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Evidence for a Major Psoriasis Susceptibility Locus at 6p21(PSORS1) and a Novel Candidate Region at 4q31 by Genome-wide Scan in Chinese Hans

2002; Elsevier BV; Volume: 119; Issue: 6 Linguagem: Inglês

10.1046/j.1523-1747.2002.19612.x

1523-1747

Xuejun Zhang, Pingping He, Zaixing Wang, Jing Zhang, Yue-Bin Li, Hongyan Wang, Shengcai Wei, Shanyu Chen, Shijie Xu, Jin Li, Sen Yang, Wei Huang,

T-cell and B-cell Immunology

Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9–62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (α) and a maximum multipoint heterogeneity lod score of 4.25 (α=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (α=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (α=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes. Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9–62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (α) and a maximum multipoint heterogeneity lod score of 4.25 (α=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (α=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (α=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes. heterogeneity log odds nonparametric linkage Psoriasis is a common chronic inflammatory and hyper-proliferative skin disease with a strong genetic component (Elder et al., 1994Elder J.T. Nair R.P. Guo S.W. Henseler T. Christophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Scopus (228) Google Scholar;Zhang et al., 2000Zhang X.J. Chen S.Y. Wang F.X. et al.Analyses on genetic epidemiology of psoriasis vulgaris.Chinese J Dermatol. 2000; 14: 221-222Google Scholar). Psoriasis vulgaris is the most common type (> 90%), whereas other clinical forms include guttate, erythrodermic, and palmoplantar psoriasis (Camp, 1998Camp R.D.R. Psoriasis.in: Champion R.H. Burton J.L. Burns D.A. Breatnatch S.M. Textbook of Dermatology. Blackwell Science, Oxford1998: 1589-1649Google Scholar). The disease is characterized by hyperproliferation in the epidermis, which results in red scaly patches mainly affecting the scalp, elbows, and knees. It has long been suggested that psoriasis is an autoimmune disease involving interaction between cytokines and various cells of immune system (Baadsgaard et al., 1990Baadsgaard O. Fisher G. Voorhees J.J. Cooper K.D. The role of the immune system in the pathogenesis of psoriasis.J Invest Dermatol. 1990; 95: 32S-34SAbstract Full Text PDF Google Scholar). An infiltration of lymphocytes and macrophages is seen in psoriatic lesions and the abnormal keratinocyte proliferation is mediated through the activated T cells (Valdimarsson et al., 1995Valdimarsson H. Baker B.S. Jonsdottir I. Powles A. Fry L. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens?.Immunol Today. 1995; 16: 145-149Abstract Full Text PDF PubMed Scopus (329) Google Scholar). Psoriasis prevalence ranges from 0 to 3% and shows a wide variability among ethnic groups (Capon et al., 2000Capon F. Dallapiccola B. Novelli G. Advances in the search for psoriasis susceptibility genes.Mol Genet Metab. 2000; 71: 250-255Abstract Full Text PDF PubMed Scopus (26) Google Scholar). The estimated prevalence of psoriasis is 2% in the U.S.A. and northern Europe (Krueger and Duvic, 1994Krueger G.G. Duvic M. Epidemiology of psoriasis: clinical issues.J Invest Dermatol. 1994; 102: 14S-18SCrossref PubMed Scopus (113) Google Scholar). In China, psoriasis affects 0.123% of the population and there have been more than 3 million cases reported since 1984 (Shao, 1996Shao C.G. The prevalence, prevention and treatment of psoriasis in China.Chin J Dermatol. 1996; 29: 75-76Google Scholar). Psoriasis is considered to be a genetically complex disease with an inheritance pattern not following any simple Mendelian model (Elder et al., 1994Elder J.T. Nair R.P. Guo S.W. Henseler T. Christophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Scopus (228) Google Scholar). Several genome-wide scans have been conducted in the psoriasis pedigrees (Tomfohrde et al., 1994Tomfohrde J. Silverman A. Barnes R. et al.Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar;Matthews et al., 1996Matthews D. Fry L. Powles A. et al.Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (183) Google Scholar;Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis-susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (357) Google Scholar;Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (440) Google Scholar;Capon et al., 1999aCapon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (162) Google Scholar;Enlund et al., 1999bEnlund F. Samuelsson L. Enerback C. et al.Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.Eur J Hum Genet. 1999; 7: 783-790Crossref PubMed Scopus (118) Google Scholar;Lee et al., 2000Lee Y.A. Ruschendorf F. Windemuth C. et al.Genomewide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar;Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (122) Google Scholar). PSORS1 at 6p21 is a major psoriasis susceptibility locus that has been confirmed by several studies (Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (440) Google Scholar;Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis-susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (357) Google Scholar;Capon et al., 1999bCapon F. Semprini S. Dallapiccola B. Novelli G. Evidence for interaction between psoriasis-susceptibility loci on chromosomes 6p21 and 1q21.Am J Hum Genet. 1999; 65: 1798-1800Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar;Enlund et al., 1999aEnlund F. Samuelsson L. Enerback C. et al.Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families: confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q.Hum Hered. 1999; 49: 2-8Crossref PubMed Scopus (71) Google Scholar;Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (122) Google Scholar). Recently, PSORS1 was further mapped within a 60 kb genomic segment telomeric to HLA-C (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: 1833-1844Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). Other significant linkages have been reported at the loci on chromosomes 17q (PSORS2) (Tomfohrde et al., 1994Tomfohrde J. Silverman A. Barnes R. et al.Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.Science. 1994; 264: 1141-1145Crossref PubMed Scopus (363) Google Scholar), 4q (PSORS3) (Matthews et al., 1996Matthews D. Fry L. Powles A. et al.Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (183) Google Scholar), 1q (PSORS4) (Capon et al., 1999aCapon F. Novelli G. Semprini S. et al.Searching for psoriasis susceptibility genes in Italy genome scan and evidence for a new locus on chromosome 1.J Invest Dermatol. 1999; 112: 32-35Crossref PubMed Scopus (162) Google Scholar), 3q (PSORS5) (Enlund et al., 1999bEnlund F. Samuelsson L. Enerback C. et al.Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.Eur J Hum Genet. 1999; 7: 783-790Crossref PubMed Scopus (118) Google Scholar), 19p (PSORS6) (Lee et al., 2000Lee Y.A. Ruschendorf F. Windemuth C. et al.Genomewide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.Am J Hum Genet. 2000; 67: 1020-1024Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar), and 1p (PSORS7) (Veal et al., 2001Veal C.D. Clough R.L. Barber R.C. et al.Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci.J Med Genet. 2001; 38: 7-13Crossref PubMed Scopus (122) Google Scholar). Evidence for suggestive linkage was also found on chromosomes 2q, 8q, 16q, and 20p (Matthews et al., 1995Matthews D. Fry L. Powles A. Weissenbach J. Williamson R. Confirmation of genetic heterogeneity in familial psoriasis.J Med Genet. 1995; 32: 546-548Crossref PubMed Scopus (37) Google Scholar;Nair et al., 1997Nair R.P. Henseler T. Jenisch S. et al.Evidence for two psoriasis-susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.Hum Mol Genet. 1997; 6: 1349-1356Crossref PubMed Scopus (357) Google Scholar;Trembath et al., 1997Trembath R.C. Clough R.L. Rosbotham J.L. et al.Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.Hum Mol Genet. 1997; 6: 813-820Crossref PubMed Scopus (440) Google Scholar;Bhalerao and Bowcock, 1998Bhalerao J. Bowcock A.M. The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar;Enlund et al., 1999bEnlund F. Samuelsson L. Enerback C. et al.Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.Eur J Hum Genet. 1999; 7: 783-790Crossref PubMed Scopus (118) Google Scholar). In addition, the loci on chromosomes 17q and 1q have been reported in at least two independent genome scans (Bhalerao and Bowcock, 1998Bhalerao J. Bowcock A.M. The genetics of psoriasis: a complex disorder of the skin and immune system.Hum Mol Genet. 1998; 7: 1537-1545Crossref PubMed Scopus (230) Google Scholar;Capon et al., 2000Capon F. Dallapiccola B. Novelli G. Advances in the search for psoriasis susceptibility genes.Mol Genet Metab. 2000; 71: 250-255Abstract Full Text PDF PubMed Scopus (26) Google Scholar). Independent replications of most psoriasis susceptibility loci, however, have proved to be difficult. The lack of consistence among different studies may indicate that the susceptibility genes could vary considerably among populations. Identification of susceptibility genes for psoriasis has proved much more difficult. Not only could the phenotype be largely influenced by many environmental factors, but the susceptibility to psoriasis is also affected by heterogeneity and ethnic variation of the relevant genes. A total of 61 Chinese Han multiplex families from east and south-east China with at least two affected siblings were identified by experienced dermatologists in the Department of Dermatology, First Affiliated Hospital of Anhui Medical University (Hefei, China). The characteristics of the families studied were summarized in Table I. A diagnosis of psoriasis vulgaris was made under standard clinical criteria (Camp, 1998Camp R.D.R. Psoriasis.in: Champion R.H. Burton J.L. Burns D.A. Breatnatch S.M. Textbook of Dermatology. Blackwell Science, Oxford1998: 1589-1649Google Scholar). Only patients who showed clear signs of plaque type in scalp, elbows, knees, or other areas at the time of examination, were scored as affected. Symptom-free family members younger than 20 y of age were excluded from the study because the peak age of onset for psoriasis vulgaris is about 25 y of age (Zhang et al., 2000Zhang X.J. Chen S.Y. Wang F.X. et al.Analyses on genetic epidemiology of psoriasis vulgaris.Chinese J Dermatol. 2000; 14: 221-222Google Scholar). Families with both parents affected were excluded, and nobody's disease status was classified as unknown in this study. The mean age of onset in this group of 189 affected individuals [107 male (56.6%) and 82 female (43.4%)] was 23.8 y (range 2–64). The protocol of the study was approved by the Ethical Committee of the Chinese National Human Genome Center at Shanghai.Table IDetails of psoriasis families used for genotypingStructure of familiesNo. of families in groupTwo affected members17Three affected members33Four affected members6Five to ten affected members5Total independent families61Total affected family members189Total affected male107Total affected female82Total family members355One-generation families1Two-generation families51Three-generation families9 Open table in a new tab Genomic DNA were extracted from peripheral blood leukocytes by the standard procedure (Miller et al., 1988Miller S. Dykes D. Polesky H. A simple salting out procedure for extraction of high molecular weight DNA from human nucleated cells.Nucleic Acids Res. 1988; 16: 1215Crossref PubMed Scopus (17176) Google Scholar). Microsatellite markers (ABI Prism Linkage Mapping Set Version 2) were purchased from Applied Biosystems (Foster City, CA). All the markers were subdivided into 30 panels following the guidelines of the kit and were amplified using multiplex polymerase chain reaction with a touchdown algorithm to meet the different annealing temperatures of these markers. Initially, 276 microsatellites from Linkage Mapping Set Version 2 were successfully amplified. In the candidate regions, which showed “nominal” evidence for linkage (p≤0.05), 28 additional microsatellite markers were selected to confirm these regions. Therefore, a total of 304 microsatellite markers were typed, with the mean resolution of 11.5 cM. The Genethon linkage map (Dib et al., 1996Dib C. Faure S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar) was used to establish intermarker distances for the genome scan. The mean heterozygosity of these markers was 0.77. Polymerase chain reactions were carried out in a cocktail of 5 μl, including 10 mM Tris–HCl, pH 8.3, 50 mM KCl, 0.1 mg gelatin per ml, 3.0 mM MgCl2, 0.2 mM deoxyribonucleoside triphosphate (each), 0.2 U AmpliTaq GoldTM, 0.04 μM of each primer, and 10 ng of genomic DNA. The polymerase chain reaction conditions were: Taq activation at 94°C for 12 min, followed by 40 cycles, each having denaturation at 94°C for 30 s, annealing at 56°C for 60 s and extension at 72°C for 90 s, except that in the first 15 cycles the annealing temperature decreased from 63°C to 56°C by 0.5°C per cycle, and the final extension was 72°C for 10 min.The polymerase chain reaction products were separated on a MegaBACE-1000 DNA sequencer (Amersham Pharmacia Biotech). Genetic Profiler software was used for size calculation of all the alleles. All genotyping data were verified by PedCheck (O'Connell and Weeks, 1998O'Connell J.R. Weeks D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis.Am J Hum Genet. 1998; 63: 259-266Abstract Full Text Full Text PDF PubMed Scopus (1806) Google Scholar). Genotypes of each locus were further reviewed and scored independently by two observers and retyped in case of discrepancy. GENEHUNTER (Version 2.0) was used for nonparametric linkage (NPL) and parametric linkage analyses. We performed two-point and multipoint NPL analyses based on the degree of identity by descent allele sharing among affected members. In addition, we calculated two-point and multipoint LOD scores under both homogeneity and heterogeneity in different models of inheritance. It has been shown that maximizing LOD scores over multiple genetic models increases the power to detect linkage when the true mode of inheritance of the disease is unknown (Hodge et al., 1997Hodge S.E. Abreu P.C. Greenberg D.A. Magnitude of type I error when single-locus linkage analysis is maximized over models: a simulation study.Am J Hum Genet. 1997; 60: 217-227PubMed Google Scholar). Using a population prevalence of 0.123% (Chinese Investigation Group of Psoriasis Prevalence, 1986Chinese Investigation Group of Psoriasis Prevalence A countrywide investigation of psoriasis prevalence in 1984.Chin J Dermatol. 1986; 19: 253-261Google Scholar), we maximized LOD scores under the dominant and recessive modes of inheritance over various penetrance models (10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 99%). Under the assumption of locus heterogeneity, HLOD scores were maximized for varying fractions of linked families (alpha) by use of GENEHUNTER (Kruglyak et al., 1996Kruglyak L. Daly M.J. Reeve-Daly M.P. Lander E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar). All the loci with “nominal” evidence for linkage (p≤0.05) under NPL analysis and the loci with LOD score≥1 under parametric linkage analysis were presented in Table II. The maximized LOD and HLOD scores of these loci shown in Table II and Figure 1 and Figure 2 were obtained under the assumption of a dominant inheritance model with the disease-allele frequency of 0.0062 and penetrance of 0.10. The average information content (part of GENEHUNTER) was 80% for the genome-wide scan. The information contents on chromosomes 4q and 6p were shown in Figure 3 and Figure 4, respectively. Multipoint linkage analysis of chromosome 4 showed a putative peak of NPL scores > 3 in the range of 152.5–165.1 cM, and D4S413, which was 157.9 cM from pter gave the maximum NPL score of 3.69 with the corresponding p-value of 0.00033. Multipoint NPL scores of the five neighboring markers (D4S424 at 143.8 cM, D4S3008 at 152.5 cM, D4S2997 at 159.1 cM, D4S1597 at 169.1 cM, and D4S2979 at 170.9 cM) were 2.57 (p=0.0061), 3.03 (p=0.0019), 3.59 (p=0.00042), 2.83 (p=0.0032), and 2.62 (p=0.0054), respectively (Figure 1). We also observed a maximum multipoint HLOD score of 2.31 (α=46%) at 163.1 cM (between D4S2997 and D4S1597) (Figure 1). Two-point parametric analysis revealed the maximum LOD score of 2.43 under homogeneity and a HLOD score of 3.94 with 77% as the proportion of linked families at D4S1597. The maximum two-point NPL score of 2.68 (p=0.0047) was observed at D4S2982, which was 10 cM proximal to D4S1597 (Table II)Table IISummary of two-point nonparametric and parametric linkage analysesChromosomal locationMarkerDistance (cM)aAccording to the final Genethon human linkage map (Dib et al, 1996). (from pter)Nonparametric analysisParametric analysisNPLp valueLODHLODα2p14D2S39174.62.060.021.410.382p13D2S33784.12.130.0171.550.352p11D2S28698.41.810.0350.620.284q28D4S424143.82.130.0180.600.244q28D4S3008152.52.050.0221.520.464q31D4S413157.92.340.0111.340.424q31D4S2982159.12.680.00471.950.404q31D4S2997159.12.550.00662.230.474q31D4S1597169.12.270.0132.433.940.774q31D4S2979170.91.820.0361.870.426p21D6S42235.72.570.00621.250.366p21D6S169142.73.110.00151.740.376p21D6S27644.92.660.00491.570.376p21D6S156847.62.950.00231.450.376p21D6S161848.23.020.00191.550.376p21D6S164548.33.560.000463.870.616p21D6S162948.42.670.00481.003.230.676p21D6S160252.42.400.00941.530.416p21D6S161053.93.860.000214.300.586p12D6S156258.22.620.00552.630.616p12D6S157562.33.360.000781.600.366q14D6S46090.02.610.00561.560.399q33D9S1682136.22.740.00383.760.529q33D9S290142.72.270.0122.610.4413q22D13S15981.52.440.00830.740.2813q31D13S17396.02.020.0221.630.4420q11D20S10754.92.570.00621.870.44a According to the final Genethon human linkage map (Dib et al., 1996Dib C. Faure S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar). Open table in a new tab Figure 2Multipoint nonparametric and parametric linkage analyses of chromosome 6.View Large Image Figure ViewerDownload (PPT)Figure 3Information contents on chromosome 4q (part of GENEHUNTER output).View Large Image Figure ViewerDownload (PPT)Figure 4Information contents on chromosome 6p (part of GENEHUNTER output).View Large Image Figure ViewerDownload (PPT) On chromosome 6, multipoint linkage analysis showed NPL scores>3 throughout a region between 39.9 cM and 62.3 cM with a maximum peak of 4.58 (p=0.000032) at 48.3 cM, which locates D6S1645. Multipoint NPL scores of the 10 neighboring markers were as follows (Figure 2): D6S422 at 35.7 cM=2.73 (p=0.004) D6S1691 at 42.7 cM=3.44 (p=0.00062) D6S276 at 44.9 cM=3.68 (p=0.00033) D6S1568 at 47.6 cM=3.78 (p=0.00026) D6S1618 at 48.2 cM=3.93 (p=0.00018) D6S1629 at 48.4 cM=4.27 (p=0.000072) D6S1602 at 52.4 cM=3.82 (p=0.00023) D6S1610 at 53.9 cM=4.00 (p=0.00015) D6S1562 at 58.2 cM=3.72 (p=0.0003) D6S1575 at 62.3 cM=3.49 (p=0.00054). We also observed a multipoint HLOD score peak of 4.25 (α=53%) at D6S1645 (Figure 2). Two-point linkage analysis revealed the highest HLOD score of 4.30 with α=58% of linked families and NPL score of 3.86 (p=0.00021) at D6S1610 (Table II). The results above exceeded the criterion of p=0.01 required for independent confirmation of previously documented significant linkage (Lander and Kruglyak, 1995Lander E. Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar). The remained of the loci listed in Table II did not reach the generally accepted threshold of suggestive evidence for linkage (p≤7.4×10–4 or LOD score≥1) (Lander and Kruglyak, 1995Lander E. Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar), but we reported these results because of their potential interests. The pathogenesis of psoriasis is complex, with both genetic and environmental factors contributing to the development of the disease. Many unaffected individuals carry one or more alleles, but lack other genetic and/or environmental factors necessary to produce disease (Elder 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). Genes that contribute to susceptibility to psoriasis are still unknown. Many studies in different populations have shown evidence for linkage on different chromosomes, implying an ethnic variation in the genetic susceptibility to psoriasis. Until now, most genome-wide scans for psoriasis were conducted in Caucasians. There are very few data from east and south-east Asian populations. Comparison of data from different ethnic groups apparently would add to our understanding of the genetic causes of psoriasis vulgaris. Here we reported the results of a genome-wide scan for the psoriasis genes in a Chinese Han population residing in east and south-east China using nonparametric and parametric linkage analyses. We confirmed a previous reported locus PSORS1 at 6p21 with significant linkage evidence. The information contents of most markers at 6p were higher than 90%. The maximum multipoint NPL value of 4.58 (p=0.000032) and HLOD score of 4.25 (α=53%) were reached at locus D6S1645 (at 48.3 cM), which is sufficiently close to the HLA complex. Multipoint linkage analysis showed NPL scores>3 throughout a region (39.9–62.3 cM) that includes the major histocompatibility complex (MHC) and some other genes. Although the candidate interval at 6p21 is still large (comprising≥22.4 cM) and it is hard to ascertain susceptibility genes within the HLA region or outside it from this study, we will still aim at HLA region in further studies as our previous case–control studies have shown association of psoriasis with certain class I and II MHC alleles (Zhang et al., 2002Zhang X.J. Wei S.C. Wang Z.X. Zhang A.P. Yang S. The association of HLA-DQA1 and DQB1 alleles with genetic susceptibility to psoriasis vulgaris in Han Chinese.Chin J Dermatol. 2002; 35: 120-123Google Scholar). In addition, the psoriasis process comprises immune-mediated cutaneous inflammation and keratinocyte hyperproliferation. (Van de Kerkhof and Bos, 1995Van de Kerkhof P.C. Bos J.D. Pathogenic aspects of psoriasis.Clin Dermatol. 1995; 13: 97-98Abstract Full Text PDF PubMed Scopus (11) Google Scholar), so HLA is very critical positional and functional candidate region for searching psoriasis susceptibility genes. The HLA complex is nearly 3.5 million pairs long and contains more than 200 genes, and about 40% of the expressed genes are involved in the immune system, some of which are potential candidates as psoriasis susceptibility genes both on the basis of their chromosomal position and their function (The MHC Sequencing Consortium, 1999The MHC Sequencing Consortium Complete sequence and gene map of a human major histocompatibility complex.Nature. 1999; 401: 921-923Crossref PubMed Scopus (860) Google Scholar). MICA (MHC class I chain-related gene A), which is located 46 kb from HLA-B and encodes a 383-amino acid cell surface protein of 43 kDa, has been previously been found to be associated with psoriasis and psoriatic arthritis in Caucasian (Gonzalez et al., 1999Gonzalez S. Martinez-Borra J. Torre-Alonso J.C. et al.The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriasis arthritis and is independent of the association of CW*0602 in psoriasis.Arthritis Rheum. 1999; 42: 1010-1016Crossref PubMed Scopus (140) Google Scholar). Recently,Cheng et al., 2000Cheng L. Zhang S.Z. Xiao C.Y. et al.The A5.1 allele of the major histocompatibility complex class I chain-related gene A is associated with psoriasis vulgaris in Chinese.Br J Dermatol. 2000; 143: 324-329Crossref PubMed Scopus (38) Google Scholar reported significant association between chronic plaque psoriasis and a polymorphism in the MICA gene in a Chinese population. The biologic function of MICA is not yet established but it is speculated that it is a marker of cellular distress, targeting a cell for destruction by natural killer cells or cytotoxic T cells (Bauer et al., 1999Bauer S. Groh V. Wu J. Steinle A. Phillips J.H. Lanier L.L. Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.Science. 1999; 285: 727-729Crossref PubMed Scopus (2066) Google Scholar). This may be relevant to some models of the immunopathogenesis of psoriasis that have recently been proposed (Nickoloff et al., 1999Nickoloff B.J. Wrone-Smith T. Bonish B. Porcelli S.A. Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typically present on natural killer cells, including CD94, CD158, and CD161.Arch Dermatol. 1999; 135: 546-552Crossref PubMed Scopus (118) Google Scholar). Therefore, MICA gene may be one of positional and functional candidate genes for susceptibility to psoriasis in Chinese Hans. Likewise, other important candidate genes of interest in MHC are HLA-C, CDSN, and HCR, although novel genes yet unknown may also exist; however, accumulating evidence shows that HLA-C is not itself the causative gene but rather a marker for a gene close by that is in linkage disequilibrium with it (Barker, 2001Barker J.N. Genetic aspects of psoriasis.Clin Exp Dermatol. 2001; 26: 321-325Crossref PubMed Scopus (76) Google Scholar). CDSN gene, previously referred to as “S” gene, which locates about 160 kb telomeric to HLA-C is expressed exclusively in differentiating epidermal keratinocytes and encodes corneodesmosin, a protein showing significant homologies to granular cell layer components (Zhou and Chaplin, 1993Zhou Y. Chaplin D.D. Identification in the HLA class I region of a gene expressed late in keratinocyte differentiation.Proc Natl Acad Sci USA. 1993; 90: 9470-9474Crossref PubMed Scopus (83) Google Scholar). Recent studies have demonstrated strong association between allele 5 (a particular allelic form of CDSN) and psoriasis (Allen et al., 1999Allen M.H. Veal C. Faassen A. Powis S.H. Vaughan R.W. Trembath R.C. Barker J.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), and comparative association analysis revealed that corneodesmosin was more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families (Schmitt-Egenolf et al., 2001Schmitt-Egenolf M. Windemuth C. Hennies H.C. et al.Comparative association analysis reveals that corneodesmosin is more closely associated with psoriasis than HLA-Cw*0602-B*5701 in German families.Tissue Antigens. 2001; 57: 440-446Crossref PubMed Scopus (29) Google Scholar). Another candidate gene HCR (also known as PG8) is located 110 kb telomeric to HLA-C. At present its function remains unknown, although the mRNA is overexpressed in keratinocytes of psoriatic lesions.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 have screened HCR for nucleotide polymorphisms and have shown a significant association with psoriasis in a sample of Finnish patients and controls. Coding haplotype analysis also supported HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus (Asumalahti et al., 2002Asumalahti K. Veal C. Laitinen T. et al.Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus.Hum Mol Genet. 2002; 11: 589-597Crossref PubMed Scopus (109) 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, however, concluded that HCR polymorphisms displayed association with psoriasis due to linkage disequilibrium with HLA-Cw*0602 and was unlikely to be a psoriasis susceptibility gene. Currently, Nair et al (2000) localized PSORS1 to a 60 kb interval extending from 30 to 90 kb from HLA-C toward the telomere end of chromosome 6p, but no genes have been identified in this region to date. Evidence for a second dominant psoriasis susceptibility locus near D4S1535 (PSORS3) on chromosome 4q has recently been reported in one English and five Irish families (Matthews et al., 1996Matthews D. Fry L. Powles A. et al.Evidence that a locus for familial psoriasis maps to chromosome 4q.Nat Genet. 1996; 14: 231-233Crossref PubMed Scopus (183) Google Scholar). In their study, this locus gave a maximum total pairwise LOD score of 3.03 under a dominant model with 70% penetrance and demonstrated significant excess allele sharing, with p=0.00026. Although this locus could not be confirmed in other studies, Nair et al (1997) found weak linkage to D4S413 (LOD=1.01, allele sharing p=0.04), which is about 40 cM proximal to D4S1535. Our results showed highly suggestive evidence for linkage on chromosome 4q. The average information contents of markers at 4q reached 84%. Multipoint nonparametric linkage anlaysis revealed the NPL scores were all >3 in the range of 152.5–165.1 cM and the highest NPL score of 3.69 (p=0.00033) was reached at D4S413, which provided evidence of highly suggestive linkage (p≤7.4×10–4) based on stringent criteria for a novel candidate region on chromosome 4q (Lander and Kruglyak, 1995Lander E. Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.Nat Genet. 1995; 11: 241-247Crossref PubMed Scopus (4381) Google Scholar). The maximum two-point LOD score of 2.43 and HLOD score of 3.94 (α=77%) were obtained at D4S1597; however, D4S1535, which is about 30 cM distal to D4S1597, yielded an NPL score of 0.74 (p=0.23) and a maximum HLOD of –0.0036 in our data. Our results couldn’t confirm linkage between psoriasis and PSORS3, but we identified another candidate region of highly suggestive linkage proximal to the previously reported locus (PSORS3) at 4q. Several important genes have been mapped to this candidate region. Interleukin (IL)-15, which is located on chromosome 4q31, encodes a cytokine that affects T cell activation and proliferation similarly to IL-2.Grabstein et al., 1994Grabstein K.H. Eisenman J. Shanebeck K. et al.Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor.Science. 1994; 264: 965-968Crossref PubMed Scopus (1285) Google Scholar found that IL-15 was transcribed in a variety of cell types, including fibroblasts, epithelial cells, and monocytes.Ku et al., 2000Ku C.C. Murakami M. Sakamoto A. Kappler J. Marrack P. Control of homeostasis of CD8+ memory T cells by opposing cytokines.Science. 2000; 288: 675-678Crossref PubMed Scopus (693) Google Scholar reported that the number of CD8+ memory T cells in animals was controlled by a balance between IL-15 and IL-2. As psoriasis resembles a T cell-mediated autoimmune disease, IL-15 represents an interesting positional and functional candidate at 4q for psoriasis susceptibility. In conclusion, using a genome-wide scan method, significant evidence was found for linkage with psoriasis vulgaris on chromosome 6p21 (PSORS1) and highly suggestive evidence for linkage on chromosome 4q31 in Chinese Han families. This study has not replicated the linkage results at 17q (PSORS2), 4q (PSORS3), 1q (PSORS4), 3q (PSORS5), 19p (PSORS6), and 1p (PSORS7). These results are consistent with the notion that the molecular genetic basis of psoriasis is complex with heterogeneity and multiple genes involved. The susceptibility locus PSORS1 appears to represent the major locus in this disorder. Further studies on the typing of HLA-B and HLA-C and linkage disequilibrium analysis would be needed to make fine scale mapping of this region feasible and help to compare our data with reports on the Caucasian population. The elucidation of the molecular mechanisms underlying such genetic interactions must await the identification and functional analysis of the relevant genes. This work was funded by a grant from the “Chinese High Tech Program (863)” (Z19-01-04-04), grants from the “National Natural Science Foundation Key Program” (39993420, 39896200), a grant from “National Key Program on Basic Research (973)” (G1998051002), a grant from “National Natural Science Foundation of China” (39970350), and a grant from Chinese Medical Board (98–688IITD), People's Republic of China. We are most grateful to all the families with psoriasis who have so willingly participated and encouraged us with these studies. Our thanks are also given to Drs Wei-Da Liu, Shu-Lin Zhang, Yong Guo, Guang-Fu Zhang, Tao-Feng Liu, and Fu-Xi Wang, who recruited the families for the study.