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【medical-news】安徽医大张学军教授参与的多中心研究：银屑病的特异基因及其免疫途径

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Multiple Studies Associate Psoriasis With Specific Genes and Pathways
Jacquelyn K. Beals, PhD
http://www.medscape.com/viewarticle/587324
January 26, 2009 — Three genomewide studies have identified gene variants and pathways associated with an increased risk for psoriasis. The reports, published online yesterday in Nature Genetics, suggest that disrupting the normal skin barrier increases susceptibility to psoriasis and demonstrate the importance of immune response regulation in the disease.

Psoriasis is commonly recognized as an immune-mediated disorder characterized by inflammation and affecting the joints, skin, and nails. Its prevalence ranges from 2% to 5% in populations of Western European origin to a much lower 0.1% to 0.3% in East Asian populations. Symptoms commonly include a reddish, scaly rash, with itching and flaking skin. Psoriasis has been linked to environmental, genetic, and immunological factors.

Immune-Related Genes Prominent in Psoriasis

A multi-institutional study by scientists in the United States, Canada, Germany, and France searched for psoriasis susceptibility loci among white individuals of European heritage — 1409 patients with psoriasis and 1436 control patients. Initial comparisons confirmed well-accepted risk loci such as HLA-C, ILI12B, and IL23R and led to the selection of 21 single nucleotide polymorphisms (SNPs) for further study. Genotyping additional patients with psoriasis (n = 5048) and control patients (n = 5051) narrowed the field to 7 loci (combined P < 5 × 10−8).

These 7 susceptibility loci, in addition to HLA-C, included IL23A, IL12B, and IL23R, which play a role in interleukin 23 (IL-23) signaling; 2 genes (TNFAIP3 and TNIP1) that regulate NF-kappaB signaling; and 2 genes (IL4 and IL13) that influence responses of type 2 helper T cells — all of which are involved in the regulation of immune responses.

Asked about the representation of immune-related genes in the top-ranked loci, senior author Anne M. Bowcock, PhD, from the Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, told Medscape Pathology & Lab Medicine via email: "The top hits seemed to be immune-related genes. However, at least 1 region selected for follow-up (IL23A/P19) was selected because it fit into the pathway we knew from genetics and immunology."

The authors note that "hundreds of genes" are expressed differently in normal and psoriatic skin cells and suggest that the genes identified in this study may trigger the progression of psoriasis. Analysis of biopsies of normal and involved skin from psoriatic patients (n = 58) and from control patients (n = 64) found that 4 of the genes have significantly different expression levels in affected and unaffected skin (P < 10−9 for each of the 4 genes: HLA-C, IL12B, IL23A, and TNIP1).

Late Cornified Envelope Genes in the West

The second study, by European and US researchers, investigated copy number variants (CNVs) associated with psoriasis susceptibility. Their study identified a deleted region associated with psoriasis susceptibility on the long arm of human chromosome 1 — part of the "late cornified envelope (LCE) gene cluster." This cluster contains multiple genes that code for proteins of the stratum corneum, the tough outermost layer of the epidermis.

After determining from pooled samples that a CNV on chromosome 1q21 was associated with psoriasis, the study analyzed samples from single psoriatic individuals. Deletion of a 32.2-kb region containing LCE3C and LCE3B was more common in people with psoriasis than in control patients (in the Spanish sample, 64% vs 55%; P = .0028). Similar results were obtained in Italian, Dutch, and US samples.

Overall, the LCE3C and LCE3B deletion occurred in 68% of patients with psoriasis and 59% of control patients (overall odds ratio [OR], 1.38; 95% confidence interval [CI], 1.19 – 1.61; P = 1.38 × 10−8). Interestingly, for individuals who were homozygous or heterozygous for the deletion, ORs indicated a dose effect on psoriasis susceptibility: Individuals with 2 copies of LCE3B and LCE3C were "protected" against psoriasis (P < .0001).

The study investigated disruption of the normal skin barrier as a physiological stimulus for LCE3 activity. "Tape-stripping" the stratum corneum from the skin of normal subjects increased the expression of genes active in forming the skin barrier: LCE3C activity was induced as a repair response. The authors suggest that when LCE3C and LCE3B are absent, an inappropriate repair response might occur after barrier disruption.

Senior author Xavier Estivill, MD, PhD, from the Genetic Causes of Disease Lab, Genes and Disease Programme, Center for Genomic Regulation, and Public Health and Epidemiology Network Biomedical Research Center, Pompeu Fabra University, Barcelona, Spain, discussed this possibility with Medscape Pathology & Lab Medicine.

"The involvement of the LCE genes in psoriasis predisposition is a new concept in the pathophysiology of this disorder. We still do not know how this is involved in the disease," said Dr. Estivill via email. "We speculate that absence of intact LCE3C and LCE3B genes could lead to an inappropriate repair response following barrier disruption.... A more leaky epidermal barrier following skin injury would allow easier penetration of exogenous agents (allergens and/or microorganisms) that have been postulated to be involved in the development of the disease."

He suggested that the "development of therapies that protect the skin against exogenous agents could be an approach that has not been tried so far."

Late Cornified Envelope Genes in the East

An investigation by Xue-Jun Zhang, MD, from the Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University, Hefei; the Key Laboratory of Gene Resource Utilization for Severe Diseases, Ministry of Education and Anhui Province, Hefei; and the Department of Dermatology and Venereology, Anhui Medical University, Hefei, China, and numerous colleagues throughout China and Singapore, was the "first large genome-wide association study...in a Chinese population" and demonstrated psoriasis susceptibility variants in the LCE gene cluster. The first stage of this case-control study enrolled only individuals of Han Chinese heritage. Psoriasis was significantly associated with 4 SNPs in the LCE gene cluster and 2 SNPs in IL12B.

Replication in Han Chinese (ncase = 5182; ncontrol = 6516) and Uygur Chinese (ncase = 539; ncontrol = 824) identified a previously unknown susceptibility locus in the LCE gene cluster — a SNP in gene LCE3D (OR, .76; 95% CI, .72 – .80; P for the combined analyses = 6.69 × 10−30).

The report points out that this new locus "has biological implications. The LCE genes encode the stratum-corneum proteins of cornified envelope that have an important role in epidermal terminal differentiation.... [R]apid keratinocyte proliferation may cause the production of parakeratotic keratinocytes [which retain their nuclei in the stratum corneum] in psoriatic skin, and thus the formation of poorly adherent stratum corneum, which in turn results in the characteristic scales or flakes of psoriasis lesions."

Stefan Schreiber, MD, from the Institute for Clinical Molecular Biology, University of Kiel, Germany, and a coauthor of the immune-related study above, said to Medscape Pathology & Lab Medicine via email: "LCE appears to be a gene that is [as] important for epidermal integrity as it is important for differentiation of keratinocytes. The involvement of this gene nourishes the hypothesis that one of the primary causes of psoriasis could be a barrier problem, that is, a mishandling of the natural bacterial environment.

"[What's] remarkable," added Dr. Schreiber, "is that the responsible gene, LCE, is relevant across ethnicities (ie, Asian and European). This dates the responsible mutation quite further back than 40,000 years and is very unusual for complex diseases."

The Chinese study closes by suggesting that "by causing the production of abnormal stratum-corneum proteins...genetic susceptibility variant(s) within the LCE genes may influence the development of psoriasis by interrupting the terminal differentiation of keratinocytes."

Disrupted Barrier May Trigger Immune System

Jonathan Barker, MD, FRCP, FRCPath, from St. John's Institute of Dermatology (King's College), Guy's Hospital, London, United Kingdom, pointed out to Medscape Pathology & Lab Medicine that a disrupted barrier may trigger an immune system response.

"As pointed out in both the Chinese and Estivill papers, a key component of the psoriasis process is an abnormal barrier, namely, rapid proliferation with loss of differentiation. Clinically, this is characterized by thick scale formation, a hallmark of the disease," said Dr. Barker in an email. He was not involved in the studies.

"[A] second major component of the psoriasis process is inflammation and immunology, with clear functional evidence implicating both innate and adaptive immunity," Dr. Barker continued. He also noted that the third component of psoriasis is changes in the vasculature, which is not supported by current genetic findings.

"Thus, involvement of both stratum corneum and immune genes makes complete sense and further suggests mechanistic pathways touched on in the...Chinese paper. But I think we can say more," concluded Dr. Barker, "namely, that disruption of the stratum corneum may provide a trigger to the immune system."

Dr. Bowcock has disclosed no relevant financial relationships. Dr. Estivill is affiliated with the Center for Genomic Regulation, which has patented the use of the LCE3B/LCE3C deletion as a diagnostic for predisposition and risk of developing psoriasis. Dr. Schreiber advises Life Technologies (formerly Applied Biosystems). Dr. Barker has advised several companies making biologic therapies for psoriasis unrelated to this study.

Nat Genet. Published online January 25, 2009

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2009-01-28 11:11 浏览 : 2562 回复 : 2

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基本完成，背景知识不够，完成的很吃力，大家多多拍砖，谢谢。

2009-02-02 12:53

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yingtiao 编辑于 2009-02-03 20:40

• 综合医院全科门诊中乏力患者特征及就诊原因分析

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银屑病相关基因及信号通路的多中心研究
By Jacquelyn k. Beals,PhD 1月26日，2009年
近期，三项全基因组研究GWS证实：基因变种和信号通路同银屑病具有相关性：昨天，Nature Genetics网站刊出一篇报道，称皮肤屏障受损可增加银屑病的患病风险，且免疫调节在银屑病发病过程中发挥重要作用。
银屑病被普遍认为是一种免疫介导的疾病，其特征是侵犯关节，皮肤和甲并引发炎症反应。在西欧，有2-5%的人群患病，但在东亚地区，患病率只有0.1-0.3%。银屑病的症状主要是红色鳞屑性皮疹伴有瘙痒及皮肤脱屑。银屑病被认为同环境，遗传及免疫等因素都有关系。

免疫相关基因与银屑病具有显著相关性
美，加，德，法进行了一项多中心研究，以寻找欧洲人群的银屑病易感位（银屑病组：n=1409，对照组：n=1436）。初步比较的结果证实了广为认同的一些易感位点如HLA-C,IL112B和IL23R同银屑病的相关性，并在此基础上，筛选出21个单核苷酸多态性位点SNPs进行进一步分析。对5048名银屑病患者和5051名健康对照进行基因分型分析后，又将21个易感位点缩减到了7个(combined P < 5 × 10*−8).
这7个位点所处基因都同免疫相关，这些基因包括HLA-C基因，同IL-23信号通路相关的IL-23A基因，IL-12B和IL-23R基因，调控NF-KappaB信号通路相关的TNFAIP3和TNIP1基因，以及影响Th2型细胞的IL-4和IL-13基因
该文章作者Anne M. Bowcock博士来自华盛顿大学医学院遗传系，当被问到为何银屑病相关基因都是免疫相关基因，是否具有代表性时，他通过E-mail答复说：银屑病相关基因似乎都是免疫相关基因，但从遗传学和免疫学角度我们发现这些基因中至少有一个是同信号通路有关，该基因（IL23A /P19）已经被选作进一步追踪。
该文的作者还强调：在正常人和银屑病患者皮肤细胞中，有数百基因表达存在差异，这表明本研究鉴定的相关基因可能是引发银屑病的因素。对58名银屑病患者和64名健康者皮肤活检结果进一步证实，有4个基因(HLA-C,IL12B,IL23A,TNIP1）在表达水平上存有显著差异。

西方人群中的晚期角化包膜研究
第二项研究中，欧洲和美国学者研究了拷贝数变异CNVs同银屑病的相关性。他们发现人类1号染色体长臂上的某个区域（位于晚期角化包膜LCE基因簇内）缺失同银屑病有显著相关性，LCE基因簇内包含多个编码角质层蛋白的基因，在角质层形成方面具有重要作用。
该研究首先通过对混杂样本分析确定染色体1q21的CNV同银屑病具有相关性，之后又对银屑病患者进行单一样本分析。结果显示银屑病人群中一段长度32.2-kb（包含LCE3C和LCE3B基因）的缺失比正常人群常见，西班牙人：64% vs 55% 、P=0.028，对意大利人，荷兰人和美国人的抽样调查也获得类似结果。
对欧美人群分析结果显示，LCE3C和LCE3B基因缺失在银屑病人群中总发生率为69%，但在正常人群为59%（OR值1.38，95%CI：1.19-1.61，P=1.38x10*-8）,有趣的是，纯合子和杂合子分析显示此两基因缺失同银屑病患病率呈剂量相关关系，可能是一种保护性基因。
该研究还考察了皮肤屏障功能受损作为生理刺激因子对LCE3基因的激活作用。采用胶带剥脱法刺激皮肤角质层，发现相应的角质层修复基因表达增加。据此推测LCE3C和LCE3B基因缺失时，其修复过程可能遇到障碍。
Xavier Estivill同Medscape讨论了这种可能性，他指出这种LCE基因先天缺陷是银屑病病理生理学中的一个新概念，目前我们并不了解其作用机制，但他同意上述的推测，即LCE基因的缺失可能使得角质层受损后的修复过程不畅，结果未能修复的角质层使得其他外来刺激因素如过敏原，微生物更容易透过皮肤屏障，从而共同引发银屑病。

东方人群的晚期角质化膜相关研究
安徽医科大学张学军教授牵头，中国和新加坡诸多学者参与的中国人银屑病基因研究也表明LCE基因同银屑病具有相关性。该研究第一阶段发现：汉族人群LCE基因的4个SNPs位点和IL12B基因的2个SNPs位点同银屑病具有显著相关性。
针对汉族人群（病例组5182，对照组6516）的重复研究和对维吾尔族人群（病例组539，对照组824）的研究还发现了一个先前未有报道的银屑病相关SNP（位于LCE3D，OR,0 .76; 95% CI, 0.72 – 0.80; P = 6.69 × 10−30）
该研究认为此新位点具有生物学意义。LCE基因编码角质化包膜的角蛋白，而角质化包膜对表皮终末分化起重要作用…....银屑病中角质细胞增殖活跃会表现为角化不全（即到达角质层的细胞仍有胞核），因此角质层粘附力减弱，所以表现临床上特征性的鳞屑
Stefan Schreiber在Email中说：LCE基因的重要性不仅体现在保持表皮完整，还体现在角质细胞正常分化方面，LEC基因的相关发现丰富了关于皮肤屏障受损继而对外界刺激反应失当可能引发银屑病的相关假设。
更有意义的是LCE基因在不同种族的表现也存有一定差异

皮肤屏障损伤激活免疫系统
Jonathan Barker教授未参与上述各项研究，他认为皮肤屏障受损可能会激活免疫反应。
他指出如同张学军教授等和Estivill研究发现一样，银屑病的发生首要关键是皮肤屏障的受损，即快速增殖及分化缺失，临床表现为的特征性的鳞屑。其次发病的关键是炎症和免疫反应（包括天然和获得免疫）；第三他认为是脉管系统的变化，但当前的发现并不支持此观点。
Dr. Baker总结说：因此中国的关于角质层受损和免疫相关基因的改变同银屑病相关性发现是有意义的，但他还强调可能是皮肤屏障受损激发了免疫反应。

Dr. Bowcock未发表任何财政相关声明。Dr. Estivill为检测LCE3B和LCE3C缺失作为一种银屑病遗传和患病评估手段申请专利。Dr. Schreiber建议开展Life Technologies项目，Dr. Barker建议企业开展此研究以外的银屑病的生物治疗研发

2009-02-03 20:39

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