MHC，LCE和IL12B基因交互作用与银屑病的相关性研究
摘要
研究背景银屑病(Psoriasis)是一种常见的以红斑、鳞屑为主要临床表现的慢性复发性炎症性皮肤病。在汉族人中发病率约为0.123%,目前我国银屑病患者约400万。临床上以寻常型银屑病最多见,占患者总数的90%以上。银屑病确切发病机制尚未完全明确,目前认为该病是一种遗传与环境等多种因素共同作用的复杂性疾病。其中可能的遗传易感基因包括人类白细胞抗原(Human leukocyte antigen,HLA)相关基因和非HLA相关基因的共同作用导致发病。全基因组关联分析(Genome wide association studies,GWAS)产生大量数据,进一步研究基因与基因交作用(Gene interaction),特别是MHC与其他基因的交互作用对银屑病发病的影响有重要意义。
目的验证MHC区域与银屑病的相关性,分析MHC,LCE与IL12B的基因交互作用对银屑病发病影响,以及估计MHC与LCE,MHC与IL12B的联合作用效应。
方法本研究首先对SNP rs1265181(在MHC区域)在5067个银屑病病例和6404个对照进行基因分型,做关联分析,验证MHC与银屑病的相关性。然后把此次验证数据与先前的GWAS数据结合,分别估计MHC,LCE和IL12B变异的最佳关联模型。之后用logistic回归方法分析MHC,LCE和IL12B的基因交互作用,并根据变异的最佳关联模型,估计MHC与LCE,MHC与IL12B的联合作用效应。最后,我们根据联合效应,对所有病例进行分组,比较携带上述基因危险变异的银屑病患者和不携带危险变异的银屑病患者的临床特征差异。
结果①MHC_rs1265181在5067个病例和6404个对照中的关联分析结果为P combined < 1E-300, OR = 16.52,提示MHC与银屑病的强关联性;②与之前的GWAS研究数据相结合,分析MHC,LCE和IL12B变异的关联模型得知:LCE_rs4085613_A的最佳关联模型是隐形模型( Recessive model ) ,IL12B_rs3213094_A的最佳关联模型是累加模型( Additive model ) ,MHC_rs1265181_G的最佳关联模型是显性模型(Dominant model);③基因交互作用结果如下:我们发现在初筛阶段,MHC和LCE,MHC和IL12B有显著的基因交互作用(分别为p=0.0379和p=0.0287),此交互作用在验证阶段依然显著(MHC和LCE,p=0.0091;MHC和IL12B,p=0.046),在联合样本中,基因交互作用更加显著(MHC和LCE,p=0.0016;MHC和IL12B,p=0.0036)。④我们根据各个变异的关联模型,估计基因联合效应。我们发现同时含有MHC和LCE危险基因型的个体的发病风险比同时含有保护基因型的个体高26倍,同时含有MHC和IL12B危险基因型的个体的发病风险比同时含有保护基因型的个体高36倍。○5根据这两个SNP的联合效应,我们发现携带有危险变异的银屑病患者和不携带有危险变异的银屑病患者的临床特征有显著差异。
结论本研究进一步验证了MHC区域与银屑病的相关性,并发现MHC与LCE,MHC与IL12B在有显著的基因交互作用,同时提示MHC是银屑病发病的主效基因。本研究还发现携带MHC,LCE和IL12B危险变异的患者和不携带有危险变异的患者有不同的临床表型。
Background Psoriasis is a common inflammatory cutaneous disorder characterized by red scaly patches. The prevalevence of psoriasis is about 0.123% in Chinese Han population. So far there have heen about 4 million psoriasis patients in China. Clinically, psoriasis vulgaris is the most common, accounting for the total number of patients over 90%. The exact pathogenesis of psoriasis remains unclear. It is agreed generally that the psoriasis is a complex disease which arises from genetic and environmental factors. The predisposing genes can be grouped into two parts: HLA-associated and lacking HLA associations genes. As genome wide association (GWA) studies have produced a large amount of data, further study on gene-gene interaction and multi-marker association would be important for elucidating the biological and biochemical pathways that underline disease.
Objective We evaluated the associations of single nucleotide polymorphisms (SNP) in MHC region with psoriasis, and determined the epistasis and combined effects of MHC locus and IL12B, LCE on risk for psoriasis.
Method We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. According the combined effects, we finally compared the clinical difference between the carriers of the risk alleles and non-carriers psoriasis patients.
Result①Extremely high significance of association was detected between rs1265181 and psoriasis (P combined <10E-300, OR =16.52, 95%CI: 15.28-18.44).②For rs4085613_A, the most significant association evidence was observed under recessive model, the homozygous and heterozygous odds ratio (ORhom / ORhet) estimates of this SNP supported this recessive model. Additive model is the best fit for the association of rs3213094_A, the ORhom / ORhet estimates further suggested the additive effects of this SNP. Similarly, the dominant association model was fit for rs1265181_G, where GG and CG show similar risk effects.③We observed significant interactions between MHC and LCE (p=0.0379) and between MHC and IL12B (p=0.0287) in the discovery sample. Interaction between MHC and LCE was significant in the replication sample (p=0.0091) while interaction between MHC and IL12B just show marginal significance (p=0.066). Analysis of combined sample showed pronounced evidence for both MHC by LCE (p=0.0016) and MHC by IL12B (0.0036) interaction after adjusting for potential study sample effect.④We further analyzed the combined effect of MHC, LCE and IL12B on the risk for psoriasis. the risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. The risk effects decreased in individuals with risk allele in one gene and protective allele in another, as compared with those with risk alleles in both genes.⑤We compared the clinical features between the carriers of the risk alleles and non-carriers psoriasis patients, and observed obvious clinical difference between the two group.
Conclusion This study had confirmed a significant association between MHC region and psoriasis. More important, we provided evidence for interactions between MHC and LCE and between MHC and IL12B in determining the risk of psoriasis in Chinese population and estimated the combined effects of these genes. Besides, we suggested that MHC might be the main effect gene on the risk for psoriasis. We also found that carriers of the risk alleles have obvious clinical difference with non-carriers.
目的验证MHC区域与银屑病的相关性,分析MHC,LCE与IL12B的基因交互作用对银屑病发病影响,以及估计MHC与LCE,MHC与IL12B的联合作用效应。
方法本研究首先对SNP rs1265181(在MHC区域)在5067个银屑病病例和6404个对照进行基因分型,做关联分析,验证MHC与银屑病的相关性。然后把此次验证数据与先前的GWAS数据结合,分别估计MHC,LCE和IL12B变异的最佳关联模型。之后用logistic回归方法分析MHC,LCE和IL12B的基因交互作用,并根据变异的最佳关联模型,估计MHC与LCE,MHC与IL12B的联合作用效应。最后,我们根据联合效应,对所有病例进行分组,比较携带上述基因危险变异的银屑病患者和不携带危险变异的银屑病患者的临床特征差异。
结果①MHC_rs1265181在5067个病例和6404个对照中的关联分析结果为P combined < 1E-300, OR = 16.52,提示MHC与银屑病的强关联性;②与之前的GWAS研究数据相结合,分析MHC,LCE和IL12B变异的关联模型得知:LCE_rs4085613_A的最佳关联模型是隐形模型( Recessive model ) ,IL12B_rs3213094_A的最佳关联模型是累加模型( Additive model ) ,MHC_rs1265181_G的最佳关联模型是显性模型(Dominant model);③基因交互作用结果如下:我们发现在初筛阶段,MHC和LCE,MHC和IL12B有显著的基因交互作用(分别为p=0.0379和p=0.0287),此交互作用在验证阶段依然显著(MHC和LCE,p=0.0091;MHC和IL12B,p=0.046),在联合样本中,基因交互作用更加显著(MHC和LCE,p=0.0016;MHC和IL12B,p=0.0036)。④我们根据各个变异的关联模型,估计基因联合效应。我们发现同时含有MHC和LCE危险基因型的个体的发病风险比同时含有保护基因型的个体高26倍,同时含有MHC和IL12B危险基因型的个体的发病风险比同时含有保护基因型的个体高36倍。○5根据这两个SNP的联合效应,我们发现携带有危险变异的银屑病患者和不携带有危险变异的银屑病患者的临床特征有显著差异。
结论本研究进一步验证了MHC区域与银屑病的相关性,并发现MHC与LCE,MHC与IL12B在有显著的基因交互作用,同时提示MHC是银屑病发病的主效基因。本研究还发现携带MHC,LCE和IL12B危险变异的患者和不携带有危险变异的患者有不同的临床表型。
Background Psoriasis is a common inflammatory cutaneous disorder characterized by red scaly patches. The prevalevence of psoriasis is about 0.123% in Chinese Han population. So far there have heen about 4 million psoriasis patients in China. Clinically, psoriasis vulgaris is the most common, accounting for the total number of patients over 90%. The exact pathogenesis of psoriasis remains unclear. It is agreed generally that the psoriasis is a complex disease which arises from genetic and environmental factors. The predisposing genes can be grouped into two parts: HLA-associated and lacking HLA associations genes. As genome wide association (GWA) studies have produced a large amount of data, further study on gene-gene interaction and multi-marker association would be important for elucidating the biological and biochemical pathways that underline disease.
Objective We evaluated the associations of single nucleotide polymorphisms (SNP) in MHC region with psoriasis, and determined the epistasis and combined effects of MHC locus and IL12B, LCE on risk for psoriasis.
Method We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. According the combined effects, we finally compared the clinical difference between the carriers of the risk alleles and non-carriers psoriasis patients.
Result①Extremely high significance of association was detected between rs1265181 and psoriasis (P combined <10E-300, OR =16.52, 95%CI: 15.28-18.44).②For rs4085613_A, the most significant association evidence was observed under recessive model, the homozygous and heterozygous odds ratio (ORhom / ORhet) estimates of this SNP supported this recessive model. Additive model is the best fit for the association of rs3213094_A, the ORhom / ORhet estimates further suggested the additive effects of this SNP. Similarly, the dominant association model was fit for rs1265181_G, where GG and CG show similar risk effects.③We observed significant interactions between MHC and LCE (p=0.0379) and between MHC and IL12B (p=0.0287) in the discovery sample. Interaction between MHC and LCE was significant in the replication sample (p=0.0091) while interaction between MHC and IL12B just show marginal significance (p=0.066). Analysis of combined sample showed pronounced evidence for both MHC by LCE (p=0.0016) and MHC by IL12B (0.0036) interaction after adjusting for potential study sample effect.④We further analyzed the combined effect of MHC, LCE and IL12B on the risk for psoriasis. the risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. The risk effects decreased in individuals with risk allele in one gene and protective allele in another, as compared with those with risk alleles in both genes.⑤We compared the clinical features between the carriers of the risk alleles and non-carriers psoriasis patients, and observed obvious clinical difference between the two group.
Conclusion This study had confirmed a significant association between MHC region and psoriasis. More important, we provided evidence for interactions between MHC and LCE and between MHC and IL12B in determining the risk of psoriasis in Chinese population and estimated the combined effects of these genes. Besides, we suggested that MHC might be the main effect gene on the risk for psoriasis. We also found that carriers of the risk alleles have obvious clinical difference with non-carriers.
引文
1. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314: 1461-1463.
2. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273-290.
3. (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678.
4. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087-1093.
5. Altshuler D, Daly M (2007) Guilt beyond a reasonable doubt. Nat Genet 39: 813-815.
6. Andrieu N, Goldstein AM. Ep idemiologic and genetic app roaches in the study of gene2environment interaction: an overview of available methods. Epidem iol Rev, 1998, 20 (2) : 137 - 147.
7. Manolio TA,Bailey2Wilson JE, Collins FS. Genes, environment and the value of p rospective cohort studies. Nat Rev Genet, 2006, 7 (10) : 812 - 820.
8. Ottman R. Gene2environment interaction: definitions and study designs. PrevMed, 1996, 25 (6) : 764 - 770.
9. Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidem iol, 1980, 112 (4) : 467 - 470.
10. Cordell HJ. Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet, 2002, 11 (20) : 2 463 - 2 468.
11. Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet, 2005, 6 (4) : 287 - 298.
12. Capon, F., et al., Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet, 2008. 17(13): p. 1938-45.
13. Liu, Y., et al., A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet, 2008. 4(3): p. e1000041.
14. Nair, R.P., et al., Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet, 2009. 41(2): p. 199-204.
15. Zhang, X.J., et al., Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet, 2009. 41(2): p. 205-10.
16. de Cid, R., et al., Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet, 2009. 41(2): p. 211-5.
17. Nair, R.P., et al., Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet, 2006. 78(5): p. 827-51.
18. Fan, X., et al., Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genet, 2008. 4(3): p. e1000038.
19. Elder, J.T., Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun, 2009. 10(3): p. 201-9.
20.Nestle, F.O., D.H. Kaplan, and J. Barker, Psoriasis. N Engl J Med, 2009. 361(5): p. 496-509.
21.Nelson, G.W., et al., Cutting edge: heterozygote advantage in autoimmune disease:hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol, 2004. 173(7): p. 4273-6.
22. Feng, B.J., et al., Multiple Loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet, 2009. 5(8): p. e1000606.
23. Shao CG. The prevalence, prevention and treatment of psoriasis in China. Chin J Dermatol 1996;29:75-76
24.全国银屑病流行调查组。.全国1984年银屑病流行调查报告。.中华皮肤科杂志1986;19:253-261
25. Brandrup F, Holm N, Grunnet N, Henningsen K, Hansen HE. Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution. Acta dermato-venereologica 1982;62(3):229-236
26. Duffy DL, Spelman LS, Martin NG. Psoriasis in Australian twins. Journal of the American Academy of Dermatology 1993;29(3):428-434
27.杨森,魏生才,张学军等.寻常型银屑病诱因流行病学分析.中国麻风皮肤病杂志2000;16:159-162
28. Zhang X, Wang H, Te-Shao H, Yang S, Wang F. Frequent use of tobacco and alcohol in Chinese psoriasis patients. International journal of dermatology 2002;41(10):659-662
29. Sagoo GS, Tazi-Ahnini R, Barker JW, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population. The Journal of investigative dermatology 2004;122(6):1401-1405
30. Tiilikainen A, Lassus A, Karvonen J, Vartiainen P, Julin M. Psoriasis and HLA-Cw6. The British journal of dermatology 1980;102(2):179-184
31. Mallon E, Newson R, Bunker CB. HLA-Cw6 and the genetic predisposition to psoriasis: a meta-analysis of published serologic studies. The Journal of investigative dermatology 1999;113(4):693-695
32. Gudjonsson JE, Karason A, Antonsdottir A, et al. Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk ofdeveloping psoriasis compared with Cw6 heterozygotes. The British journal of dermatology 2003;148(2):233-235
33. Zhang XJ, Zhang AP, Yang S, et al. Association of HLA class I alleles with psoriasis vulgaris in southeastern Chinese Hans. J Dermatol Sci 2003;33(1):1-6
34. Ikaheimo I, Tiilikainen A, Karvonen J, Silvennoinen-Kassinen S. HLA risk haplotype Cw6,DR7,DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris. Archives of dermatological research 1996;288(7):363-365
35. Enerback C, Martinsson T, Inerot A, et al. Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP). Acta dermato-venereologica 1997;77(4):273-276
36. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. Journal of the American Academy of Dermatology 1985;13(3):450-456
37. Gudjonsson JE, Karason A, Antonsdottir AA, et al. HLA-Cw6-positive and HLA-Cw6-negative patients with Psoriasis vulgaris have distinct clinical features. The Journal of investigative dermatology 2002;118(2):362-365
38. Gudjonsson JE, Karason A, Runarsdottir EH, et al. Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients. The Journal of investigative dermatology 2006;126(4):740-745
39.张学军主编.皮肤性病学.第五版.北京.人民卫生出版社2001:117-122
40. Weiss G, Shemer A, Trau H. The Koebner phenomenon: review of the literature. J Eur Acad Dermatol Venereol 2002;16(3):241-248
41. Mallbris L, Larsson P, Bergqvist S, et al. Psoriasis phenotype at disease onset: clinical characterization of 400 adult cases. The Journal of investigative dermatology 2005;124(3):499-504
42. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64Suppl 2:ii14-17
43. Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. Journal of the American Academy of Dermatology 2004;51(4):563-569
44. Zachariae R, Zachariae H, Blomqvist K, et al. Self-reported stress reactivity and psoriasis-related stress of Nordic psoriasis sufferers. J Eur Acad Dermatol Venereol 2004;18(1):27-36
45. Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients’beliefs and attitudes towards the disease. Br J Dermatol.1996,135: 533-537.
46. Shao CG. The prevalence, prevention and treatment of psoriasis in China. Chin J Dermatol 1996, 29:75-76.
47. Lomholt G. Psoriasis Prevalence, spontaneous course and genetics: a census study on the prevalence of skin diseases on the Faroe Island. Copenhagen; G E C Gad: 1963.
48. Farber EM, Nall L. Epidemiology: natural history and genetics. In: Roenigk HH, Maibach HI (eds) Psoriasis. 2nd edn. Marcel Dekker, New York, 1991, pp 209-258.
49. Brandrup P, Holm N, Grunnet N, et al. Psoriasis in monozygotic twins: variations in expression in individauls with identical genetic constitution. Acta Derm Venerol. 1982, 62: 229-236.
50. Duffy DL, Spelamn LS, Martin NG. Psoriasis in Australian twins. J Am Acad Dermatol. 1993, 29: 428-434.
51. Zhang XJ, Wang HY, HsuTe-shao, et al. Study on Genetic Epidemiology of Psoriasis Vulgaris in Chinese Han people. Int J Dermatol. 2002, 41: 663-669.
52.王红艳,张学军,杨森,等.银屑病危险因素的研究.中华流行病学杂志2001, 22: 215-218
53. Zhang XJ, Wang HY, HsuTe-shao, et al. Frequent Use of Tobacco and AlcoholUse in Chinese Psoriatic Patients. Int J Dermatol. 2002, 41:659-662.
54. Dobson RL. The inheritance of psoriasis. Arch Dermatol. 1980, 116:657.
55. Elant-Johnson RC. Probability model and statistic methods on genetics. NY: Wiley, 1971: 512-613.
56. Capon F, Dallapiccola B, Novelli G. Advances in the search for psoriasis susceptibility genes. Mol Genet Metab. 2000, 71:250-255.
57. Zhang XJ, Wang HY, HsuTe-shao, et al. Study on Genetic Epidemiology of Psoriasis Vulgaris in Chinese Han people. Int J Dermatol. 2002, 41: 663-669.
58. Elder JT, Nair RP, Guo SW, et al. The genetics of psoriasis. Arch Dermatol. 1994,130: 216-224.
59. Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis.Nat Genet. 2003 Dec;35(4):349-56
60. Speckman RA, Wright Daw JA, Helms C, et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet, 2003, 112:34-41
61. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, et al. (2006). "Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene." Am J Hum Genet 78(5): 827-51.
62. Capon F, Helms C, Veal CD, et al. Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J. Med. Genet, 2004, 41: 459-460
63. Huffmeier U, Traupe H, Burkhardt H, et al. Lack of Evidence for Genetic Association to RUNX1 Binding Site at PSORS2 in Different German Psoriasis Cohorts. J Invest Dermatol, 2005, 124:107–110
64. Sagoo GS, Tazi-Ahnini R, Barker J, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28–q31 in Caucasian and Chinese Hans population. J Invest Dermatol. 2004, 122(6):1401-1405.
65.Jakobsson P-J. Mancini JA, Ford-Hutchinson AW: Identification and Characterization of a Novel Human Microsomal Glutathione S-Transferase with Leukotriene C4 Synthase Activity and Significant Sequence Identity to 5-Lipoxygenase-activating Protein and Leukotriene C4 Synthase . J Biol Chem. 1996, 271(36):22203-22210.
66. Bettina Wedi and Alexander Kapp: Pathophysiological Role of Leukotrienes in Dermatological Diseases. Bio Drugs. 2001, 15(11):729-743.
67.Iversen L, Deleuran B, Hoberg AM, et al. LTA4 hydrolase in human skin: decreased activity but normal concentration in lesional psoriatic skin. Arch Dermatol Res. 1996, 288(5-6): 217-241.
68.Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest. 2003, 112(10):1571-1580.
69.Baker BS, Ovigne JM, Powles AV, et al. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol, 2003, 148: 670–679.
70.Cario E, Podolsky DK:Differential alteration in intestinal epithelial cell expression of toll-like receptor 3(TLR3) and TLR4 in inflammatory bowel disease. Infect Immunity, 2000,68:7010-7017
71.Helen S.Young, Angela M.Summers, Monica Bhushan, et al. Single-Nucleotide Polymorphisms of Vascular Endothelial Growth Factor in Psoriasis of Early Onset. J Invest Dermatol, 2004, 122:209–215
72. Foerster J, Nolte I, Schweiger S, et al. Evaluation of the IRF-2 Gene as a Candidate for PSORS3. J Invest Dermatol, 2004, 122: 61–64
73.Parkinson J, Charon C, Baker BS, et al. Variation at the IRF2 Gene and Susceptibility to Psoriasis in Chromosome 4q-Linked Families. J Invest Dermatol, 2004, 122:640–643
74. Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population.Nat Genet.42; 1005-1009.
75. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38; 1166-1172.
76. Huffmeier U, Bergboer JG, Becker T, Armour JA, Traupe H, Estivill X, et al. Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. J Invest Dermatol.130; 979-984.
77. Riveira-Munoz E, He SM, Escaramis G, Stuart PE, Huffmeier U, Lee C, et al. Meta-Analysis Confirms the LCE3C_LCE3B Deletion as a Risk Factor for Psoriasis in Several Ethnic Groups and Finds Interaction with HLA-Cw6. J Invest Dermatol.
78. Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet.42; 985-990.
79. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447; 661-678.
80. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993;101; 701-705.
81. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13; 139-145.
82. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116; 1310-1316.
83. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201; 233-240.
84. Wang A, Johnson DG, MacLeod MC. Molecular cloning and characterization of anovel mouse epidermal differentiation gene and its promoter. Genomics. 2001;73; 284-290.
85. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21. J Invest Dermatol. 1996;106; 989-992.
86. Engelkamp D, Schafer BW, Mattei MG, Erne P, Heizmann CW. Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E. Proc Natl Acad Sci U S A. 1993;90; 6547-6551.
87. Backendorf C, Hohl D. A common origin for cornified envelope proteins? Nat Genet. 1992;2; 91.
1.杨森,魏生才,张学军,等。寻常型银屑病诱因流行病学分析。中国麻风皮肤病杂志2000,16:159-162。
2. Zhang X, Wang H, Te-Shao H, et al. The genetic epidemiology of psoriasis vulgaris in Chinese Han. International journal of dermatology 2002; 41(10):663-669
3. Michael Allen , Jonathan W. N. Barker, Anne M. Bowcock,et al.,Consortium. TIPG. The International Psoriasis Genetics Study: assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs. American journal of human genetics 2003; 73(2):430-437
4. Asumalahti K, Laitinen T, Lahermo P, et al. Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1. TheJournal of investigative dermatology 2003; 121(4):735-740
5. Nair RP, 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. Human molecular genetics 1997; 6(8):1349-1356
6. Nair RP, Henseler T, Jenisch S, et al. Localization of psoriasis susceptibility locus PSORS1 to a 60 kilobase intervals telomeric to HLA-C. Am J Hum Genet. 2000, 66: 1833-1844
7. Orru S, Giuressi E, Carcassi C, et al. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN). American journal of human genetics 2005; 76(1):164-171
8. Speckman RA, Wright Daw JA, Helms C, et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Human genetics 2003; 112(1):34-41
9. Capon F, Semprini S, Chimenti S, et al. Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. The Journal of investigative dermatology 2001; 116(5):728-730
10. Zhang XJ, He PP, Wang ZX, et al. Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans. J Invest Dermatol. 2002, 119:1361–1366
11. Capon F, Munro M, Barker J, et al. Searching for the major histocompatibility complex psoriasis susceptibility gene. The Journal of investigative dermatology 2002; 118(5):745-751
12. Capon F, Allen MH, Ameen M, et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Human molecular genetics 2004; 13(20):2361-2368
13. Holm SJ, Carlen LM, Mallbris L, et al. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Experimental dermatology 2003; 12(4):435-444
14. Foerster J, Nolte I, Junge J, et al. Haplotype sharing analysis identifies a retroviral dUTPase as candidate susceptibility gene for psoriasis. The Journal of investigative dermatology 2005; 124(1):99-102
15. Helms C, Cao L, Krueger JG, et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet, 2003, 35:349-56
16. Capon F, Helms C, Veal CD, et al. Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J. Med. Genet, 2004, 41: 459-460
17. Huffmeier U, Traupe H, Burkhardt H,et al. Lack of Evidence for Genetic Association to RUNX1 Binding Site at PSORS2 in Different German Psoriasis Cohorts. J Invest Dermatol, 2005, 124:107–110
18. Sagoo GS, Tazi-Ahnini R, Barker JW, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population. The Journal of investigative dermatology 2004; 122(6):1401-1405
19. Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. The Journal of clinical investigation 2003; 112(10):1571-1580
20. Helen S.Young, Angela M.Summers, Monica Bhushan, et al. Single-Nucleotide Polymorphisms of Vascular Endothelial Growth Factor in Psoriasis of Early Onset. J Invest Dermatol, 2004, 122:209–215
21. Foerster J, Nolte I, Schweiger S, et al. Evaluation of the IRF-2 gene as a candidate for PSORS3. The Journal of investigative dermatology 2004; 122(1):61-64
22. Parkinson J, Charon C, Baker BS, et al. Variation at the IRF2 gene and susceptibility to psoriasis in chromosome 4q-linked families. The Journal of investigative dermatology 2004; 122(3):640-643
23. Samuelsson L, Stiller C, Friberg C, et al. Association analysis of cystatin A and zinc finger protein 148, two genes located at the psoriasis susceptibility locusPSORS5. The Journal of investigative dermatology 2004; 122(6):1399-1400
24. Hewett D, Samuelsson L, Polding J, et al. Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics 2002; 79(3):305-314
25. Giardina E, Capon F, De Rosa MC, et al. Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus. Annals of human genetics 2004; 68(Pt 6):639-645
26. Rahman P, Bartlett S, Siannis F, et al. CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. American journal of human genetics 2003; 73(3):677-681
27. Giardina E, Novelli G, Costanzo A, et al. Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. The Journal of investigative dermatology 2004; 122(5):1106-1107
28. Young C, Allen MH, Cuthbert A, et al. A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis. Experimental dermatology 2003; 12(4):506-509
29. Plant D, Lear J, Marsland A, et al. CARD15/NOD2 single nucleotide polymorphisms do not confer susceptibility to type I psoriasis. The British journal of dermatology 2004; 151(3):675-678
30. Reich K, Mossner R, Konig IR, et al. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset. The Journal of investigative dermatology 2002; 118(1):155-163
31. Koks S, Kingo K, Ratsep R, et al. Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes and immunity 2004; 5(8):662-667
32. Cargill M, Schrodi SJ, Chang M,et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am J Hum Genet. 2007;80:273–290
33. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007; 356:580–592
34. Nair RP, Ruether A, Stuart PE,et al. Polymorphisms of the IL12B and IL23R genes are associated with Psoriasis. J Invest Dermatol. 2008,128: 1653-1661
35. Capon F, Di MP, Szaub J,et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet. 2007; 122:201–206
36. Liu C, Batliwalla F, Li W,et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med. 2008; 14:575–581
37. Nair RP, Duffin KC, Helms C,et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41:199–204
38. Zhang XJ, Huang W, Yang S,et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet. 2009; 41:205–210
39. Chen HJ, Toh TKL, Szeverenyi I, et al. Association of Skin Barrier Genes within the PSORS4 Locus Is Enriched in Singaporean Chinese with Early-Onset Psoriasis J Invest Dermatol. 2009(129): 3: 606-614
40. Hollox EJ, Huffmeier U, Zeeuwen PL,et al. Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet. 2008;40:23–25
41. de Cid R, Riveira-Munoz E, Zeeuwen PL,et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet. 2009; 41:211–215
2. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273-290.
3. (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678.
4. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087-1093.
5. Altshuler D, Daly M (2007) Guilt beyond a reasonable doubt. Nat Genet 39: 813-815.
6. Andrieu N, Goldstein AM. Ep idemiologic and genetic app roaches in the study of gene2environment interaction: an overview of available methods. Epidem iol Rev, 1998, 20 (2) : 137 - 147.
7. Manolio TA,Bailey2Wilson JE, Collins FS. Genes, environment and the value of p rospective cohort studies. Nat Rev Genet, 2006, 7 (10) : 812 - 820.
8. Ottman R. Gene2environment interaction: definitions and study designs. PrevMed, 1996, 25 (6) : 764 - 770.
9. Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidem iol, 1980, 112 (4) : 467 - 470.
10. Cordell HJ. Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet, 2002, 11 (20) : 2 463 - 2 468.
11. Hunter DJ. Gene-environment interactions in human diseases. Nat Rev Genet, 2005, 6 (4) : 287 - 298.
12. Capon, F., et al., Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet, 2008. 17(13): p. 1938-45.
13. Liu, Y., et al., A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet, 2008. 4(3): p. e1000041.
14. Nair, R.P., et al., Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet, 2009. 41(2): p. 199-204.
15. Zhang, X.J., et al., Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet, 2009. 41(2): p. 205-10.
16. de Cid, R., et al., Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet, 2009. 41(2): p. 211-5.
17. Nair, R.P., et al., Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet, 2006. 78(5): p. 827-51.
18. Fan, X., et al., Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genet, 2008. 4(3): p. e1000038.
19. Elder, J.T., Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun, 2009. 10(3): p. 201-9.
20.Nestle, F.O., D.H. Kaplan, and J. Barker, Psoriasis. N Engl J Med, 2009. 361(5): p. 496-509.
21.Nelson, G.W., et al., Cutting edge: heterozygote advantage in autoimmune disease:hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol, 2004. 173(7): p. 4273-6.
22. Feng, B.J., et al., Multiple Loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet, 2009. 5(8): p. e1000606.
23. Shao CG. The prevalence, prevention and treatment of psoriasis in China. Chin J Dermatol 1996;29:75-76
24.全国银屑病流行调查组。.全国1984年银屑病流行调查报告。.中华皮肤科杂志1986;19:253-261
25. Brandrup F, Holm N, Grunnet N, Henningsen K, Hansen HE. Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution. Acta dermato-venereologica 1982;62(3):229-236
26. Duffy DL, Spelman LS, Martin NG. Psoriasis in Australian twins. Journal of the American Academy of Dermatology 1993;29(3):428-434
27.杨森,魏生才,张学军等.寻常型银屑病诱因流行病学分析.中国麻风皮肤病杂志2000;16:159-162
28. Zhang X, Wang H, Te-Shao H, Yang S, Wang F. Frequent use of tobacco and alcohol in Chinese psoriasis patients. International journal of dermatology 2002;41(10):659-662
29. Sagoo GS, Tazi-Ahnini R, Barker JW, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population. The Journal of investigative dermatology 2004;122(6):1401-1405
30. Tiilikainen A, Lassus A, Karvonen J, Vartiainen P, Julin M. Psoriasis and HLA-Cw6. The British journal of dermatology 1980;102(2):179-184
31. Mallon E, Newson R, Bunker CB. HLA-Cw6 and the genetic predisposition to psoriasis: a meta-analysis of published serologic studies. The Journal of investigative dermatology 1999;113(4):693-695
32. Gudjonsson JE, Karason A, Antonsdottir A, et al. Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk ofdeveloping psoriasis compared with Cw6 heterozygotes. The British journal of dermatology 2003;148(2):233-235
33. Zhang XJ, Zhang AP, Yang S, et al. Association of HLA class I alleles with psoriasis vulgaris in southeastern Chinese Hans. J Dermatol Sci 2003;33(1):1-6
34. Ikaheimo I, Tiilikainen A, Karvonen J, Silvennoinen-Kassinen S. HLA risk haplotype Cw6,DR7,DQA1*0201 and HLA-Cw6 with reference to the clinical picture of psoriasis vulgaris. Archives of dermatological research 1996;288(7):363-365
35. Enerback C, Martinsson T, Inerot A, et al. Evidence that HLA-Cw6 determines early onset of psoriasis, obtained using sequence-specific primers (PCR-SSP). Acta dermato-venereologica 1997;77(4):273-276
36. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. Journal of the American Academy of Dermatology 1985;13(3):450-456
37. Gudjonsson JE, Karason A, Antonsdottir AA, et al. HLA-Cw6-positive and HLA-Cw6-negative patients with Psoriasis vulgaris have distinct clinical features. The Journal of investigative dermatology 2002;118(2):362-365
38. Gudjonsson JE, Karason A, Runarsdottir EH, et al. Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients. The Journal of investigative dermatology 2006;126(4):740-745
39.张学军主编.皮肤性病学.第五版.北京.人民卫生出版社2001:117-122
40. Weiss G, Shemer A, Trau H. The Koebner phenomenon: review of the literature. J Eur Acad Dermatol Venereol 2002;16(3):241-248
41. Mallbris L, Larsson P, Bergqvist S, et al. Psoriasis phenotype at disease onset: clinical characterization of 400 adult cases. The Journal of investigative dermatology 2005;124(3):499-504
42. Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64Suppl 2:ii14-17
43. Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. Journal of the American Academy of Dermatology 2004;51(4):563-569
44. Zachariae R, Zachariae H, Blomqvist K, et al. Self-reported stress reactivity and psoriasis-related stress of Nordic psoriasis sufferers. J Eur Acad Dermatol Venereol 2004;18(1):27-36
45. Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence, severity and patients’beliefs and attitudes towards the disease. Br J Dermatol.1996,135: 533-537.
46. Shao CG. The prevalence, prevention and treatment of psoriasis in China. Chin J Dermatol 1996, 29:75-76.
47. Lomholt G. Psoriasis Prevalence, spontaneous course and genetics: a census study on the prevalence of skin diseases on the Faroe Island. Copenhagen; G E C Gad: 1963.
48. Farber EM, Nall L. Epidemiology: natural history and genetics. In: Roenigk HH, Maibach HI (eds) Psoriasis. 2nd edn. Marcel Dekker, New York, 1991, pp 209-258.
49. Brandrup P, Holm N, Grunnet N, et al. Psoriasis in monozygotic twins: variations in expression in individauls with identical genetic constitution. Acta Derm Venerol. 1982, 62: 229-236.
50. Duffy DL, Spelamn LS, Martin NG. Psoriasis in Australian twins. J Am Acad Dermatol. 1993, 29: 428-434.
51. Zhang XJ, Wang HY, HsuTe-shao, et al. Study on Genetic Epidemiology of Psoriasis Vulgaris in Chinese Han people. Int J Dermatol. 2002, 41: 663-669.
52.王红艳,张学军,杨森,等.银屑病危险因素的研究.中华流行病学杂志2001, 22: 215-218
53. Zhang XJ, Wang HY, HsuTe-shao, et al. Frequent Use of Tobacco and AlcoholUse in Chinese Psoriatic Patients. Int J Dermatol. 2002, 41:659-662.
54. Dobson RL. The inheritance of psoriasis. Arch Dermatol. 1980, 116:657.
55. Elant-Johnson RC. Probability model and statistic methods on genetics. NY: Wiley, 1971: 512-613.
56. Capon F, Dallapiccola B, Novelli G. Advances in the search for psoriasis susceptibility genes. Mol Genet Metab. 2000, 71:250-255.
57. Zhang XJ, Wang HY, HsuTe-shao, et al. Study on Genetic Epidemiology of Psoriasis Vulgaris in Chinese Han people. Int J Dermatol. 2002, 41: 663-669.
58. Elder JT, Nair RP, Guo SW, et al. The genetics of psoriasis. Arch Dermatol. 1994,130: 216-224.
59. Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis.Nat Genet. 2003 Dec;35(4):349-56
60. Speckman RA, Wright Daw JA, Helms C, et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet, 2003, 112:34-41
61. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, et al. (2006). "Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene." Am J Hum Genet 78(5): 827-51.
62. Capon F, Helms C, Veal CD, et al. Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J. Med. Genet, 2004, 41: 459-460
63. Huffmeier U, Traupe H, Burkhardt H, et al. Lack of Evidence for Genetic Association to RUNX1 Binding Site at PSORS2 in Different German Psoriasis Cohorts. J Invest Dermatol, 2005, 124:107–110
64. Sagoo GS, Tazi-Ahnini R, Barker J, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28–q31 in Caucasian and Chinese Hans population. J Invest Dermatol. 2004, 122(6):1401-1405.
65.Jakobsson P-J. Mancini JA, Ford-Hutchinson AW: Identification and Characterization of a Novel Human Microsomal Glutathione S-Transferase with Leukotriene C4 Synthase Activity and Significant Sequence Identity to 5-Lipoxygenase-activating Protein and Leukotriene C4 Synthase . J Biol Chem. 1996, 271(36):22203-22210.
66. Bettina Wedi and Alexander Kapp: Pathophysiological Role of Leukotrienes in Dermatological Diseases. Bio Drugs. 2001, 15(11):729-743.
67.Iversen L, Deleuran B, Hoberg AM, et al. LTA4 hydrolase in human skin: decreased activity but normal concentration in lesional psoriatic skin. Arch Dermatol Res. 1996, 288(5-6): 217-241.
68.Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest. 2003, 112(10):1571-1580.
69.Baker BS, Ovigne JM, Powles AV, et al. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Br J Dermatol, 2003, 148: 670–679.
70.Cario E, Podolsky DK:Differential alteration in intestinal epithelial cell expression of toll-like receptor 3(TLR3) and TLR4 in inflammatory bowel disease. Infect Immunity, 2000,68:7010-7017
71.Helen S.Young, Angela M.Summers, Monica Bhushan, et al. Single-Nucleotide Polymorphisms of Vascular Endothelial Growth Factor in Psoriasis of Early Onset. J Invest Dermatol, 2004, 122:209–215
72. Foerster J, Nolte I, Schweiger S, et al. Evaluation of the IRF-2 Gene as a Candidate for PSORS3. J Invest Dermatol, 2004, 122: 61–64
73.Parkinson J, Charon C, Baker BS, et al. Variation at the IRF2 Gene and Susceptibility to Psoriasis in Chromosome 4q-Linked Families. J Invest Dermatol, 2004, 122:640–643
74. Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, et al. Association analyses identify six new psoriasis susceptibility loci in the Chinese population.Nat Genet.42; 1005-1009.
75. de Bakker PI, McVean G, Sabeti PC, Miretti MM, Green T, Marchini J, et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet. 2006;38; 1166-1172.
76. Huffmeier U, Bergboer JG, Becker T, Armour JA, Traupe H, Estivill X, et al. Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors. J Invest Dermatol.130; 979-984.
77. Riveira-Munoz E, He SM, Escaramis G, Stuart PE, Huffmeier U, Lee C, et al. Meta-Analysis Confirms the LCE3C_LCE3B Deletion as a Risk Factor for Psoriasis in Several Ethnic Groups and Finds Interaction with HLA-Cw6. J Invest Dermatol.
78. Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet.42; 985-990.
79. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447; 661-678.
80. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol. 1993;101; 701-705.
81. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13; 139-145.
82. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116; 1310-1316.
83. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201; 233-240.
84. Wang A, Johnson DG, MacLeod MC. Molecular cloning and characterization of anovel mouse epidermal differentiation gene and its promoter. Genomics. 2001;73; 284-290.
85. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21. J Invest Dermatol. 1996;106; 989-992.
86. Engelkamp D, Schafer BW, Mattei MG, Erne P, Heizmann CW. Six S100 genes are clustered on human chromosome 1q21: identification of two genes coding for the two previously unreported calcium-binding proteins S100D and S100E. Proc Natl Acad Sci U S A. 1993;90; 6547-6551.
87. Backendorf C, Hohl D. A common origin for cornified envelope proteins? Nat Genet. 1992;2; 91.
1.杨森,魏生才,张学军,等。寻常型银屑病诱因流行病学分析。中国麻风皮肤病杂志2000,16:159-162。
2. Zhang X, Wang H, Te-Shao H, et al. The genetic epidemiology of psoriasis vulgaris in Chinese Han. International journal of dermatology 2002; 41(10):663-669
3. Michael Allen , Jonathan W. N. Barker, Anne M. Bowcock,et al.,Consortium. TIPG. The International Psoriasis Genetics Study: assessing linkage to 14 candidate susceptibility loci in a cohort of 942 affected sib pairs. American journal of human genetics 2003; 73(2):430-437
4. Asumalahti K, Laitinen T, Lahermo P, et al. Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1. TheJournal of investigative dermatology 2003; 121(4):735-740
5. Nair RP, 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. Human molecular genetics 1997; 6(8):1349-1356
6. Nair RP, Henseler T, Jenisch S, et al. Localization of psoriasis susceptibility locus PSORS1 to a 60 kilobase intervals telomeric to HLA-C. Am J Hum Genet. 2000, 66: 1833-1844
7. Orru S, Giuressi E, Carcassi C, et al. Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN). American journal of human genetics 2005; 76(1):164-171
8. Speckman RA, Wright Daw JA, Helms C, et al. Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Human genetics 2003; 112(1):34-41
9. Capon F, Semprini S, Chimenti S, et al. Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. The Journal of investigative dermatology 2001; 116(5):728-730
10. Zhang XJ, He PP, Wang ZX, et al. Evidence for a major psoriasis susceptibility locus at 6p21 (PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese Hans. J Invest Dermatol. 2002, 119:1361–1366
11. Capon F, Munro M, Barker J, et al. Searching for the major histocompatibility complex psoriasis susceptibility gene. The Journal of investigative dermatology 2002; 118(5):745-751
12. Capon F, Allen MH, Ameen M, et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Human molecular genetics 2004; 13(20):2361-2368
13. Holm SJ, Carlen LM, Mallbris L, et al. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Experimental dermatology 2003; 12(4):435-444
14. Foerster J, Nolte I, Junge J, et al. Haplotype sharing analysis identifies a retroviral dUTPase as candidate susceptibility gene for psoriasis. The Journal of investigative dermatology 2005; 124(1):99-102
15. Helms C, Cao L, Krueger JG, et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet, 2003, 35:349-56
16. Capon F, Helms C, Veal CD, et al. Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J. Med. Genet, 2004, 41: 459-460
17. Huffmeier U, Traupe H, Burkhardt H,et al. Lack of Evidence for Genetic Association to RUNX1 Binding Site at PSORS2 in Different German Psoriasis Cohorts. J Invest Dermatol, 2005, 124:107–110
18. Sagoo GS, Tazi-Ahnini R, Barker JW, et al. Meta-analysis of genome-wide studies of psoriasis susceptibility reveals linkage to chromosomes 6p21 and 4q28-q31 in Caucasian and Chinese Hans population. The Journal of investigative dermatology 2004; 122(6):1401-1405
19. Villadsen LS, Schuurman J, Beurskens F, et al. Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. The Journal of clinical investigation 2003; 112(10):1571-1580
20. Helen S.Young, Angela M.Summers, Monica Bhushan, et al. Single-Nucleotide Polymorphisms of Vascular Endothelial Growth Factor in Psoriasis of Early Onset. J Invest Dermatol, 2004, 122:209–215
21. Foerster J, Nolte I, Schweiger S, et al. Evaluation of the IRF-2 gene as a candidate for PSORS3. The Journal of investigative dermatology 2004; 122(1):61-64
22. Parkinson J, Charon C, Baker BS, et al. Variation at the IRF2 gene and susceptibility to psoriasis in chromosome 4q-linked families. The Journal of investigative dermatology 2004; 122(3):640-643
23. Samuelsson L, Stiller C, Friberg C, et al. Association analysis of cystatin A and zinc finger protein 148, two genes located at the psoriasis susceptibility locusPSORS5. The Journal of investigative dermatology 2004; 122(6):1399-1400
24. Hewett D, Samuelsson L, Polding J, et al. Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics 2002; 79(3):305-314
25. Giardina E, Capon F, De Rosa MC, et al. Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus. Annals of human genetics 2004; 68(Pt 6):639-645
26. Rahman P, Bartlett S, Siannis F, et al. CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. American journal of human genetics 2003; 73(3):677-681
27. Giardina E, Novelli G, Costanzo A, et al. Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. The Journal of investigative dermatology 2004; 122(5):1106-1107
28. Young C, Allen MH, Cuthbert A, et al. A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis. Experimental dermatology 2003; 12(4):506-509
29. Plant D, Lear J, Marsland A, et al. CARD15/NOD2 single nucleotide polymorphisms do not confer susceptibility to type I psoriasis. The British journal of dermatology 2004; 151(3):675-678
30. Reich K, Mossner R, Konig IR, et al. Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset. The Journal of investigative dermatology 2002; 118(1):155-163
31. Koks S, Kingo K, Ratsep R, et al. Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes and immunity 2004; 5(8):662-667
32. Cargill M, Schrodi SJ, Chang M,et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am J Hum Genet. 2007;80:273–290
33. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007; 356:580–592
34. Nair RP, Ruether A, Stuart PE,et al. Polymorphisms of the IL12B and IL23R genes are associated with Psoriasis. J Invest Dermatol. 2008,128: 1653-1661
35. Capon F, Di MP, Szaub J,et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet. 2007; 122:201–206
36. Liu C, Batliwalla F, Li W,et al. Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. Mol Med. 2008; 14:575–581
37. Nair RP, Duffin KC, Helms C,et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009;41:199–204
38. Zhang XJ, Huang W, Yang S,et al. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet. 2009; 41:205–210
39. Chen HJ, Toh TKL, Szeverenyi I, et al. Association of Skin Barrier Genes within the PSORS4 Locus Is Enriched in Singaporean Chinese with Early-Onset Psoriasis J Invest Dermatol. 2009(129): 3: 606-614
40. Hollox EJ, Huffmeier U, Zeeuwen PL,et al. Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet. 2008;40:23–25
41. de Cid R, Riveira-Munoz E, Zeeuwen PL,et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet. 2009; 41:211–215