, p < 9 × 10−7, Pc < 7 × 10−5), A30 (relative risk = 5.5, p < 2 × 10−5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 × 10−6, Pc < 3 × 10−4), B37 (relative risk = 30.3, p < 7 × 10−7, Pc < 6 × 10−5), DRB1*07 (relative risk = 5.9, p < 2 × 10−6, Pc < 8 × 10−5), DRB1*10 (relative risk = 26.4, p < 4 × 10−6, Pc < 3 × 10−4), DQA1*02 (relative risk = 6.2, p < 5 × 10−7, Pc < 4 × 10−4), DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk = 24.6, p < 9 × 10−6, Pc < 7 × 10−4) were also significantly increased in Korean psoriasis patients. Type I and type II psoriasis were subdivided into groups of below and above 30 y of age, because of the significant difference found in HLA-Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0.009). In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13-Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13-DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis. The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered to be a high-risk factor in Koreans. To summarize, this study demonstrates the differential association of HLA according to sex, and identifies a newly found high-risk haplotype and a protective haplotype in Korean psoriasis patients. To identify HLA markers that may contribute to the genetic susceptibility of Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The distribution of HLA markers and the associated haplotypes were analyzed according to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis (relative risk = 36.0, p < 10−8, Pc < 8 × 10−7). The frequencies of A1 (relative risk = 17.0, p < 9 × 10−7, Pc < 7 × 10−5), A30 (relative risk = 5.5, p < 2 × 10−5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 × 10−6, Pc < 3 × 10−4), B37 (relative risk = 30.3, p < 7 × 10−7, Pc < 6 × 10−5), DRB1*07 (relative risk = 5.9, p < 2 × 10−6, Pc < 8 × 10−5), DRB1*10 (relative risk = 26.4, p < 4 × 10−6, Pc < 3 × 10−4), DQA1*02 (relative risk = 6.2, p < 5 × 10−7, Pc < 4 × 10−4), DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk = 24.6, p < 9 × 10−6, Pc < 7 × 10−4) were also significantly increased in Korean psoriasis patients. Type I and type II psoriasis were subdivided into groups of below and above 30 y of age, because of the significant difference found in HLA-Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0.009). In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13-Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13-DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis. The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered to be a high-risk factor in Koreans. To summarize, this study demonstrates the differential association of HLA according to sex, and identifies a newly found high-risk haplotype and a protective haplotype in Korean psoriasis patients. amplification refractory mutation system sequence specific oligonucleotide probes relative risk Psoriatic lesions are characterized by epidermal hyperplasia and the presence of acute and chronic inflammatory cells. Activated lymphocytes, other immune accessory cells and lymphokines have also been detected in psoriatic plaques (Elder et al., 1994aElder J.T. Nair R.P. Gue S.W. Henseler T. Chrostophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Scopus (222) Google Scholar;Henseler, 1997Henseler T. The genetics of psoriasis.J Am Acad Dermatol. 1997; 37: S1-S11Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar;Elder and Voorhees, 1998Elder J.T. Voorhees J.J. Psoriasis.in: Jameson J.L. Principles of Molecular Medicine. Humana Press Inc, Totowa1998: 793-800Crossref Google Scholar). It has been estimated that 1–3% of the population are affected by psoriasis in most countries (Ikäheimo et al., 1996aIkäheimo I. Silvennoinen-Kassinen S. Karvonen J. Jarvinen T. Tiilikainen A. Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2, B13, Cw6, DR7, DQA1*0201 and A1, B17, Cw6, DR7, DQA*0201.Arch Dermatol Res. 1996; 288: 63-67Crossref PubMed Scopus (37) Google Scholar). Epidemiologic studies, including concordance rates in twin pairs and siblings suggest that genetic factors are strongly involved in the pathogenesis of the disease (Elder et al., 1994bElder J.T. Nair R.P. Voorhees J.J. Epidemiology and the genetics of psoriasis.J Invest Dermatol. 1994; 102: 24s-27sCrossref PubMed Scopus (63) Google Scholar). Psoriasis has been reported to be significantly associated with the HLA-A1, A2, A30, B13, B17 (B57, B58), B37, B39, B46, Cw6, Cw7, Cw9, Cw11, DR7, and DQA1*0201. This relationship, however, tends to vary between patients of different racial and ethnic backgrounds (Tiwari et al., 1982Tiwari J.L. Lowed N.J. Abramovits W. Hawkins B.R. Park M.S. Association of psoriasis with HLA-DR7.Br J Dermatol. 1982; 106: 227-230Crossref PubMed Scopus (25) Google Scholar;Tiwari and Terasaki, 1985Tiwari J.L. Terasaki P.I. Dermatology.in: HLA and Disease Association. Springer-Verlag, New York1985: 112-127Crossref Google Scholar; Elder et al., 1994aElder J.T. Nair R.P. Gue S.W. Henseler T. Chrostophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Scopus (222) Google Scholar;Muto et al., 1995Muto M. Nagai K. Mogami S. Nakano J. Sasazuki T. Asagami C. HLA antigens in Japanese patients with psoriatic arthritis.Tissue Antigens. 1995; 43: 362-364Crossref Scopus (28) Google Scholar; Ikäheimo et al., 1996aIkäheimo I. Silvennoinen-Kassinen S. Karvonen J. Jarvinen T. Tiilikainen A. Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2, B13, Cw6, DR7, DQA1*0201 and A1, B17, Cw6, DR7, DQA*0201.Arch Dermatol Res. 1996; 288: 63-67Crossref PubMed Scopus (37) Google Scholar;Henseler, 1997Henseler T. The genetics of psoriasis.J Am Acad Dermatol. 1997; 37: S1-S11Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar;Ikäheimo et al., 1997Ikäheimo I. Silvennoinen-Kassinen S. Karvonen J. Tiilikainen A. The frequency of QAP2.1 is increase in psoriasis vulgaris patients but no unusual linkage between QAP/DQA1 or DBP/DQB1.Arch Dermatol Res. 1997; 289: 373-377Crossref PubMed Scopus (4) Google Scholar;Elder and Voorhees, 1998Elder J.T. Voorhees J.J. Psoriasis.in: Jameson J.L. Principles of Molecular Medicine. Humana Press Inc, Totowa1998: 793-800Crossref Google Scholar). The largest and most consistently reported relative risk (RR) factor for psoriasis is HLA-Cw6 (Asahina et al., 1991Asahina A. Akazaki S. Nakagawa H. Kuwata S. Tokunaga K. Ishibashi Y. Juji T. Analysis of a specific HLA-C gene sequence in Japanese patients with psoriasis vulgaris.in: Tsuji K. Aizawa M. Sasazuki T. HLA. Vol. I. Oxford University Press, Oxford1991: 535-536Google Scholar,Asahina et al., 1996Asahina A. Kuwata S. Tokunaga K. Juji T. Nakagawa H. Study of aspartate at residue 9 HLA-C molecules in Japanese patients with psoriasis vulgaris.J Dermatol. 1996; 13: 125-133Scopus (19) Google Scholar;Ikäheimo et al., 1994Ikäheimo I. Silvennoinen-Kassinen S. Karvonen J. Tiilikainen A. Alanine at position 73 of HLA-C is associated with psoriasis vulgaris in Finland.Br J Dermatol. 1994; 131: 257-259Crossref PubMed Scopus (33) Google Scholar). Furthermore, HLA-Cw*0602 was reported to have a strong association with the age of disease onset before 40 y, which showed significant differences at familial inheritance rates (Henseler and Christophers, 1985Henseler T. Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris.J Am Acad Dermatol. 1985; 13: 450-456Abstract Full Text PDF PubMed Scopus (730) Google Scholar; Elder et al., 1994aElder J.T. Nair R.P. Gue S.W. Henseler T. Chrostophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Scopus (222) Google Scholar;Krueger and Duvic, 1994Krueger G.G. Duvic M. Epidemiology of psoriasis; Clinical Issues.J Invest Dermatol. 1994; 102: 14s-18sCrossref PubMed Scopus (110) Google Scholar;Enerbäck et al., 1997Enerbäck C. Martinsson T. Inerot A. Wahlström J. Enlund F. Yhr M. Swanbeck G. Evidence that HLA-Cw6 determines early onset of psoriasis obtained using sequence-specific primers (PCR-SSP).Acta Derm Venereol. 1997; 77: 273-276PubMed Google Scholar).Ikäheimo et al., 1996aIkäheimo I. Silvennoinen-Kassinen S. Karvonen J. Jarvinen T. Tiilikainen A. Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2, B13, Cw6, DR7, DQA1*0201 and A1, B17, Cw6, DR7, DQA*0201.Arch Dermatol Res. 1996; 288: 63-67Crossref PubMed Scopus (37) Google Scholar have demonstrated the presence of HLA-A2-B13-Cw6-DR7-DQA1*0201 and HLA-A1-B17-Cw6-DR7-DQA1*0201 and similarlyNakagawa et al., 1991Nakagawa H. Akazaki S. Asahina A. et al.Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis.Arch Dermatol Res. 1991; 283: 281-284Crossref PubMed Scopus (57) Google Scholar have shown the presence of HLA-A2-Cw11-B46-C2C-BFs-C4A4-C4B2-DR8 in Finnish and Japanese psoriasis populations, respectively. To identify HLA markers that may contribute to the genetic susceptibility to psoriasis, we investigated the distributions of HLA alleles in 84 Korean psoriasis patients and the associated haplotypes were analyzed. The subjects were 84 Korean patients (46 women and 38 men) who registered at the department of dermatology, Seoul National University Medical School. The ages of the patients ranged from 12 to 83 y. Their results were compared with those of a control group, which was comprised of 98 Korean drawn from the normal population. Peripheral blood (10 ml) was collected and heparinized mononuclear cells were isolated by density gradient centrifugation a Ficoll-Hypaque. HLA-A, B typing was done according to a standard microlymphocytotoxicity technique (Terasaki et al., 1964Terasaki P.I. Mandell M. van de Water J. Edginton T.S. Human blood lymphocyte cytotoxicity reaction with allogenic antisera.Ann NY Acad Sci. 1964; 120: 332-334Google Scholar). Cells and serum were incubated together for 30 min at 25°C and incubated at 25°C for 1 h by the addition of complement. Cell death was assessed by the addition of Eosin-Y and read on a microscope. The standard nomenclature system was followed throughout to describe the HLA alleles HLA-C typing was performed by the Amplification Refractory Mutation System (ARMS)-PCR method (Sadeler et al., 1994Sadeler A.M. Petronzelli F. Krausa P. Marsh S.G.E. Guttridge M.G. Low-resolution DNA typing for LA-B using sequence-specific primers in allele- or groups-specific ARMS/PCR.Tissue Antigens. 1994; 44: 148-154Crossref PubMed Scopus (92) Google Scholar). Each tube contained a primer mix consisting of the allele- or group-specific primer pairs as well as a positive control primer, which matched the nonallelic sequences. HLA-C typing included 23 sets of primer mixtures. Polymerase chain reactions were performed in a volume of 7 μl, as modified in the class I ARMS-PCR reference manual of the 12th International Histocompatibility Workshop. PCR products were defined on 1.5% agarose gel prestained with ethidium bromide. DNA was extracted from heparinized blood samples by the salting out method and class II typing performed by the PCR-Sequence Specific Oligonucleotide Probes method (Jordan et al., 1995Jordan F. Mcwhinnie A.J. Turner S. Comparison of HLA-DRB1 typing by DNA-RFLP, PCR-SSO and PCR-SSP methods and their application in providing matched unrelated donors for bone marrow transplantation.Tissue Antigens. 1995; 45: 103-110Crossref PubMed Scopus (52) Google Scholar). HLA-DRB1, -DQA1, and -DQB1 generic types were defined by low resolution typing and DPB1 subtypes by high resolution typing. The method was essentially as that described in the 12th International Histocompatibility Workshop, with minor modifications. For each locus, specific primers were used to amplify products, which were then denatured and immobilized on a nylon membrane and probed with a series of digoxigenin labeled oligonucleotides specific for the known hypervariable sequences. Stringent washing was performed in the presence of tetramethyl ammonium chloride (TMAC, Sigma, St Louis, MO). The hybridized probe was detected according to the manufacturer’s instructions with anti-digoxigenin antibody conjugated with alkaline phosphatase and followed by the addition of chemiluminescent substrate CSPD (Boehringer Mannheim, GmbH, Germany). Chemiluminescence was detected by exposure to X-ray film. Comparisons between patients and controls were analyzed by the two-tailed Fisher’s exact test. RR was calculated using the method of Woolf (Haldane’s modification was used in sets containing 0). Corrected p-value (Pc) was obtained by multiplying the p-value by number of alleles tested for all loci (n = 79) and Pc values less than 0.05 were considered statistically significant; however, in the comparison of the haplotype frequencies between psoriasis patients and normal controls and of HLA phenotype frequencies between two groups according to sex or age of onset within patients, the p-values were not corrected. The frequencies of HLA-A1 (RR = 17.0, p < 9 × 10−7, Pc < 7 × 10−5), -A30 (RR = 5.5, p < 2 × 10−5, Pc < 0.001), -B13 (RR = 5.6, p < 4 × 10−6, Pc < 3 × 10−4), and -B37 (RR = 30.3, p < 7 × 10−7, Pc < 6 × 10−5) were increased in psoriasis patients compared with the controls. HLA-Cw*0602 (RR = 36.0 p < 10−8, Pc < 8 × 10−7) was the most strongly associated with psoriasis. The frequencies of HLA-A2, -B39, -B57, -B27, and -Cw*0101, however, were slightly increased, whereas the frequencies of HLA-A11, -A33, -B51, -B7, -B44, and -Cw*1401 were significantly decreased in the psoriasis patients (Table 1). HLA-DRB1*07 (RR = 5.9, p < 2 × 10−6, Pc < 8 × 10−5), -DRB1*10 (RR = 26.4, p < 4 × 10−6, Pc < 3 × 10−4), -DQA1*02 (RR = 6.2, p < 5 × 10−7, Pc < 4 × 10−4), -DQB1*02 (RR = 2.5 p < 0.005, Pc = ns), and -DPB1*1701 (RR = 24.6, p < 9 × 10−6, Pc < 7 × 10−4) were found to be associated with psoriasis, and those of -DRB1*08, DRB1*11, -DQB1*05, and -DPB1*0201 were slightly increased. HLA-DRB1*03, -DRB1*04, -DRB1*13, -DQA1*01, -DQA1*03, -DQB1*03, -DQB1*06, and -DPB1*0401, however, were found to be negatively associated with psoriasis (Table 2).Table IDistribution of HLA-A, -B, and HLA-C phenotype frequencies in psoriasis patients and normal controlsHLA antigensPatients (n = 84) N(%)Controls (n = 98) N(%)HLA antigensPatients (n = 84) N(%)Controls (n = 98) N(%)A1 22(26.1)aRR = 17.0, p<9 × 10−7, Pc<7 × 10–52(2.0)B51 4(4.7)eRR = 0.2, p<0.003, Pc = ns19(19.3)A246(54.7)42(42.8)B523(3.5)6(6.1)A34(4.7)3(3.0)B7 1(1.1) fRR = 0.1, p<0.02, Pc = ns9(9.1)A11 13(15.4)bRR = 0.4, p<0.02, Pc = ns30(30.6)B13 33(39.2)gRR = 5.6, p<4 × 10−6, Pc<3 × 10−410(10.2)A2425(29.7)41(41.8)B6215(17.8)26(26.5)A267(8.3)15(15.3)B751(1.1)4(4.0)A30 30(35.7)cRR = 5.5, p<2 × 10−5 Pc<0.0019(9.1)B382(2.3)2(2.0)A313(3.5)6(6.1)B397(8.3)6(6.1)A321(1.1)0(0.0)B575(5.9)1(1.0)A33 13(15.4)dRR = 0.3, p<0.009, Pc = ns31(31.6)B5810(11.9)13(13.2)B546(7.1)9(9.1)Cw*010119(22.6)21(21.4)B277(8.3)3(3.0)Cw*02012(2.3)0(0.0)B3510(11.9)14(14.2)Cw*04015(5.9)16(16.3)B37 20(23.8)hRR = 30.3 p<7 × 10−7, Pc<4 × 10−61(1.0)Cw*060264(76.1)jRR = 36.0, p<10−8, Pc<8 × 10−78(8.1)B602(2.3)8(8.1)Cw*070114(16.6)23(23.4)B6110(11.9)14(14.2)Cw*08018(9.5)18(18.3)B44 7(8.3)iR = 0.3, p<0.02, Pc = ns20(20.4)Cw*03025(5.9)7(7.1)B465(5.9)6(6.1)Cw*030316(19.0)28(28.5)B482(2.3)8(8.1)Cw*03049(10.7)19(19.3)B591(1.1)3(3.0)Cw*12032(2.3)1(1.0)B671(1.1)2(2.0)Cw*1401 7(8.3)kRR = 0.2, p<0.005, Pc = ns. Pc = ns, non significant.23(23.4)Cw*15012(2.3)2(2.0)Cw*07041(1.1)0(0.0)a RR = 17.0, p<9 × 10−7, Pc<7 × 10–5b RR = 0.4, p<0.02, Pc = nsc RR = 5.5, p<2 × 10−5 Pc<0.001d RR = 0.3, p<0.009, Pc = nse RR = 0.2, p<0.003, Pc = nsf RR = 0.1, p<0.02, Pc = nsg RR = 5.6, p<4 × 10−6, Pc<3 × 10−4h RR = 30.3 p<7 × 10−7, Pc<4 × 10−6i R = 0.3, p<0.02, Pc = nsj RR = 36.0, p<10−8, Pc<8 × 10−7k RR = 0.2, p<0.005, Pc = ns. Pc = ns, non significant. Open table in a new tab Table IIDistribution of HLA-DRB1, -DQA1, -DQB1, and -DPB1 phenotype frequencies in psoriasis patients and normal controlsHLA allelesPatients (n = 84) N(%)Controls (n = 98) N(%)HLA allelesPatients (n = 84) N(%)Controls (n = 98) N(%)DRB1*015(5.9)12(12.2)DPB1*01011(1.1)0(0.0)DRB1*0216(19.0)30(30.6)DPB1*020136(42.8)41(41.8)DRB1*03 1(1.1)aRR = 0.1, p<0.03, Pc = ns8(8.1)DPB1*020212(14.2)9(9.1)DRB1*04 21(25.0)bRR = 0.4, p<0.02, Pc = ns41(41.8)DPB1*03016(7.1)10(10.2)DRB1*07 36(42.8)cRR = 5.9, p<2 × 10−6, Pc<8 × 10−511(11.2)DPB1*04016(7.1)lRR = 0.1, p<0.007, Pc = ns21(21.4)DRB1*0817(20.0)13(13.2)DPB1*040210(11.9)12(12.2)DRB1*09 9(10.7)16(16.3)DPB1*050146(54.7)54(55.1)DRB1*10 18(21.4)dRR = 26.4, p<4 × 10−6, Pc<3 × 10−41(1.0)DPB1*09016(7.1)6(6.1)DRB1*1111(13.0)7(7.1)DPB1*13015(5.9)13(13.2)DRB1*128(9.5)18(18.3)DPB1*14012(2.3)1(1.0)DRB1*13 7(8.3)eRR = 0.3, p<0.05, Pc = ns20(20.4)DPB1*170117(20.2)mRR = 24.6, p<9 × 10−6, Pc<7 × 10−4. Pc = ns, non significant.1(1.0)DRB1*14 9(10.7)16(16.3)DPB1*19011(1.1)2(2.0)DQA1*0156(66.6)fRR = 0.2, p<0.0006, Pc<0.0586(87.7)DQB1*02 31(36.9)iRR = 2.5, p<0.005, Pc = ns18(18.3)DQA1*02 37(44.0)gRR = 6.2, p<5 × 10−7, Pc<4 × 10−411(11.2)DQB1*0342(50.0)jRR = 0.4, p<0.003, Pc = ns70(71.4)DQA1*03 30(35.7)hRR = 0.3, p<0.0002, Pc<0.0562(63.2)DQB1*0414(16.6)21(21.4)DQA1*041(1.1)1(1.0)DQB1*0531(36.9)31(31.6)DQA1*0518(21.4)28(28.5)DQB1*06 33(39.2)kRR = 0.4, p<0.02, Pc = ns56(57.1)DQA1*064(4.7)8(8.1)a RR = 0.1, p<0.03, Pc = nsb RR = 0.4, p<0.02, Pc = nsc RR = 5.9, p<2 × 10−6, Pc<8 × 10−5d RR = 26.4, p<4 × 10−6, Pc<3 × 10−4e RR = 0.3, p<0.05, Pc = nsf RR = 0.2, p<0.0006, Pc<0.05g RR = 6.2, p<5 × 10−7, Pc<4 × 10−4h RR = 0.3, p<0.0002, Pc<0.05i RR = 2.5, p<0.005, Pc = nsj RR = 0.4, p<0.003, Pc = nsk RR = 0.4, p<0.02, Pc = nsl RR = 0.1, p<0.007, Pc = nsm RR = 24.6, p<9 × 10−6, Pc<7 × 10−4. Pc = ns, non significant. Open table in a new tab Significant linkage disequilibria between HLA-A1 and B37, and between A30 and B13 antigens were found by the analysis of two locus haplotype in the HLA-class I alleles. All of these alleles are genetically linked with HLA-Cw*0602. HLA-DRB1*07 was associated with B13, DQA1*02, DQB1*02, and DPB1*1701. HLA-DRB1*10 was also found to have significant linkage disequililbria with B37, DQA1*01, and DQB1*05 (Table 3). From these results, two haplotypes,HLA-A30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02-DPB1*17-01 (HP-2) and HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 (HP-3), were suggested to be associated with psoriasis in Koreans. The HLA-A33-B44-Cw*1401-DRB1*13-DQA1*01-DQB1*06 (HP-4) haplotype was found to be negatively associated with psoriasis (Table 4).Table IIIAnalysis of two locus haplotypes among HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and -DPB1 alleles showing significant association with psoriasis in patient groupLocus+++––+––LDHFp valueHLA-AHLA-B A1 B371664580.0810.097<10−8 A30 B133003510.1540.193<10−8HLA-BHLA-C B13 Cw*060231233180.0820.183<0.002 B37 Cw*060220044200.0620.122<0.002HLA-AHLA-C A1 Cw*060221143190.0560.123<0.01 A30 Cw*060229135190.0840.175<6×10−4HLA-BHLA-DRB1 B13 DRB1*072769420.1180.166<10−8 B37 DRB1*101731630.0920.105<10−8HLA-DRB1HLA-DQA1 DRB1*07 DQA1*023601470.1820.236<10−8 DRB1*10 DQA1*0118038280.0650.110<0.002HLA-DQA1HLA-DQB1 DQA1*01 DQB1*0531250280.1180.187<6×10−8 DQA1*02 DQB1*023071460.1450.191<10−8HLA-DRB1HLA-DQB1 DRB1*07 DQB1*023061470.1470.191<10−8 DRB1*10 DQB1*0518013530.0900.112<10−8HLA-DRB1HLA-DPB1 DRB1*07 DPB1*170117190480.0800.103<4×10−8 Open table in a new tab Table IVFrequencies of haplotypes associated with psoriasis (HP) in psoriasis patients and normal controlsHaplotypePatients (n = 84) N(%)Controls (n = 98) N(%)RRp valueA30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02 (HP-1)24(28.5)2(2.0)19.2<2×10−7A30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02-DPB1*1701 (HP-2)15(17.8)1(1.0)21.0<5×10−5A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 (HP-3)13(15.4)1(1.0)17.7<3×10−4A33-B44-Cw*1401-DRB1*13-DQA1*01-DQB1*06 (HP-4)1(1.1)9(9.1)0.1<0.02 Open table in a new tab The average age at onset is 21.4 y in Korean psoriasis patients. The patients were divided into groups according to the age at onset, i.e., 15, 20, 25, 30, 35, or 40 y, Because a significant difference in HLA-Cw*0602 phenotype frequency was found between those who were older than 30 and those under 30 y of age (83.9% vs. 54.5%, p < 0.009), type I and type II might be more properly defined about this age (Figure 1). The frequencies of HLA-B37 (30.6% and 4.5%, p < 0.01), -Cw*0602 (83.8% and 54.5%, p < 0.009), and -DPB1*1701 (25.8% and 4.5%, p < 0.03) were significantly increased in type I compared with type II psoriasis (Table 5). These data suggest that HLA-B37 and DPB1*1701 in addition to Cw*0602 might be genetic factors associated with early onset of psoriasis.Table VDistribution of HLA phenotype frequencies in type I (<30) and type II (≥30)psoriasis patients compared with normal controlsType I (n = 62)Type II (n = 22)Controls (n=98) N(%)HLAN(%)RRp valueap value, compared with normal controlsPc valueN(%)RRp valueap value, compared with normal controlsPc valueN(%)Cw *0602 52(83.8)bp value < 0.05, difference between type I and type II psoriasis; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Pc = ns, non significant.58.5<10−8<8×10−712(54.5)13.5<4×10−6<10−88(8.1)A3024(38.7)6.2<1×10−7<8×10−66(27.2)3.7<0.04ns9(9.1)B1327(43.5)6.7<2×10−6<2×10−46(27.2)3.3<0.05ns10(10.2)DRB1 *0728(45.1)6.5<2×10−6<2×10−48(36.3)4.5<0.008ns11(11.2)DQA1 *0229(46.7)6.9<7×10−7<6×10−58(36.3)4.5<0.008ns11(11.2)DQB1 *0225(40.3)3.0<0.003ns6(27.2)18(18.3)DPB1 *1701 16(25.8)bp value < 0.05, difference between type I and type II psoriasis; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Pc = ns, non significant.33.7<9×10−7<8×10−51(4.5)1(1.0)A118(29.0)19.6<7×10−7<6×10−54(18.1)10.6<0.02ns2(2.0)B37 19(30.6)bp value < 0.05, difference between type I and type II psoriasis; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Pc = ns, non significant.42.8<3×10−8<3×10−61(4.5)1(1.0)DRB1 *1016(25.8)33.7<9×10−7<7×10−52(9.0)1(1.0)HP-119(30.6)14.0<3×10−75(22.7)3.0<0.032(2.0)HP-2 14(22.5)bp value < 0.05, difference between type I and type II psoriasis; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Pc = ns, non significant.19.4<7×10−61(4.5)1(1.0)HP-312(19.3)23.2<6×10−51(4.5)1(1.0)a p value, compared with normal controlsb p value < 0.05, difference between type I and type II psoriasis; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-1, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Pc = ns, non significant. Open table in a new tab When the distributions of HLA alleles were compared between female and male, the frequencies of HLA-A30 (50.0% and 23.9%, p < 0.02), -B13 (52.6% and 28.2%, p < 0.02), and -DQB1*02 (50.0% and 26.0%, p < 0.03) were found to be higher in female patients. The extended haplotype, HLA-A30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02 (HP-1, 44.8% vs. 18.1%, p < 0.03), and its related alleles including DPB1*1701 were higher in the type I females than their male counterparts. HLA-B13, DRB1*07, DQA1*02 and DPB1*1701 also showed a different distribution between type I and type II female patients (Table 6). The distributions of HLA-A1, B37, DRB1*10 and the related haplotype, HLA-A1-B37-Cw*0602-DRB1*10-DQA1* 01-DQB1*05 (HP-3) were not affected by sex. This result suggested that haplotype HLA-A30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02 (HP-1) might be a more useful genetic marker for psoriasis in females, and particularly in females of the type I group (Table 6).Table VIComparison of HLA phenotype frequencies according to sex in type I (<30) and type II (↛30) psoriasis patientsSexType IType IIHLAmale (n=46) N(%)female (n=38) N(%)pap value, difference between male and femalemale (n=33) N(%)female (n=29) N(%)pbp value, diference between male and female in type Imale (n=13) N(%)female (n=9) N(%)pcp value, difference between male and female in type IIpdp value, difference between type I and type II in malepep value, difference between type I and type II in female; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-3, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05.Cw *060234(73.9)30(78.9)27(81.8)25(86.2)7(53.8)5(55.5)A3011(23.9)19(50.0)<0.027(21.2)17(58.6)<0.0034(30.7)2(22.2)B1313(28.2)20(52.6)<0.029(27.2)18(62.0)<0.0064(30.7)2(22.2)<0.05DRB1 *0716(34.7)20(52.6)10(30.3)18(62.0)<0.026(46.1)2(22.2)<0.05DQA1 *0217(36.9)20(52.6)11(33.3)18(62.0)<0.036(46.1)2(22.2)<0.05DQB1 *0212(26.0)19(50.0)<0.038(24.2)17(58.6)<0.0074(30.7)2(22.2)DPB1 *17016(13.0)11(28.9)5(15.1)11(37.9)<0.041(7.6)0(0.0)<0.03A113(28.2)9(23.6)11(33.3)7(24.1)2(15.3)2(22.2)B3713(28.2)7(18.4)12(36.3)7(24.1)1(7.6)0(0.0)DRB1 *1010(21.7)7(18.4)9(27.2)6(20.6)1(7.6)1(11.1)HP-110(21.7)14(36.8)6(18.1)13(44.8)<0.034(30.7)1(11.1)HP-25(10.8)9(23.6)5(15.1)9(31.0)1(7.6)0(0.0)HP-38(17.3)5(13.1)7(21.1)5(17.2)1(7.6)0(0.0)a p value, difference between male and femaleb p value, diference between male and female in type Ic p value, difference between male and female in type IId p value, difference between type I and type II in malee p value, difference between type I and type II in female; HP-1, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02; HP-2, haplotype A30-B13-Cw *0602-DRB1 *07-DQA1 *02-DQB1 *02-DPB1 *1701; HP-3, haplotype A1-B37-Cw *0602-DRB1 *10-DQA1 *01-DQB1 *05. Open table in a new tab We demonstrated that the frequencies of HLA-A1, A30, B13, B37, Cw*0602, DRB1*07, DRB1*10, DQA1*02, DQB1*02, and DPB1*1701 were significantly increased in Korean psoriasis patients. The frequencies of HLA-A1, A2, B39, Bw46, Cw6, Cw7, and Cw11 were significantly increased in Japanese psoriasis patients (Nakagawa et al., 1991Nakagawa H. Akazaki S. Asahina A. et al.Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis.Arch Dermatol Res. 1991; 283: 281-284Crossref PubMed Scopus (57) Google Scholar). Associations of HLA-A1, -B13, -B17, -B37, -Cw6, -Cw7, and DR7 have been described in Caucasians (Gonzaga et al., 1996Gonzaga H.F.S. Torres E.A. Alchorne M.M.A. Gerbase-Delima M. Both psoriasis and benign migratory glossitis are associated with HLA-Cw6.Br J Dermatol. 1996; 135: 368-370Crossref PubMed Scopus (54) Google Scholar). HLA-A30 has not been reported as a genetic marker of psoriasis in the Japanese, which are genetically similar to the Korean. We did not find a significant elevation of HLA-A2, B17 (B57 and B58), -B39, -B46, Cw7, and Cw11, although the frequencies of HLA-A2, -B39, and -B57 were slightly increased in Korean psoriasis patients. In our study, HLA-Cw*0602 (RR = 36.0 p < 10−8, Pc < 8 × 10−7) had the strongest association in Korean patients and was increased to more than the frequency of Ala 73 in the HLA-C locus (RR = 5.5, p < 9 × 10−7), which was previously known as a susceptibility factor on psoriasis. The association of HLA-DRB1*10, DQB1*02 and DPB1*1701 with psoriasis, has not been previously reported. HLA-A2-Cw11-B46-C2C-BFs-C4A4-C4B2-DR8, has been demonstrated as a high-risk haplotype in Japanese psoriasis patients (Nakagawa et al., 1991Nakagawa H. Akazaki S. Asahina A. et al.Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis.Arch Dermatol Res. 1991; 283: 281-284Crossref PubMed Scopus (57) Google Scholar). HLA-A2-B13-Cw6-DR7-DQA1*0201 and HLA-A1-B17-Cw6-DR7-DQA1*0201 were identified as the associated haplotypes in a study of 70 Finnish subjects with psoriasis (Ikäheimo et al., 1996aIkäheimo I. Silvennoinen-Kassinen S. Karvonen J. Jarvinen T. Tiilikainen A. Immunogenetic profile of psoriasis vulgaris: association with haplotypes A2, B13, Cw6, DR7, DQA1*0201 and A1, B17, Cw6, DR7, DQA*0201.Arch Dermatol Res. 1996; 288: 63-67Crossref PubMed Scopus (37) Google Scholar). Recently, two ancestral haplotypes HLA-A30-Cw6-B13-DR7-DQ2 (13.1) and HLA-A1-Cw6–B57-DRB1*07-DQA1*0201-DQB1*0303 (57.1) were found to be associated with psoriasis (Schmitt-Egenolf et al., 1996Schmitt-Egenolf M. Eiermann T.H. Boehncke W.H. Stander M. Sterry W. Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6–B57-DRB1*0701-DQA1*0201-DQB1*0303: a population- and family-based study.J Invest Dermatol. 1996; 106: 711-714Crossref PubMed Scopus (111) Google Scholar;Elder and Voorhees, 1998Elder J.T. Voorhees J.J. Psoriasis.in: Jameson J.L. Principles of Molecular Medicine. Humana Press Inc, Totowa1998: 793-800Crossref Google Scholar). In this study, two haplotypes, HLA-A30-B13-Cw*0602-DRB1*07-DQA1*02-DQB1*02-DPB1*1701 (HP-2) and HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 (HP-3) were expressed in Korean psoriasis patients. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype differs from the HLA-DRB1*07-DQA1*02-DQB1*03 haplotype, demonstrated in other ethnic groups (Schmitt-Egenolf et al., 1993Schmitt-Egenolf M. Boehncke W.H. Stander M. Eiermann T.H. Sterry W. Oligonucleotide typing reveals association of type I psoriasis with the HLA-DRB1*0701/2-DQA1*0201-DQB1*0303 extended haplotype.J Invest Dermatol. 1993; 100: 749-752Abstract Full Text PDF PubMed Google Scholar), because HLA-DRB1*07 is mainly associated with DQB1*02 in Koreans. HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 (HP-3) was found to be a new high-risk haplotype in terms of Korean psoriasis. Furthermore, it was found that the HLA-A33-Cw*1401-B44-DRB1*13-DQA1*01-DQB1*06 haplotype is negatively associated with Korean psoriasis. Two types of psoriasis can be distinguished on the basis of the age of onset. A strong association between HLA-Cw6 and type I psoriasis was established in other studies (Henseler and Christophers, 1985Henseler T. Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris.J Am Acad Dermatol. 1985; 13: 450-456Abstract Full Text PDF PubMed Scopus (730) Google Scholar;Tiwari and Terasaki, 1985Tiwari J.L. Terasaki P.I. Dermatology.in: HLA and Disease Association. Springer-Verlag, New York1985: 112-127Crossref 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). HLA-DR7, B13, and B57 were present more frequently in patients with early onset of the disease (Henseler, 1997Henseler T. The genetics of psoriasis.J Am Acad Dermatol. 1997; 37: S1-S11Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The high-risk haplotype, HP-2 including HLA-DPB1*1701, was significantly different in type I and type II. Our result suggests that HLA-B37 and DPB1*1701 in addition to Cw*0602 could be genetic factors associated with an early onset of psoriasis and that the HLA-DP region might affect on the progression of the disease. Henseler and Christophers, 1985Henseler T. Christophers E. Psoriasis of early and late onset: Characterization of two types of psoriasis vulgaris.J Am Acad Dermatol. 1985; 13: 450-456Abstract Full Text PDF PubMed Scopus (730) Google Scholar reported that females develop psoriasis at an earlier age than males. In this study, female onset peaked at 10–20 y in contrast to males which peaked at 20–30 y.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 studied the HLA-C genotype in psoriasis patients and suggested that an interaction between gender and immunogenetics may influence susceptibility to psoriasis. We found that the haplotypes, HP-1 and HP-2 including DPB1*1701, showed significantly increased frequencies in type I female patients compared with their male counterparts. This may be the evidence demonstrating the differential distribution of HLA haplotypes associated with HLA-Cw*0602 in male and female psoriasis patients. We are grateful to Tae-Soo Kim for his technical assistance in determining the genotype of the HLA alleles. This study is supported by a grant (HMP-97-M-1-0013) of the good health R&D Project, Ministry of Health & Welfare, R.O.K.

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