Foxp3，Fas，FasL，COMT基因多态性与汉族寻常型银屑病相关性分析
|
摘要
银屑病是一种反复发作,具有特征性鳞屑性红斑的慢性自身免疫性皮肤病,其发病率高、危害大、治疗困难。在自然人群中的发病率为0.1%-3%,我国约有300万患者,发病率有逐年上升的趋势,国际卫生组织将其列为影响人类健康的重要疾病。目前银屑病的发病机制尚不清楚,近十几年来,关于银屑病的病因和发病机制的研究主要集中于基因异常、免疫炎症机制、环境因素等方面。流行病学研究表明银屑病具有家族聚集性,是一种多基因遗传病。但任何单一因素均不能完全解释银屑病的发病机理,有学者认为多因素、多基因累积共同导致了银屑病的发生,不同的个体可能存在不同的病因组合,其中遗传基因的易感性占据了重要的地位。
寻找与疾病相关的致病基因的方法大致可以分为两种:连锁分析和关联研究。关联研究主要以病例对照研究为基础,通过研究患者和正常对照的基因多态性位点基因型和等位基因频率的差异,从而判断该基因与疾病易感性的关系。近年来的研究表明皮肤角质形成细胞异常及自身免疫失衡相关的细胞和分子在银屑病的发病机制中具有重要作用,然而目前对基因多态性与银屑病易感性的关系少有研究。为此,本课题选择了四个与皮肤角质形成细胞异常及自身免疫紧密相关的基因作为研究重点,试图寻找其基因多态性和银
屑病发病的相关性。Foxp3叉状头/翅膀状螺旋转录因子在外周T细胞中表达的精密控制对于维持免疫系统的内环境稳定具有重要意义。转录因子Foxp3可特异表达于胸腺和外周淋巴组织中天然的CD4+ CD25+调节性T细胞亚群上,可以认为Foxp3是CD4+CD25+调节性T细胞发育的调控机制中的重要开关。
CD4+CD25+Treg细胞与效应性T细胞的免疫失衡,导致自身反应性T细胞的活化是银屑病免疫学发病机制的中心环节。目前已证实Foxp3基因突变同多种自身免疫性疾病的发生相关,而在银屑病这种自身免疫性皮肤病的发生中, Foxp3基因的变化是否通过调控CD4+CD25+Treg细胞直接或者间接发挥作用尚未得到证实。在本研究中我们探讨了Foxp3基因-6054 (deletion/ATT, rs5902434)位点、-3279 (A/C, rs376158)位点、-924 (A/G, rs2232365)位点和IVS9+459 (A/G, rs2280883)基因多态性与银屑病易感性的关系。
Fas/FasL系统通过凋亡及致炎作用途径与银屑病的发生紧密联系。研究结果表明银屑病皮损组织中Fas、FasL的强表达是导致患者表皮角质形成细胞异常凋亡的机制之一。Fas、FasL的表达异常使T淋巴细胞异常凋亡,进而导致免疫耐受失控,成为自身免疫性疾病的机理之一。Fas/FasL信号通路的另一路径是诱导炎症因子,尤其是肿瘤坏死因子(TNF-α)和白介素8(IL-8),该途径在表达抗凋亡分子如Bcl-xL水平较高的细胞中有明显优势。致炎的Fas信号通路通过活化的淋巴细胞介导银屑病的发生。国外已有研究证实Fas、FasL基因多态性与自身免疫性疾病的相关性,但Fas、FasL基因多态性与汉族银屑病患者的相关性目前未见报道。为此,我们对汉族银屑病患者和正常对照者进行Fas-1377、Fas-670、FASLG-844和FASLG-IVS2nt-124基因多态性检测,探讨其基因多态性在汉族人群中的分布及其与银屑病的相关性。
儿茶酚邻位甲基转移酶(COMT)催化儿茶酚胺第3位羟基甲基化,是降解儿茶酚胺的主要代谢酶。文献表明COMT基因第4号外显子存在一个G>A点突变使158密码子从缬氨酸(Val)到蛋氨酸(Met)错义突变,导致COMT酶活性降低,神经末梢产生的儿茶酚胺类物质的增加可以直接损伤表皮细胞,同时不能阻止表皮细胞中毒物-o-醌的形成,诱发角质形成细胞氧化损伤,导致银屑病的发生和加重。有研究表明COMT-158(G>A)单核苷酸基因多态性与银屑病的发病有一定相关性。但目前COMT-158(G>A)单核苷酸基因多态性与汉族人群银屑病易感性的关系尚无研究。
目的:分析Foxp3基因、Fas基因、FasL基因、COMT基因单核苷酸多态性与中国汉族人群银屑病发病的相关性,探讨银屑病的遗传学背景及发病机制。
方法:对524例银屑病患者和549例正常对照抗凝血,抽提基因组DNA,使用PCR-RFLP和PCR-SSP方法分别检测Foxp3基因-6054 (deletion/ATT, rs5902434)、-3279 (A/C, rs376158)、-924 (A/G, rs2232365)和IVS9+459 (A/G, rs2280883)四个位点单核苷酸多态性。使用PCR-RFLP方法检测Fas-1377、Fas-670、FASLG-844和FASLG-IVS2nt-124四个位点基因单核苷酸多态性。使用PCR-SSP方法检测儿茶酚邻位甲基转移酶(COMT)基因第4外显子158密码子碱基单核苷酸多态性。对结果进行统计学分析,探讨Foxp3基因、Fas基因、FasLG基因、COMT基因单核苷酸多态性与中国汉族人群银屑病发病的相关性。
结果:Foxp3-3279 AC (adjusted odds ratio [OR], 1.32; 95% CI, 1.01-1.74)和IVS9+459 GG(adjusted odds ratio [OR], 2.24; 95% CI, 1.41-3.58)基因型中国汉族银屑病的发病与发展存在相关性;Foxp3-3279变异联合基因型AC+AA显著增加男性人群(adjusted OR=1.60, 95% CI=1.11-2.31)罹患银屑病的危险性,同时与病情较重的银屑病发病(PASI score > 20)人群(adjusted OR=1.97, 95% CI=1.41-2.75)有显著相关性。IVS9+459变异联合基因型GA+GG与病情较重的银屑病发病(PASI score > 20)人群(adjusted OR=1.69, 95%CI=1.21-2.36)有显著相关性。Foxp3-6054位点ATT插入型等位基因频率在银屑病患者和正常对照组之间没有显著差异(32.1% vs. 29.3%, P = 0.174)。Foxp3-924位点G等位基因频率在银屑病患者和正常对照组之间亦无显著差异(42.6% vs. 40.0%, P = 0.238)。
通过PCR-RFLP方法发现,所选择样本中Fas-1377位点A等位基因频率在银屑病患者和正常对照组之间没有显著差异(32.8% vs. 35.6%, P = 0.187)。Fas-670位点G等位基因频率在银屑病患者和正常对照组之间没有显著差异(37.2% vs. 39.1%, P = 0.389)。FASLG-844位点T等位基因频率在银屑病患者和正常对照组之间没有显著差异(26.5% vs. 23.4%, P = 0.100)。Fas-1377G/A和Fas -670A/G两点单倍体分析和单倍体联合分析结果发现,以没有突变的AG等位基因做为参照,GG与GA单倍体等位基因具有降低罹患银屑病危险性的趋势,AA单倍体等位基因降低罹患银屑病危险性的趋势具有统计学意义。联合分析发现以GA+AA/AA做为参照,其余三组GG/AA,GG/GG+GA, GA+AA/GG+AA显著降低罹患银屑病的危险性。
通过PCR-SSP方法发现,COMT-158位点A等位基因频率在银屑病患者中无显著增高(24.7% vs. 23.7%, P = 0.624)。与COMT-158 GG基因型相比,-158GA (adjusted odds ratio [OR], 1.00; 95% CI, 0.78-1.29)和-158AA(adjusted OR, 1.23; 95% CI, 0.70-2.15)基因型不会增加罹患银屑病的危险性。联合基因型GA+AA与银屑病发病年龄和疾病严重程度之间均无显著相关性。
结论:本研究首次分析了中国汉族人群中Foxp3、Fas、FasL、COMT基因单核苷酸多态性和单倍体基因型与银屑病发病的相关性,发现Foxp3-3279(A/C, rs376158)和IVS9+459 (A/G, rs2280883)位点基因多态性和汉族人寻常型银屑病发病相关,证实了Foxp3基因水平的变化与银屑病的关系,为研究汉族人群银屑病易感基因打下基础,也提示Foxp3可能会成为治疗银屑病的一个靶分子,为拓展银屑病的临床治疗途径提供基因学基础。Fas-1377、Fas-670、FASLG-844三个功能性多态性位点及COMT-158位点均未发现与银屑病易感性相关。Fas-1377G/A和Fas-670A/G两点单倍体分析和单倍体联合分析结果发现,GG与GA单倍体等位基因具有降低罹患银屑病危险性的趋势,AA单倍体等位基因降低罹患银屑病危险性的趋势具有统计学意义,合并基因型GG/AA,GG/GG+GA,GA+AA/GG+AA均显著降低罹患银屑病的危险性。此外,由于种族差异,仍有必要进行大样本量、不同种族的重复性研究。
Psoriasis is a common skin disorder, characterized by focal formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. With high morbidity, severe damage to patients’health and great difficulty in treatments, psoriasis has long been listed as one of the important diseases threatening human health. 1-3% of population is afflicted with Psoriasis worldwide. In china it’s estimated that more than 3000,000 people are suffering from this disease, and the mobility still exhibits a increasing tendency. Epidemic researches has demonstrated that the psoriasis could be recognized as a polygenic disease with a strong tendency of familial aggregation. Nowadays, the pathomechanism of psoriasis has still not been completely clarified, although, in recent years, various possible hypotheses have been proposed, including the genetic factors, the immune-mediatedandthe genetic factors and the environmental factor. None of those factors mentioned above, however, could explain the development of psoriasis perfectly. Clinical evidence and experimental data suggest that psoriasis is an autoimmune disease, in which polygenic inheritance and suspect genes play an important role.
There are two main methods to find susceptible genes related to disease: linkage analysis and association study. Association study is mainly based on case-control study, investigating the difference of genotypes and alleles frequency of genes in cases and controls and determining whether the polymorphisms of genes are associated with the suscepatbility of disease. In recent years, cellular and molecular components of keratinocyte damage and autoimmunity were found to play an important role in the pathology of psoriasis, however, only a few studies about polymorphisms of innate immunity related genes and the susceptibility of psoriasis were reported. In this study, we chose 4 candidate genes associated with keratinocyte damage and autoimmunity and explored the relationship between the functional polymorphisms of these genes and the susceptibility of psoriasis.
The Foxp3 gene is primarily expressed in CD4+CD25+ T-regs in normal physiological conditions. the protein coded by Foxp3 gene is involved in the regulation of T cell activation, belonging to the forkhead/winged-helix family of transcription factors. The Foxp3 protein functions as a transcriptional repressor and down-regulates cytokine production in T cells. Further, some studies have suggested that gene transfer of Foxp3 confers a regulatory T cell phenotype on CD4+T cells that ameliorates autoaggression. While the exact pathogenesis of psoriasis remains unclear, several features of the disease suggest an immune system-mediated process; much evidence indicates that regulatory T cells (T-regs) are involved. Foxp3 deficiency may contribute to the occurrence of some autoimmune diseases, perhaps because of the lack of functional CD4+CD25+ T-regs. Here, we hypothesized that defects in the Foxp3 gene may be involved in the etiology of psoriasis. In this study, we examined four SNPs (-6054, deletion/ATT; -3279, A/C; -924, A/G; IVS9+459, A/G) in psoriatic patients, and assessed the association of genotype and allele frequencies between patients and normal controls.
Fas/FasL signaling is associated with psoriasis by the pathway of apoptosis and the induction of inflammatory cytokines. For the pathway of apoptosis, Fas/FasL signaling can modulate the apoptosis of Keratinocytes. Some researches indicated that Fas/FasL could be secreted by psoriasis keratinocytes and be expressed at high level in psoriasis. The unbalance of the Fas and FasL expressed could render apoptosis abnormal of T lymphocytes. Therefore, Dysregulation of the expression of the Fas and FasL genes may be important in the development of autoimmune disease, because of pathological effects on immune system maintenance and disturbances in the balance between pro- and anti-inflammatory cytokines. Fas/FasL signaling has been best known for induction of apoptosis. However, there also exists an alternate pathway of Fas signaling that induces inflammatory cytokines, particularly tumor necrosis factor (TNF)-αand interleukin(IL)-8. This pathway is prominent in cells that express high levels of anti-apoptotic molecules such as Bcl-xL. Because TNF-αis central to the pathogenesis of psoriasis and inflammatory, Fas signaling mediates induction of psoriasis by activated lymphocytes. Fas/FasL gene polymorphism may be involved in some autoimmune diseases, but the associations between Fas/FasL gene and the susceptibility of psoriasis were not determined. In this study, we examined four SNPs (Fas-1377; Fas-670; FASLG-844; FASLG-IVS2nt-124) in psoriatic patients, and assessed the association of genotype and allele frequencies between patients and normal controls.
Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the O-methylation of biologically active or toxic catechols and plays an important role in the metabolism of drugs and neurotransmitters. A common single nucleotide polymorphism (SNP) in codon 158 of the COMT gene codes for a substitution of valine (Val) by methionine (met), resulting in reduced thermostability and activity of the enzyme. In keratinocytes, this SNP may inflence the activity of the enzyme, induce high level of toxic o-quinones and destroy the keratinocytes. COMT-158 G>A polymorphism proved to be related to the susceptibility of psoriasis, but the associations of it and the susceptibility of psoriasis in the Han Chinese population were not determined.
Objective: We hypothesized the Foxp3, Fas, FasL gene SNPs and COMT-158 G>A polymorphism were associated with the risk of psoriasis in Han Chinese people.
Methods: In a hospital-based case-control study of 524 patients with psoriasis and 549 psoriasis-free controls was made in frequency according to the age and gender. Foxp3-6054, -3279 , -924 and COMT-158 G>A polymorphism were genotyped by the PCR sequence specific primer (PCR-SSP) technique. Foxp3 IVS9+459 polymorphism and Fas-1377, Fas-670, FASLG-844, FASLG-IVS2nt-124 polymorphism were genotyped with the PCR-RFLP technique.
Results: We found that an increased risk of psoriasis was associated with the Foxp3-3279 AC (adjusted odds ratio [OR], 1.32; 95% CI, 1.01-1.74) and IVS9+459 GG(adjusted odds ratio [OR], 2.24; 95% CI, 1.41-3.58) genotypes, compared with the -3279CC genotype and IVS9+459AA genotype, respectively. Consistently, the combined Foxp3-3279 AC+AA genotype was associated with a significantly higher risk of psoriasis in males (OR, 1.60; 95% CI, 1.11-2.31). The frequency of the -3279 AC+AA and IVS9+459 GA+GG genotypes was significantly higher among patients with severer psoriatic (PASI > 20) than among the controls. (45.9% versus 31.1%, 46.9% versus 36.1%, P < 0.001 and P = 0.002). Meanwhile, the Foxp3 -3279 AC+AA genotype and IVS9+459 GA+GG genotype were also associated with more severely psoriatic (PASI score > 20)patients (adjusted OR = 1.97, 95% CI = 1.41-2.75; adjusted OR = 1.69, 95% CI = 1.21-2.36). Significant difference could not be detected in the distribution of Foxp3-6054 ATT among the case and control subjects(32.1% vs. 29.3%, P = 0.174). Moreover, significant difference failed to be established among the distribution of Foxp3-924 G allele among the case and control subjects(42.6% vs. 40.0%, P = 0.238).
By the PCR-RFLP techniques analysis, we didn’t find significant difference in the distribution of Fas-1377 A allele among the psoriasis and control subjects(32.8% vs. 35.6%, P = 0.187).Similarly, the frequency of Fas-670 G allele (37.2% vs. 39.1%, P = 0.389) and FASLG-844 T allele (26.5% vs. 23.4%, P = 0.100) among the psoriasis and control subjects didn’t suggest significant difference. Furthermore, in the haplotype analysis of Fas-1377 and -670, we noticed that the Fas haplotype genotypes GG and GA had a tendency to decrease risk of psoriasis. Haplotype genotypes AA were associated with a decreased risk of psoriasis. We also found combined genotypes of GG/AA,GG/GG+GA,GA+AA/GG+AA can decrease significantly the risk of psoriasis.
Significant difference was not indicated in the distribution of COMT-158 A allele among the psoriasis and control subjects (24.7% vs. 23.7%, P = 0.624) by PCR-SSP techniques. We did not found the association between an increased risk of psoriasis and the COMT-158GA(adjusted OR, 1.00; 95% CI, 0.78-1.29) or -158AA (adjusted OR, 1.23; 95% CI, 0.70-2.15) genotypes, compared with the -158GG genotype. Consistently we found that psoriasis was not associated with the COMT-158 combined genotype GA+AA, compared with the -158GG genotype.
Conclusions: Hitherto, this is the first known study about the association between the Foxp3 polymorphism, the COMT-158 polymorphism, the Fas vs FasL polymorphisms and the haplotypes genotypes and the psoriasis in the Han Chinese population. Our results demonstrated Foxp3-3279(A/C, rs376158) and IVS9+459 (A/G, rs2280883) polymorphism was associated with the susceptibility of psoriasis. It confirmed the relationship between the change of Foxp3 gene and psoriasis, and provided a possible way to use Foxp3 as a target in the treatment of psoriasis.However, larger, population-based studies are still necessary to confirm these findings.
寻找与疾病相关的致病基因的方法大致可以分为两种:连锁分析和关联研究。关联研究主要以病例对照研究为基础,通过研究患者和正常对照的基因多态性位点基因型和等位基因频率的差异,从而判断该基因与疾病易感性的关系。近年来的研究表明皮肤角质形成细胞异常及自身免疫失衡相关的细胞和分子在银屑病的发病机制中具有重要作用,然而目前对基因多态性与银屑病易感性的关系少有研究。为此,本课题选择了四个与皮肤角质形成细胞异常及自身免疫紧密相关的基因作为研究重点,试图寻找其基因多态性和银
屑病发病的相关性。Foxp3叉状头/翅膀状螺旋转录因子在外周T细胞中表达的精密控制对于维持免疫系统的内环境稳定具有重要意义。转录因子Foxp3可特异表达于胸腺和外周淋巴组织中天然的CD4+ CD25+调节性T细胞亚群上,可以认为Foxp3是CD4+CD25+调节性T细胞发育的调控机制中的重要开关。
CD4+CD25+Treg细胞与效应性T细胞的免疫失衡,导致自身反应性T细胞的活化是银屑病免疫学发病机制的中心环节。目前已证实Foxp3基因突变同多种自身免疫性疾病的发生相关,而在银屑病这种自身免疫性皮肤病的发生中, Foxp3基因的变化是否通过调控CD4+CD25+Treg细胞直接或者间接发挥作用尚未得到证实。在本研究中我们探讨了Foxp3基因-6054 (deletion/ATT, rs5902434)位点、-3279 (A/C, rs376158)位点、-924 (A/G, rs2232365)位点和IVS9+459 (A/G, rs2280883)基因多态性与银屑病易感性的关系。
Fas/FasL系统通过凋亡及致炎作用途径与银屑病的发生紧密联系。研究结果表明银屑病皮损组织中Fas、FasL的强表达是导致患者表皮角质形成细胞异常凋亡的机制之一。Fas、FasL的表达异常使T淋巴细胞异常凋亡,进而导致免疫耐受失控,成为自身免疫性疾病的机理之一。Fas/FasL信号通路的另一路径是诱导炎症因子,尤其是肿瘤坏死因子(TNF-α)和白介素8(IL-8),该途径在表达抗凋亡分子如Bcl-xL水平较高的细胞中有明显优势。致炎的Fas信号通路通过活化的淋巴细胞介导银屑病的发生。国外已有研究证实Fas、FasL基因多态性与自身免疫性疾病的相关性,但Fas、FasL基因多态性与汉族银屑病患者的相关性目前未见报道。为此,我们对汉族银屑病患者和正常对照者进行Fas-1377、Fas-670、FASLG-844和FASLG-IVS2nt-124基因多态性检测,探讨其基因多态性在汉族人群中的分布及其与银屑病的相关性。
儿茶酚邻位甲基转移酶(COMT)催化儿茶酚胺第3位羟基甲基化,是降解儿茶酚胺的主要代谢酶。文献表明COMT基因第4号外显子存在一个G>A点突变使158密码子从缬氨酸(Val)到蛋氨酸(Met)错义突变,导致COMT酶活性降低,神经末梢产生的儿茶酚胺类物质的增加可以直接损伤表皮细胞,同时不能阻止表皮细胞中毒物-o-醌的形成,诱发角质形成细胞氧化损伤,导致银屑病的发生和加重。有研究表明COMT-158(G>A)单核苷酸基因多态性与银屑病的发病有一定相关性。但目前COMT-158(G>A)单核苷酸基因多态性与汉族人群银屑病易感性的关系尚无研究。
目的:分析Foxp3基因、Fas基因、FasL基因、COMT基因单核苷酸多态性与中国汉族人群银屑病发病的相关性,探讨银屑病的遗传学背景及发病机制。
方法:对524例银屑病患者和549例正常对照抗凝血,抽提基因组DNA,使用PCR-RFLP和PCR-SSP方法分别检测Foxp3基因-6054 (deletion/ATT, rs5902434)、-3279 (A/C, rs376158)、-924 (A/G, rs2232365)和IVS9+459 (A/G, rs2280883)四个位点单核苷酸多态性。使用PCR-RFLP方法检测Fas-1377、Fas-670、FASLG-844和FASLG-IVS2nt-124四个位点基因单核苷酸多态性。使用PCR-SSP方法检测儿茶酚邻位甲基转移酶(COMT)基因第4外显子158密码子碱基单核苷酸多态性。对结果进行统计学分析,探讨Foxp3基因、Fas基因、FasLG基因、COMT基因单核苷酸多态性与中国汉族人群银屑病发病的相关性。
结果:Foxp3-3279 AC (adjusted odds ratio [OR], 1.32; 95% CI, 1.01-1.74)和IVS9+459 GG(adjusted odds ratio [OR], 2.24; 95% CI, 1.41-3.58)基因型中国汉族银屑病的发病与发展存在相关性;Foxp3-3279变异联合基因型AC+AA显著增加男性人群(adjusted OR=1.60, 95% CI=1.11-2.31)罹患银屑病的危险性,同时与病情较重的银屑病发病(PASI score > 20)人群(adjusted OR=1.97, 95% CI=1.41-2.75)有显著相关性。IVS9+459变异联合基因型GA+GG与病情较重的银屑病发病(PASI score > 20)人群(adjusted OR=1.69, 95%CI=1.21-2.36)有显著相关性。Foxp3-6054位点ATT插入型等位基因频率在银屑病患者和正常对照组之间没有显著差异(32.1% vs. 29.3%, P = 0.174)。Foxp3-924位点G等位基因频率在银屑病患者和正常对照组之间亦无显著差异(42.6% vs. 40.0%, P = 0.238)。
通过PCR-RFLP方法发现,所选择样本中Fas-1377位点A等位基因频率在银屑病患者和正常对照组之间没有显著差异(32.8% vs. 35.6%, P = 0.187)。Fas-670位点G等位基因频率在银屑病患者和正常对照组之间没有显著差异(37.2% vs. 39.1%, P = 0.389)。FASLG-844位点T等位基因频率在银屑病患者和正常对照组之间没有显著差异(26.5% vs. 23.4%, P = 0.100)。Fas-1377G/A和Fas -670A/G两点单倍体分析和单倍体联合分析结果发现,以没有突变的AG等位基因做为参照,GG与GA单倍体等位基因具有降低罹患银屑病危险性的趋势,AA单倍体等位基因降低罹患银屑病危险性的趋势具有统计学意义。联合分析发现以GA+AA/AA做为参照,其余三组GG/AA,GG/GG+GA, GA+AA/GG+AA显著降低罹患银屑病的危险性。
通过PCR-SSP方法发现,COMT-158位点A等位基因频率在银屑病患者中无显著增高(24.7% vs. 23.7%, P = 0.624)。与COMT-158 GG基因型相比,-158GA (adjusted odds ratio [OR], 1.00; 95% CI, 0.78-1.29)和-158AA(adjusted OR, 1.23; 95% CI, 0.70-2.15)基因型不会增加罹患银屑病的危险性。联合基因型GA+AA与银屑病发病年龄和疾病严重程度之间均无显著相关性。
结论:本研究首次分析了中国汉族人群中Foxp3、Fas、FasL、COMT基因单核苷酸多态性和单倍体基因型与银屑病发病的相关性,发现Foxp3-3279(A/C, rs376158)和IVS9+459 (A/G, rs2280883)位点基因多态性和汉族人寻常型银屑病发病相关,证实了Foxp3基因水平的变化与银屑病的关系,为研究汉族人群银屑病易感基因打下基础,也提示Foxp3可能会成为治疗银屑病的一个靶分子,为拓展银屑病的临床治疗途径提供基因学基础。Fas-1377、Fas-670、FASLG-844三个功能性多态性位点及COMT-158位点均未发现与银屑病易感性相关。Fas-1377G/A和Fas-670A/G两点单倍体分析和单倍体联合分析结果发现,GG与GA单倍体等位基因具有降低罹患银屑病危险性的趋势,AA单倍体等位基因降低罹患银屑病危险性的趋势具有统计学意义,合并基因型GG/AA,GG/GG+GA,GA+AA/GG+AA均显著降低罹患银屑病的危险性。此外,由于种族差异,仍有必要进行大样本量、不同种族的重复性研究。
Psoriasis is a common skin disorder, characterized by focal formation of inflamed, raised plaques that constantly shed scales derived from excessive growth of skin epithelial cells. With high morbidity, severe damage to patients’health and great difficulty in treatments, psoriasis has long been listed as one of the important diseases threatening human health. 1-3% of population is afflicted with Psoriasis worldwide. In china it’s estimated that more than 3000,000 people are suffering from this disease, and the mobility still exhibits a increasing tendency. Epidemic researches has demonstrated that the psoriasis could be recognized as a polygenic disease with a strong tendency of familial aggregation. Nowadays, the pathomechanism of psoriasis has still not been completely clarified, although, in recent years, various possible hypotheses have been proposed, including the genetic factors, the immune-mediatedandthe genetic factors and the environmental factor. None of those factors mentioned above, however, could explain the development of psoriasis perfectly. Clinical evidence and experimental data suggest that psoriasis is an autoimmune disease, in which polygenic inheritance and suspect genes play an important role.
There are two main methods to find susceptible genes related to disease: linkage analysis and association study. Association study is mainly based on case-control study, investigating the difference of genotypes and alleles frequency of genes in cases and controls and determining whether the polymorphisms of genes are associated with the suscepatbility of disease. In recent years, cellular and molecular components of keratinocyte damage and autoimmunity were found to play an important role in the pathology of psoriasis, however, only a few studies about polymorphisms of innate immunity related genes and the susceptibility of psoriasis were reported. In this study, we chose 4 candidate genes associated with keratinocyte damage and autoimmunity and explored the relationship between the functional polymorphisms of these genes and the susceptibility of psoriasis.
The Foxp3 gene is primarily expressed in CD4+CD25+ T-regs in normal physiological conditions. the protein coded by Foxp3 gene is involved in the regulation of T cell activation, belonging to the forkhead/winged-helix family of transcription factors. The Foxp3 protein functions as a transcriptional repressor and down-regulates cytokine production in T cells. Further, some studies have suggested that gene transfer of Foxp3 confers a regulatory T cell phenotype on CD4+T cells that ameliorates autoaggression. While the exact pathogenesis of psoriasis remains unclear, several features of the disease suggest an immune system-mediated process; much evidence indicates that regulatory T cells (T-regs) are involved. Foxp3 deficiency may contribute to the occurrence of some autoimmune diseases, perhaps because of the lack of functional CD4+CD25+ T-regs. Here, we hypothesized that defects in the Foxp3 gene may be involved in the etiology of psoriasis. In this study, we examined four SNPs (-6054, deletion/ATT; -3279, A/C; -924, A/G; IVS9+459, A/G) in psoriatic patients, and assessed the association of genotype and allele frequencies between patients and normal controls.
Fas/FasL signaling is associated with psoriasis by the pathway of apoptosis and the induction of inflammatory cytokines. For the pathway of apoptosis, Fas/FasL signaling can modulate the apoptosis of Keratinocytes. Some researches indicated that Fas/FasL could be secreted by psoriasis keratinocytes and be expressed at high level in psoriasis. The unbalance of the Fas and FasL expressed could render apoptosis abnormal of T lymphocytes. Therefore, Dysregulation of the expression of the Fas and FasL genes may be important in the development of autoimmune disease, because of pathological effects on immune system maintenance and disturbances in the balance between pro- and anti-inflammatory cytokines. Fas/FasL signaling has been best known for induction of apoptosis. However, there also exists an alternate pathway of Fas signaling that induces inflammatory cytokines, particularly tumor necrosis factor (TNF)-αand interleukin(IL)-8. This pathway is prominent in cells that express high levels of anti-apoptotic molecules such as Bcl-xL. Because TNF-αis central to the pathogenesis of psoriasis and inflammatory, Fas signaling mediates induction of psoriasis by activated lymphocytes. Fas/FasL gene polymorphism may be involved in some autoimmune diseases, but the associations between Fas/FasL gene and the susceptibility of psoriasis were not determined. In this study, we examined four SNPs (Fas-1377; Fas-670; FASLG-844; FASLG-IVS2nt-124) in psoriatic patients, and assessed the association of genotype and allele frequencies between patients and normal controls.
Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the O-methylation of biologically active or toxic catechols and plays an important role in the metabolism of drugs and neurotransmitters. A common single nucleotide polymorphism (SNP) in codon 158 of the COMT gene codes for a substitution of valine (Val) by methionine (met), resulting in reduced thermostability and activity of the enzyme. In keratinocytes, this SNP may inflence the activity of the enzyme, induce high level of toxic o-quinones and destroy the keratinocytes. COMT-158 G>A polymorphism proved to be related to the susceptibility of psoriasis, but the associations of it and the susceptibility of psoriasis in the Han Chinese population were not determined.
Objective: We hypothesized the Foxp3, Fas, FasL gene SNPs and COMT-158 G>A polymorphism were associated with the risk of psoriasis in Han Chinese people.
Methods: In a hospital-based case-control study of 524 patients with psoriasis and 549 psoriasis-free controls was made in frequency according to the age and gender. Foxp3-6054, -3279 , -924 and COMT-158 G>A polymorphism were genotyped by the PCR sequence specific primer (PCR-SSP) technique. Foxp3 IVS9+459 polymorphism and Fas-1377, Fas-670, FASLG-844, FASLG-IVS2nt-124 polymorphism were genotyped with the PCR-RFLP technique.
Results: We found that an increased risk of psoriasis was associated with the Foxp3-3279 AC (adjusted odds ratio [OR], 1.32; 95% CI, 1.01-1.74) and IVS9+459 GG(adjusted odds ratio [OR], 2.24; 95% CI, 1.41-3.58) genotypes, compared with the -3279CC genotype and IVS9+459AA genotype, respectively. Consistently, the combined Foxp3-3279 AC+AA genotype was associated with a significantly higher risk of psoriasis in males (OR, 1.60; 95% CI, 1.11-2.31). The frequency of the -3279 AC+AA and IVS9+459 GA+GG genotypes was significantly higher among patients with severer psoriatic (PASI > 20) than among the controls. (45.9% versus 31.1%, 46.9% versus 36.1%, P < 0.001 and P = 0.002). Meanwhile, the Foxp3 -3279 AC+AA genotype and IVS9+459 GA+GG genotype were also associated with more severely psoriatic (PASI score > 20)patients (adjusted OR = 1.97, 95% CI = 1.41-2.75; adjusted OR = 1.69, 95% CI = 1.21-2.36). Significant difference could not be detected in the distribution of Foxp3-6054 ATT among the case and control subjects(32.1% vs. 29.3%, P = 0.174). Moreover, significant difference failed to be established among the distribution of Foxp3-924 G allele among the case and control subjects(42.6% vs. 40.0%, P = 0.238).
By the PCR-RFLP techniques analysis, we didn’t find significant difference in the distribution of Fas-1377 A allele among the psoriasis and control subjects(32.8% vs. 35.6%, P = 0.187).Similarly, the frequency of Fas-670 G allele (37.2% vs. 39.1%, P = 0.389) and FASLG-844 T allele (26.5% vs. 23.4%, P = 0.100) among the psoriasis and control subjects didn’t suggest significant difference. Furthermore, in the haplotype analysis of Fas-1377 and -670, we noticed that the Fas haplotype genotypes GG and GA had a tendency to decrease risk of psoriasis. Haplotype genotypes AA were associated with a decreased risk of psoriasis. We also found combined genotypes of GG/AA,GG/GG+GA,GA+AA/GG+AA can decrease significantly the risk of psoriasis.
Significant difference was not indicated in the distribution of COMT-158 A allele among the psoriasis and control subjects (24.7% vs. 23.7%, P = 0.624) by PCR-SSP techniques. We did not found the association between an increased risk of psoriasis and the COMT-158GA(adjusted OR, 1.00; 95% CI, 0.78-1.29) or -158AA (adjusted OR, 1.23; 95% CI, 0.70-2.15) genotypes, compared with the -158GG genotype. Consistently we found that psoriasis was not associated with the COMT-158 combined genotype GA+AA, compared with the -158GG genotype.
Conclusions: Hitherto, this is the first known study about the association between the Foxp3 polymorphism, the COMT-158 polymorphism, the Fas vs FasL polymorphisms and the haplotypes genotypes and the psoriasis in the Han Chinese population. Our results demonstrated Foxp3-3279(A/C, rs376158) and IVS9+459 (A/G, rs2280883) polymorphism was associated with the susceptibility of psoriasis. It confirmed the relationship between the change of Foxp3 gene and psoriasis, and provided a possible way to use Foxp3 as a target in the treatment of psoriasis.However, larger, population-based studies are still necessary to confirm these findings.
引文
1. Krueger, G., J. Koo, M. Lebwohl, A. Menter, R.S. Stern, and T. Rolstad, The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol, 2001. 137(3): p. 280-4.
2. Crown, W.H., B.W. Bresnahan, L.S. Orsini, S. Kennedy, and C. Leonardi, The burden of illness associated with psoriasis: cost of treatment with systemic therapy and phototherapy in the US. Curr Med Res Opin, 2004. 20(12): p. 1929-36.
3. Kimball, A.B., C. Jacobson, S. Weiss, M.G. Vreeland, and Y. Wu, The psychosocial burden of psoriasis. Am J Clin Dermatol, 2005. 6(6): p. 383-92.
4. Henseler, T. and E. Christophers, Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol, 1985. 13(3): p. 450-6.
5. Langley, R.G., G.G. Krueger, and C.E. Griffiths, Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis, 2005. 64 Suppl 2: p. ii18-23; discussion ii24-5.
6. Schon, M.P. and W.H. Boehncke, Psoriasis. N Engl J Med, 2005. 352(18): p. 1899-912.
7. Schafer, T., Epidemiology of psoriasis. Review and the German perspective. Dermatology, 2006. 212(4): p. 327-37.
8. 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(5)253-261.
9. Zhang, X., H. Wang, H. Te-Shao, S. Yang, and S. Chen, The genetic epidemiology of psoriasis vulgaris in Chinese Han. Int J Dermatol, 2002.41(10): p. 663-9.
10. van Steensel, M.A. and P.M. Steijlen, Genetics of psoriasis. Clin Dermatol, 1997. 15(5): p. 669-75.
11. Duffy, D.L., L.S. Spelman, and N.G. Martin, Psoriasis in Australian twins. J Am Acad Dermatol, 1993. 29(3): p. 428-34.
12. Morris, A., M. Rogers, G. Fischer, and K. Williams, Childhood psoriasis: a clinical review of 1262 cases. Pediatr Dermatol, 2001. 18(3): p. 188-98.
13. Swanbeck, G., A. Inerot, T. Martinsson, and J. Wahlstrom, A population genetic study of psoriasis. Br J Dermatol, 1994. 131(1): p. 32-9.
14. Capon, F., B. Dallapiccola, and G. Novelli, Advances in the search for psoriasis susceptibility genes. Mol Genet Metab, 2000. 71(1-2): p. 250-5.
15. Brune, A., D.W. Miller, P. Lin, D. Cotrim-Russi, and A.S. Paller, Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol, 2007. 24(1): p. 76-80.
16. Liao, Y.H., H.C. Chiu, Y.S. Tseng, and T.F. Tsai, Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-1) ointment and tacrolimus 0.3 mg g(-1) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol, 2007. 157(5): p. 1005-12.
17. Vissers, W.H., I. van Vlijmen, P.E. van Erp, E.M. de Jong, and P.C. van de Kerkhof, Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression. Br J Dermatol, 2008. 158(4): p. 705-12.
18. Gottlieb, A.B., M. Lebwohl, S. Shirin, A. Sherr, P. Gilleaudeau, G. Singer, G. Solodkina, R. Grossman, E. Gisoldi, S. Phillips, H.M. Neisler, and J.G. Krueger, Anti-CD4 monoclonal antibody treatment of moderate to severepsoriasis vulgaris: results of a pilot, multicenter, multiple-dose, placebo-controlled study. J Am Acad Dermatol, 2000. 43(4): p. 595-604.
19. Cafardi, J.A., W. Cantrell, W. Wang, C.A. Elmets, and B.E. Elewski, The safety and efficacy of high-dose alefacept compared with a loading dose of alefacept in patients with chronic plaque psoriasis. Skinmed, 2008. 7(2): p. 67-72.
20. Huang, P.H., Y.H. Liao, C.C. Wei, Y.H. Tseng, J.C. Ho, and T.F. Tsai, Clinical effectiveness and safety experience with alefacept in the treatment of patients with moderate-to-severe chronic plaque psoriasis in Taiwan: results of an open-label, single-arm, multicentre pilot study. J Eur Acad Dermatol Venereol, 2008.
21. Krell, J., C. Nelson, L. Spencer, and S. Miller, An open-label study evaluating the efficacy and tolerability of alefacept for the treatment of scalp psoriasis. J Am Acad Dermatol, 2008. 58(4): p. 609-16.
22. Tsai, T.F., M.T. Liu, Y.H. Liao, and D. Licu, Clinical effectiveness and safety experience with efalizumab in the treatment of patients with moderate-to-severe plaque psoriasis in Taiwan: results of an open-label, single-arm pilot study. J Eur Acad Dermatol Venereol, 2008. 22(3): p. 345-52.
23. Varma, R., J.A. Cafardi, W. Cantrell, and C. Elmets, Safety and efficacy of subcutaneously administered efalizumab in adults with moderate-to-severe hand and foot psoriasis: an open-label study. Am J Clin Dermatol, 2008. 9(2): p. 105-9.
24. Wozel, G. and L. Vitez, Palmoplantar Pustular Psoriasis: Successful Therapy with Efalizumab after Non-response to Infliximab. Acta Derm Venereol, 2008. 88(2): p. 169-70.
25. Boehncke, W.H. and M.P. Schon, Animal models of psoriasis. Clin Dermatol, 2007. 25(6): p. 596-605.
26. Krueger, J.G., The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol, 2002. 46(1): p. 1-23; quiz 23-6.
27. Sugiyama, H., R. Gyulai, E. Toichi, E. Garaczi, S. Shimada, S.R. Stevens, T.S. McCormick, and K.D. Cooper, Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol, 2005. 174(1): p. 164-73.
28. Lan, R.Y., A.A. Ansari, Z.X. Lian, and M.E. Gershwin, Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev, 2005. 4(6): p. 351-63.
29. Walsh, S.R. and N.H. Shear, Psoriasis and the new biologic agents: interrupting a T-AP dance. CMAJ, 2004. 170(13): p. 1933-41.
30. Prinz, J.C., Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol, 2001. 26(4): p. 326-32.
31. Jablonska, S. and S. Majewski, On the immunopathogenesis of psoriasis. Arch Dermatol, 2001. 137(2): p. 229-31.
32. Guenther, L.C. and J.P. Ortonne, Pathophysiology of psoriasis: science behind therapy. J Cutan Med Surg, 2002. 6(3 Suppl): p. 2-7.
33. Fearon, U. and D.J. Veale, Pathogenesis of psoriatic arthritis. Clin Exp Dermatol, 2001. 26(4): p. 333-7.
34. 满孝勇,郑敏.银屑病发病的遗传与免疫机制.中华皮肤科杂志;2006, 39(4)238-240
35. Raza, N., M. Usman, and A. Hameed, Chronic plaque psoriasis: streptococcus pyogenes throat carriage rate and therapeutic response to oral antibiotics in comparison with oral methotrexate. J Coll Physicians Surg Pak, 2007. 17(12): p. 717-20.
36. Guilhou, J.J. and C. Girard, [Psoriasis]. Rev Prat, 2006. 56(19): p. 2153-8.
37. Simopoulos, A.P., Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr, 2002. 21(6): p. 495-505.
38. Wolters, M., [The significance of diet and associated factors in psoriasis]. Hautarzt, 2006. 57(11): p. 999-1004.
39. Wolters, M., Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol, 2005. 153(4): p. 706-14.
40. Higgins, E., Alcohol, smoking and psoriasis. Clin Exp Dermatol, 2000. 25(2): p. 107-10.
41. Farber, E.M., G. Rein, and S.W. Lanigan, Stress and psoriasis. Psychoneuroimmunologic mechanisms. Int J Dermatol, 1991. 30(1): p. 8-12.
42. 何平平,张学军.银屑病易感基因研究进展.国外医学遗传学分册;2001,24 (6)318-321
43. Orru, S., E. Giuressi, C. Carcassi, M. Casula, and L. Contu, Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN). Am J Hum Genet, 2005. 76(1): p. 164-71.
44. Speckman, R.A., J.A. Wright Daw, C. Helms, S. Duan, L. Cao, P. Taillon-Miller, P.Y. Kwok, A. Menter, and A.M. Bowcock, Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet, 2003. 112(1): p. 34-41.
45. Capon, F., S. Semprini, S. Chimenti, G. Fabrizi, G. Zambruno, S. Murgia, C. Carcassi, M. Fazio, R. Mingarelli, B. Dallapiccola, and G. Novelli, Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. J Invest Dermatol, 2001. 116(5): p. 728-30.
46. Gonzaga, H.F., E.A. Torres, M.M. Alchorne, and M. Gerbase-Delima, Both psoriasis and benign migratory glossitis are associated with HLA-Cw6. Br J Dermatol, 1996. 135(3): p. 368-70.
47. 王 岩,翟 宁,宋芳吉. 银屑病的 HLA 等位基因及非 HLA 基因相关性研究进展.中国麻风皮肤病杂志.2005,21(6)460-462
48. Mallon, E., M. Bunce, F. Wojnarowska, and K. Welsh, HLA-CW*0602 is a susceptibility factor in type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics. J Invest Dermatol, 1997. 109(2): p. 183-6.
49. 范星,张学军,杨森.银屑病易感基因最新研究进展.国外医学皮肤性病学分册;2005,31(6) 364-366
50. Hattersley, A.T. and M.I. McCarthy, What makes a good genetic association study? Lancet, 2005. 366(9493): p. 1315-23.
51. Chang, Y.T., H.N. Liu, Y.M. Shiao, M.W. Lin, D.D. Lee, M.T. Liu, W.J. Wang, S. Wu, C.Y. Lai, and S.F. Tsai, A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol, 2005. 153(1): p. 90-6.
52. Chang, Y.T., C.T. Chou, Y.M. Shiao, M.W. Lin, C.W. Yu, C.C. Chen, C.H. Huang, D.D. Lee, H.N. Liu, W.J. Wang, and S.F. Tsai, Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes. Br J Dermatol, 2006. 155(4): p. 663-9.
53. Capon, F., M.H. Allen, M. Ameen, A.D. Burden, D. Tillman, J.N. Barker, and R.C. Trembath, A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet, 2004. 13(20): p. 2361-8.
54. Jenisch, S., S. Koch, T. Henseler, R.P. Nair, J.T. Elder, C.E. Watts, E. Westphal, J.J. Voorhees, E. Christophers, and M. Kronke, Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris. TissueAntigens, 1999. 54(5): p. 439-49.
55. Asumalahti, K., T. Laitinen, R. Itkonen-Vatjus, M.L. Lokki, S. Suomela, E. Snellman, U. Saarialho-Kere, and J. Kere, A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Hum Mol Genet, 2000. 9(10): p. 1533-42.
56. Asumalahti, K., C. Veal, T. Laitinen, S. Suomela, M. Allen, O. Elomaa, M. Moser, R. de Cid, S. Ripatti, I. Vorechovsky, J.A. Marcusson, H. Nakagawa, C. Lazaro, X. Estivill, F. Capon, G. Novelli, U. Saarialho-Kere, J. Barker, R. Trembath, and J. Kere, Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Hum Mol Genet, 2002. 11(5): p. 589-97.
57. Kaluza, W., E. Reuss, S. Grossmann, R. Hug, R.E. Schopf, P.R. Galle, E. Maerker-Hermann, and T. Hoehler, Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol, 2000. 114(6): p. 1180-3.
58. Reich, K., R. Mossner, I.R. Konig, G. Westphal, A. Ziegler, and C. Neumann, 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. J Invest Dermatol, 2002. 118(1): p. 155-63.
59. Tsunemi, Y., H. Saeki, K. Nakamura, T. Sekiya, K. Hirai, H. Fujita, N. Asano, M. Kishimoto, Y. Tanida, T. Kakinuma, H. Mitsui, Y. Tada, M. Wakugawa, H. Torii, M. Komine, A. Asahina, and K. Tamaki, Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci, 2002. 30(2): p. 161-6.
60. Cargill, M., S.J. Schrodi, M. Chang, V.E. Garcia, R. Brandon, K.P. Callis, N. Matsunami, K.G. Ardlie, D. Civello, J.J. Catanese, D.U. Leong, J.M. Panko, L.B. McAllister, C.B. Hansen, J. Papenfuss, S.M. Prescott, T.J. White, M.F. Leppert, G.G. Krueger, and A.B. Begovich, 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(2): p. 273-90.
61. Krueger, G.G., R.G. Langley, C. Leonardi, N. Yeilding, C. Guzzo, Y. Wang, L.T. Dooley, and M. Lebwohl, A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med, 2007. 356(6): p. 580-92.
62. Donn, R.P., D. Plant, F. Jury, H.L. Richards, J. Worthington, D.W. Ray, and C.E. Griffiths, Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J Invest Dermatol, 2004. 123(3): p. 484-7.
63. Plant, D., H.S. Young, R.E. Watson, J. Worthington, and C.E. Griffiths, The CX3CL1-CX3CR1 system and psoriasis. Exp Dermatol, 2006. 15(11): p. 900-3.
64. Chang, Y.C., W.M. Wu, C.H. Chen, S.H. Lee, H.S. Hong, and L.A. Hsu, Association between the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and risk for psoriasis in a Chinese population in Taiwan. Br J Dermatol, 2007. 156(4): p. 642-5.
65. Young, H.S., A.M. Summers, M. Bhushan, P.E. Brenchley, and C.E. Griffiths, Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. J Invest Dermatol, 2004. 122(1): p. 209-15.
66. Halsall, J.A., J.E. Osborne, J.H. Pringle, and P.E. Hutchinson, Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics, 2005.15(5): p. 349-55.
67. Vasku, V., J. Bienertova Vasku, M. Pavkova Goldbergova, and A. Vasku, Three retinoid X receptor gene polymorphisms in plaque psoriasis and psoriasis guttata. Dermatology, 2007. 214(2): p. 118-24.
68. Yamada, R. and K. Ymamoto, Recent findings on genes associated with inflammatory disease. Mutat Res, 2005. 573(1-2): p. 136-51.
69. Helms, C., L. Cao, J.G. Krueger, E.M. Wijsman, F. Chamian, D. Gordon, M. Heffernan, J.A. Daw, J. Robarge, J. Ott, P.Y. Kwok, A. Menter, and A.M. Bowcock, A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet, 2003. 35(4): p. 349-56.
70. Prokunina, L., C. Castillejo-Lopez, F. Oberg, I. Gunnarsson, L. Berg, V. Magnusson, A.J. Brookes, D. Tentler, H. Kristjansdottir, G. Grondal, A.I. Bolstad, E. Svenungsson, I. Lundberg, G. Sturfelt, A. Jonssen, L. Truedsson, G. Lima, J. Alcocer-Varela, R. Jonsson, U.B. Gyllensten, J.B. Harley, D. Alarcon-Segovia, K. Steinsson, and M.E. Alarcon-Riquelme, A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet, 2002. 32(4): p. 666-9.
71. Capon, F., C. Helms, C.D. Veal, D. Tillman, A.D. Burden, J.N. Barker, A.M. Bowcock, and R.C. Trembath, Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J Med Genet, 2004. 41(6): p. 459-60.
72. Holm, S.J., L.M. Carlen, L. Mallbris, M. Stahle-Backdahl, and K.P. O'Brien, Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Exp Dermatol, 2003. 12(4): p. 435-44.
73. Foerster, J., I. Nolte, S. Schweiger, C. Ehlert, M. Bruinenberg, K. Spaar, G.van der Steege, M. Mulder, V. Kalscheuer, B. Moser, Z. Kijas, P. Seeman, M. Stander, W. Sterry, and G. te Meerman, Evaluation of the IRF-2 gene as a candidate for PSORS3. J Invest Dermatol, 2004. 122(1): p. 61-4.
74. Rahman, P., S. Bartlett, F. Siannis, F.J. Pellett, V.T. Farewell, L. Peddle, C.T. Schentag, C.A. Alderdice, S. Hamilton, M. Khraishi, Y. Tobin, D. Hefferton, and D.D. Gladman, CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet, 2003. 73(3): p. 677-81.
75. Giardina, E., G. Novelli, A. Costanzo, S. Nistico, C. Bulli, C. Sinibaldi, M.L. Sorgi, S. Chimenti, F. Pallone, E. Taccari, and P. Borgiani, Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. J Invest Dermatol, 2004. 122(5): p. 1106-7.
76. Hensen, P., K. Asadullah, C. Windemuth, F. Ruschendorf, U. Huffmeier, M. Stander, M. Schmitt-Egenolf, T.F. Wienker, A. Reis, and H. Traupe, Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis. Br J Dermatol, 2003. 149(2): p. 381-5.
77. Kingo, K., S. Koks, T. Nikopensius, H. Silm, and E. Vasar, Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis. Genes Immun, 2004. 5(2): p. 117-21.
78. Koks, S., K. Kingo, R. Ratsep, M. Karelson, H. Silm, and E. Vasar, Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes Immun, 2004. 5(8): p. 662-7.
79. Wang, L., L. Yang, L. Gao, T.W. Gao, W. Li, and Y.F. Liu, A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with psoriasis. Int J Immunogenet, 2008. 35(1): p. 45-9.
80. Li, H., L. Gao, Z. Shen, C.Y. Li, K. Li, M. Li, Y.J. Lv, C.X. Li, T.W. Gao, and Y.F. Liu, Association study of NFKB1 and SUMO4 polymorphisms in Chinese patients with psoriasis vulgaris. Arch Dermatol Res, 2008.
81. Collins, F.S., L.D. Brooks, and A. Chakravarti, A DNA polymorphism discovery resource for research on human genetic variation. Genome Res, 1998. 8(12): p. 1229-31.
82. Wang, D.G., J.B. Fan, C.J. Siao, A. Berno, P. Young, R. Sapolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbell, E. Robinson, M. Mittmann, M.S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T.J. Hudson, R. Lipshutz, M. Chee, and E.S. Lander, Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998. 280(5366): p. 1077-82.
83. Reich, D.E., S.F. Schaffner, M.J. Daly, G. McVean, J.C. Mullikin, J.M. Higgins, D.J. Richter, E.S. Lander, and D. Altshuler, Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet, 2002. 32(1): p. 135-42.
84. Brookes, A.J., The essence of SNPs. Gene, 1999. 234(2): p. 177-86.
85. Sachidanandam, R., D. Weissman, S.C. Schmidt, J.M. Kakol, L.D. Stein, G. Marth, S. Sherry, J.C. Mullikin, B.J. Mortimore, D.L. Willey, S.E. Hunt, C.G. Cole, P.C. Coggill, C.M. Rice, Z. Ning, J. Rogers, D.R. Bentley, P.Y. Kwok, E.R. Mardis, R.T. Yeh, B. Schultz, L. Cook, R. Davenport, M. Dante, L. Fulton, L. Hillier, R.H. Waterston, J.D. McPherson, B. Gilman, S. Schaffner, W.J. Van Etten, D. Reich, J. Higgins, M.J. Daly, B. Blumenstiel, J. Baldwin, N. Stange-Thomann, M.C. Zody, L. Linton, E.S. Lander, and D. Altshuler, A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 2001. 409(6822): p. 928-33.
86. Lai, E., Application of SNP technologies in medicine: lessons learned and future challenges. Genome Res, 2001. 11(6): p. 927-9.
87. Mullikin, J.C., S.E. Hunt, C.G. Cole, B.J. Mortimore, C.M. Rice, J. Burton, L.H. Matthews, R. Pavitt, R.W. Plumb, S.K. Sims, R.M. Ainscough, J. Attwood, J.M. Bailey, K. Barlow, R.M. Bruskiewich, P.N. Butcher, N.P. Carter, Y. Chen, C.M. Clee, P.C. Coggill, J. Davies, R.M. Davies, E. Dawson, M.D. Francis, A.A. Joy, R.G. Lamble, C.F. Langford, J. Macarthy, V. Mall, A. Moreland, E.K. Overton-Larty, M.T. Ross, L.C. Smith, C.A. Steward, J.E. Sulston, E.J. Tinsley, K.J. Turney, D.L. Willey, G.D. Wilson, A.A. McMurray, I. Dunham, J. Rogers, and D.R. Bentley, An SNP map of human chromosome 22. Nature, 2000. 407(6803): p. 516-20.
88. Lyamichev, V., A.L. Mast, J.G. Hall, J.R. Prudent, M.W. Kaiser, T. Takova, R.W. Kwiatkowski, T.J. Sander, M. de Arruda, D.A. Arco, B.P. Neri, and M.A. Brow, Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol, 1999. 17(3): p. 292-6.
89. Cha, R.S., H. Zarbl, P. Keohavong, and W.G. Thilly, Mismatch amplification mutation assay (MAMA): application to the c-H-ras gene. PCR Methods Appl, 1992. 2(1): p. 14-20.
90. Kohara, Y., H. Noda, K. Okano, and H. Kambara, DNA probes on beads arrayed in a capillary, 'Bead-array', exhibited high hybridization performance. Nucleic Acids Res, 2002. 30(16): p. e87.
91. Taylor, J.D., D. Briley, Q. Nguyen, K. Long, M.A. Iannone, M.S. Li, F. Ye, A. Afshari, E. Lai, M. Wagner, J. Chen, and M.P. Weiner, Flow cytometric platform for high-throughput single nucleotide polymorphism analysis. Biotechniques, 2001. 30(3): p. 661-6, 668-9.
92. Sanger, F. and A.R. Coulson, A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol, 1975. 94(3): p. 441-8.
93. Hung, R.J., J. Hall, P. Brennan, and P. Boffetta, Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol, 2005. 162(10): p. 925-42.
94. 张忆,初少莉,施静艺等. 血管紧张素原基因多态性与高血压血尿醛酮水平相关. Molecular Cardiology of China; 2006, 6 (4) 212 - 217.
95. 李义, 吴国栋, 左瑾等. 应用单核苷酸多态性技术筛查 2 - 型糖尿病易感基因. 中国医学科学院学报; 2005, 27 (3) 274 - 276.
96. Tabor, H.K., N.J. Risch, and R.M. Myers, Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet, 2002. 3(5): p. 391-7.
97. Schubert, L.A., E. Jeffery, Y. Zhang, F. Ramsdell, and S.F. Ziegler, Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem, 2001. 276(40): p. 37672-9.
98. Hori, S., T. Nomura, and S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003. 299(5609): p. 1057-61.
99. O'Garra, A. and P. Vieira, Twenty-first century Foxp3. Nat Immunol, 2003. 4(4): p. 304-6.
100. Khattri, R., D. Kasprowicz, T. Cox, M. Mortrud, M.W. Appleby, M.E. Brunkow, S.F. Ziegler, and F. Ramsdell, The amount of scurfin protein determines peripheral T cell number and responsiveness. J Immunol, 2001. 167(11): p. 6312-20.
101. Brunkow, M.E., E.W. Jeffery, K.A. Hjerrild, B. Paeper, L.B. Clark, S.A. Yasayko, J.E. Wilkinson, D. Galas, S.F. Ziegler, and F. Ramsdell, Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001. 27(1): p. 68-73.
102. Bennett, C.L., M.E. Brunkow, F. Ramsdell, K.C. O'Briant, Q. Zhu, R.L. Fuleihan, A.O. Shigeoka, H.D. Ochs, and P.F. Chance, A rare polyadenylation signal mutation of the FOXP3 gene(AAUAAA-->AAUGAA) leads to the IPEX syndrome. Immunogenetics, 2001. 53(6): p. 435-9.
103. Chatila, T.A., F. Blaeser, N. Ho, H.M. Lederman, C. Voulgaropoulos, C. Helms, and A.M. Bowcock, JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest, 2000. 106(12): p. R75-81.
104. Cookson, W.O. and M.F. Moffatt, Genetics of asthma and allergic disease. Hum Mol Genet, 2000. 9(16): p. 2359-64.
105. Field, L.L., Genetic linkage and association studies of Type I diabetes: challenges and rewards. Diabetologia, 2002. 45(1): p. 21-35.
106. de Kleer, I.M., L.R. Wedderburn, L.S. Taams, A. Patel, H. Varsani, M. Klein, W. de Jager, G. Pugayung, F. Giannoni, G. Rijkers, S. Albani, W. Kuis, and B. Prakken, CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol, 2004. 172(10): p. 6435-43.
107. Bassuny, W.M., K. Ihara, Y. Sasaki, R. Kuromaru, H. Kohno, N. Matsuura, and T. Hara, A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes. Immunogenetics, 2003. 55(3): p. 149-56.
108. Polanczyk, M.J., B.D. Carson, S. Subramanian, M. Afentoulis, A.A. Vandenbark, S.F. Ziegler, and H. Offner, Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol, 2004. 173(4): p. 2227-30.
109. Park, O., I. Grishina, P.S. Leung, M.E. Gershwin, and T. Prindiville, Analysis of the Foxp3/scurfin gene in Crohn's disease. Ann N Y Acad Sci, 2005. 1051: p. 218-28.
110. Suda, T., T. Takahashi, P. Golstein, and S. Nagata, Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factorfamily. Cell, 1993. 75(6): p. 1169-78.
111. Bohana-Kashtan, O. and C.I. Civin, Fas ligand as a tool for immunosuppression and generation of immune tolerance. Stem Cells, 2004. 22(6): p. 908-24.
112. Takahashi, T., M. Tanaka, J. Inazawa, T. Abe, T. Suda, and S. Nagata, Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol, 1994. 6(10): p. 1567-74.
113. Orlinick, J.R., A.K. Vaishnaw, and K.B. Elkon, Structure and function of Fas/Fas ligand. Int Rev Immunol, 1999. 18(4): p. 293-308.
114. Ross, M.J., S. Martinka, V.D. D'Agati, and L.A. Bruggeman, NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy. J Am Soc Nephrol, 2005. 16(8): p. 2403-11.
115. Kroemer, G. and H. de The, Arsenic trioxide, a novel mitochondriotoxic anticancer agent? J Natl Cancer Inst, 1999. 91(9): p. 743-5.
116. Bettinardi, A., D. Brugnoni, E. Quiros-Roldan, A. Malagoli, S. La Grutta, A. Correra, and L.D. Notarangelo, Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood, 1997. 89(3): p. 902-9.
117. Drappa, J., A.K. Vaishnaw, K.E. Sullivan, J.L. Chu, and K.B. Elkon, Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med, 1996. 335(22): p. 1643-9.
118. Fisher, G.H., F.J. Rosenberg, S.E. Straus, J.K. Dale, L.A. Middleton, A.Y. Lin, W. Strober, M.J. Lenardo, and J.M. Puck, Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell, 1995. 81(6): p. 935-46.
119. Holzelova, E., C. Vonarbourg, M.C. Stolzenberg, P.D. Arkwright, F. Selz, A.M. Prieur, S. Blanche, J. Bartunkova, E. Vilmer, A. Fischer, F. Le Deist,and F. Rieux-Laucat, Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med, 2004. 351(14): p. 1409-18.
120. Krammer, P.H., CD95's deadly mission in the immune system. Nature, 2000. 407(6805): p. 789-95.
121. Rieux-Laucat, F., F. Le Deist, C. Hivroz, I.A. Roberts, K.M. Debatin, A. Fischer, and J.P. de Villartay, Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science, 1995. 268(5215): p. 1347-9.
122. Sneller, M.C., S.E. Straus, E.S. Jaffe, J.S. Jaffe, T.A. Fleisher, M. Stetler-Stevenson, and W. Strober, A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest, 1992. 90(2): p. 334-41.
123. Wu, J., J. Wilson, J. He, L. Xiang, P.H. Schur, and J.D. Mountz, Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest, 1996. 98(5): p. 1107-13.
124. 陈晋广,任小丽. 银屑病角质形成细胞凋亡与 Fas/ FasL 表达的关系. 浙江临床医学;2007,9 (11) 1465-1466.
125. Takahashi, H., A. Manabe, A. Ishida-Yamamoto, Y. Hashimoto, and H. Iizuka, Aberrant expression of apoptosis-related molecules in psoriatic epidermis. J Dermatol Sci, 2002. 28(3): p. 187-97.
126. Norris, D.A., J.B. Travers, and D.Y. Leung, Lymphocyte activation in the pathogenesis of psoriasis. J Invest Dermatol, 1997. 109(1): p. 1-4.
127. Gilhar, A., R. Yaniv, B. Assy, S. Serafimovich, Y. Ullmann, and R.S. Kalish, Fas pulls the trigger on psoriasis. Am J Pathol, 2006. 168(1): p. 170-5.
128. Nickoloff, B.J., T. Wrone-Smith, B. Bonish, and S.A. Porcelli, Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typicallypresent on natural killer cells, including CD94, CD158, and CD161. Arch Dermatol, 1999. 135(5): p. 546-52.
129. Nickoloff, B.J., B. Bonish, B.B. Huang, and S.A. Porcelli, Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci, 2000. 24(3): p. 212-25.
130. Gilhar, A., Y. Ullmann, H. Kerner, B. Assy, R. Shalaginov, S. Serafimovich, and R.S. Kalish, Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. J Invest Dermatol, 2002. 119(2): p. 384-91.
131. Chaudhari, U., P. Romano, L.D. Mulcahy, L.T. Dooley, D.G. Baker, and A.B. Gottlieb, Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet, 2001. 357(9271): p. 1842-7.
132. Leonardi, C.L., J.L. Powers, R.T. Matheson, B.S. Goffe, R. Zitnik, A. Wang, and A.B. Gottlieb, Etanercept as monotherapy in patients with psoriasis. N Engl J Med, 2003. 349(21): p. 2014-22.
133. Qin, J.Z., P. Bacon, V. Chaturvedi, and B.J. Nickoloff, Role of NF-kappaB activity in apoptotic response of keratinocytes mediated by interferon-gamma, tumor necrosis factor-alpha, and tumor-necrosis-factor-related apoptosis-inducing ligand. J Invest Dermatol, 2001. 117(4): p. 898-907.
134. Biancone, L., A.D. Martino, V. Orlandi, P.G. Conaldi, A. Toniolo, and G. Camussi, Development of inflammatory angiogenesis by local stimulation of Fas in vivo. J Exp Med, 1997. 186(1): p. 147-52.
135. Huang, Q.R., S.M. Teutsch, M.M. Buhler, B.H. Bennetts, R.N. Heard, N. Manolios, and G.J. Stewart, Evaluation of the apo-1/Fas promoter mva I polymorphism in multiple sclerosis. Mult Scler, 2000. 6(1): p. 14-8.
136. van Veen, T., N.F. Kalkers, J.B. Crusius, L. van Winsen, F. Barkhof, P.J. Jongen, A.S. Pena, C.H. Polman, and B.M. Uitdehaag, The FAS-670 polymorphism influences susceptibility to multiple sclerosis. J Neuroimmunol, 2002. 128(1-2): p. 95-100.
137. Huang, Q.R., V. Danis, M. Lassere, J. Edmonds, and N. Manolios, Evaluation of a new Apo-1/Fas promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus patients. Rheumatology (Oxford), 1999. 38(7): p. 645-51.
138. Kanemitsu, S., K. Ihara, A. Saifddin, T. Otsuka, T. Takeuchi, J. Nagayama, M. Kuwano, and T. Hara, A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus. J Rheumatol, 2002. 29(6): p. 1183-8.
139. Lee, Y.H., J.D. Ji, J. Sohn, and G.G. Song, Polymorphsims of CTLA-4 exon 1 +49, CTLA-4 promoter -318 and Fas promoter -670 in spondyloarthropathies. Clin Rheumatol, 2001. 20(6): p. 420-2.
140. Sibley, K., S. Rollinson, J.M. Allan, A.G. Smith, G.R. Law, P.L. Roddam, C.F. Skibola, M.T. Smith, and G.J. Morgan, Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res, 2003. 63(15): p. 4327-30.
141. Wu, J., C. Metz, X. Xu, R. Abe, A.W. Gibson, J.C. Edberg, J. Cooke, F. Xie, G.S. Cooper, and R.P. Kimberly, A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol, 2003. 170(1): p. 132-8.
142. Stuck, B.J., M.A. Pani, F. Besrour, M. Segni, M. Krause, K.H. Usadel, and K. Badenhoop, Fas ligand gene polymorphisms are not associated with Hashimoto's thyroiditis and Graves' disease. Hum Immunol, 2003. 64(2): p. 285-9.
143. Pinti, M., L. Troiano, M. Nasi, L. Moretti, E. Monterastelli, A. Mazzacani, C. Mussi, P. Ventura, F. Olivieri, C. Franceschi, G. Salvioli, and A. Cossarizza, Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians. Cell Death Differ, 2002. 9(4): p. 431-8.
144. Bertocci, B., V. Miggiano, M. Da Prada, Z. Dembic, H.W. Lahm, and P. Malherbe, Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proc Natl Acad Sci U S A, 1991. 88(4): p. 1416-20.
145. Grossman, M.H., B.S. Emanuel, and M.L. Budarf, Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2. Genomics, 1992. 12(4): p. 822-5.
146. Karayiorgou, M., M. Altemus, B.L. Galke, D. Goldman, D.L. Murphy, J. Ott, and J.A. Gogos, Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A, 1997. 94(9): p. 4572-5.
147. Dimon-Gadal, S., P. Gerbaud, P. Therond, J. Guibourdenche, W.B. Anderson, D. Evain-Brion, and F. Raynaud, Increased oxidative damage to fibroblasts in skin with and without lesions in psoriasis. J Invest Dermatol, 2000. 114(5): p. 984-9.
148. Shilov, V.N. and V.I. Sergienko, Oxidative stress in keratinocytes as an etiopathogenetic factor of psoriasis. Bull Exp Biol Med, 2000. 129(4): p. 309-13.
149. Erdal, M.E., U. Tursen, T.I. Kaya, A. Kanik, E. Derici, and G. Ikizoglu, Association between Cathechol-O-Metyltransferase polymorphism and psoriasis. Int J Dermatol, 2004. 43(4): p. 312-4.
150. de Rie, M.A., A.Y. Goedkoop, and J.D. Bos, Overview of psoriasis. Dermatol Ther, 2004. 17(5): p. 341-9.
151. Kwok, P.Y., Methods for genotyping single nucleotide polymorphisms. Annu Rev Genomics Hum Genet, 2001. 2: p. 235-58.
152. Chen, X. and P.F. Sullivan, Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput. Pharmacogenomics J, 2003. 3(2): p. 77-96.
153. Feuilhade de Chauvin, M., New diagnostic techniques. J Eur Acad Dermatol Venereol, 2005. 19 Suppl 1: p. 20-4.
154. Marchand, S., P. Hajdari, P. Hackman, B. Udd, and I. Richard, Touch-down method for high-performance sequencing of polymerase chain reaction products. Anal Biochem, 2003. 315(2): p. 270-2.
155. Bovenschen, H.J., I.M. van Vlijmen-Willems, P.C. van de Kerkhof, and P.E. van Erp, Identification of lesional CD4+ CD25+ Foxp3+ regulatory T cells in Psoriasis. Dermatology, 2006. 213(2): p. 111-7.
156. Wrone-Smith, T. and B.J. Nickoloff, Dermal injection of immunocytes induces psoriasis. J Clin Invest, 1996. 98(8): p. 1878-87.
157. Gilhar, A., M. David, Y. Ullmann, T. Berkutski, and R.S. Kalish, T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice. J Invest Dermatol, 1997. 109(3): p. 283-8.
158. de Boer, O.J., C.M. van der Loos, P. Teeling, A.C. van der Wal, and M.B. Teunissen, Immunohistochemical analysis of regulatory T cell markers FOXP3 and GITR on CD4+CD25+ T cells in normal skin and inflammatory dermatoses. J Histochem Cytochem, 2007. 55(9): p. 891-8.
159. Bos, J.D. and M.A. De Rie, The pathogenesis of psoriasis: immunological facts and speculations. Immunol Today, 1999. 20(1): p. 40-6.
160. Boehncke, W.H., D. Dressel, T.M. Zollner, and R. Kaufmann, Pulling the trigger on psoriasis. Nature, 1996. 379(6568): p. 777.
161. Lin, W., D. Haribhai, L.M. Relland, N. Truong, M.R. Carlson, C.B. Williams, and T.A. Chatila, Regulatory T cell development in the absence of functional Foxp3. Nat Immunol, 2007. 8(4): p. 359-68.
162. Nieves, D.S., R.P. Phipps, S.J. Pollock, H.D. Ochs, Q. Zhu, G.A. Scott, C.K. Ryan, I. Kobayashi, T.M. Rossi, and L.A. Goldsmith, Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol, 2004. 140(4): p. 466-72.
163. Li, C., D. Larson, Z. Zhang, Z. Liu, S.S. Strom, J.E. Gershenwald, V.G. Prieto, J.E. Lee, M.I. Ross, P.F. Mansfield, J.N. Cormier, M. Duvic, E.A. Grimm, and Q. Wei, Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma. Pharmacogenet Genomics, 2006. 16(4): p. 253-63.
2. Crown, W.H., B.W. Bresnahan, L.S. Orsini, S. Kennedy, and C. Leonardi, The burden of illness associated with psoriasis: cost of treatment with systemic therapy and phototherapy in the US. Curr Med Res Opin, 2004. 20(12): p. 1929-36.
3. Kimball, A.B., C. Jacobson, S. Weiss, M.G. Vreeland, and Y. Wu, The psychosocial burden of psoriasis. Am J Clin Dermatol, 2005. 6(6): p. 383-92.
4. Henseler, T. and E. Christophers, Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol, 1985. 13(3): p. 450-6.
5. Langley, R.G., G.G. Krueger, and C.E. Griffiths, Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis, 2005. 64 Suppl 2: p. ii18-23; discussion ii24-5.
6. Schon, M.P. and W.H. Boehncke, Psoriasis. N Engl J Med, 2005. 352(18): p. 1899-912.
7. Schafer, T., Epidemiology of psoriasis. Review and the German perspective. Dermatology, 2006. 212(4): p. 327-37.
8. 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(5)253-261.
9. Zhang, X., H. Wang, H. Te-Shao, S. Yang, and S. Chen, The genetic epidemiology of psoriasis vulgaris in Chinese Han. Int J Dermatol, 2002.41(10): p. 663-9.
10. van Steensel, M.A. and P.M. Steijlen, Genetics of psoriasis. Clin Dermatol, 1997. 15(5): p. 669-75.
11. Duffy, D.L., L.S. Spelman, and N.G. Martin, Psoriasis in Australian twins. J Am Acad Dermatol, 1993. 29(3): p. 428-34.
12. Morris, A., M. Rogers, G. Fischer, and K. Williams, Childhood psoriasis: a clinical review of 1262 cases. Pediatr Dermatol, 2001. 18(3): p. 188-98.
13. Swanbeck, G., A. Inerot, T. Martinsson, and J. Wahlstrom, A population genetic study of psoriasis. Br J Dermatol, 1994. 131(1): p. 32-9.
14. Capon, F., B. Dallapiccola, and G. Novelli, Advances in the search for psoriasis susceptibility genes. Mol Genet Metab, 2000. 71(1-2): p. 250-5.
15. Brune, A., D.W. Miller, P. Lin, D. Cotrim-Russi, and A.S. Paller, Tacrolimus ointment is effective for psoriasis on the face and intertriginous areas in pediatric patients. Pediatr Dermatol, 2007. 24(1): p. 76-80.
16. Liao, Y.H., H.C. Chiu, Y.S. Tseng, and T.F. Tsai, Comparison of cutaneous tolerance and efficacy of calcitriol 3 microg g(-1) ointment and tacrolimus 0.3 mg g(-1) ointment in chronic plaque psoriasis involving facial or genitofemoral areas: a double-blind, randomized controlled trial. Br J Dermatol, 2007. 157(5): p. 1005-12.
17. Vissers, W.H., I. van Vlijmen, P.E. van Erp, E.M. de Jong, and P.C. van de Kerkhof, Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: the effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression. Br J Dermatol, 2008. 158(4): p. 705-12.
18. Gottlieb, A.B., M. Lebwohl, S. Shirin, A. Sherr, P. Gilleaudeau, G. Singer, G. Solodkina, R. Grossman, E. Gisoldi, S. Phillips, H.M. Neisler, and J.G. Krueger, Anti-CD4 monoclonal antibody treatment of moderate to severepsoriasis vulgaris: results of a pilot, multicenter, multiple-dose, placebo-controlled study. J Am Acad Dermatol, 2000. 43(4): p. 595-604.
19. Cafardi, J.A., W. Cantrell, W. Wang, C.A. Elmets, and B.E. Elewski, The safety and efficacy of high-dose alefacept compared with a loading dose of alefacept in patients with chronic plaque psoriasis. Skinmed, 2008. 7(2): p. 67-72.
20. Huang, P.H., Y.H. Liao, C.C. Wei, Y.H. Tseng, J.C. Ho, and T.F. Tsai, Clinical effectiveness and safety experience with alefacept in the treatment of patients with moderate-to-severe chronic plaque psoriasis in Taiwan: results of an open-label, single-arm, multicentre pilot study. J Eur Acad Dermatol Venereol, 2008.
21. Krell, J., C. Nelson, L. Spencer, and S. Miller, An open-label study evaluating the efficacy and tolerability of alefacept for the treatment of scalp psoriasis. J Am Acad Dermatol, 2008. 58(4): p. 609-16.
22. Tsai, T.F., M.T. Liu, Y.H. Liao, and D. Licu, Clinical effectiveness and safety experience with efalizumab in the treatment of patients with moderate-to-severe plaque psoriasis in Taiwan: results of an open-label, single-arm pilot study. J Eur Acad Dermatol Venereol, 2008. 22(3): p. 345-52.
23. Varma, R., J.A. Cafardi, W. Cantrell, and C. Elmets, Safety and efficacy of subcutaneously administered efalizumab in adults with moderate-to-severe hand and foot psoriasis: an open-label study. Am J Clin Dermatol, 2008. 9(2): p. 105-9.
24. Wozel, G. and L. Vitez, Palmoplantar Pustular Psoriasis: Successful Therapy with Efalizumab after Non-response to Infliximab. Acta Derm Venereol, 2008. 88(2): p. 169-70.
25. Boehncke, W.H. and M.P. Schon, Animal models of psoriasis. Clin Dermatol, 2007. 25(6): p. 596-605.
26. Krueger, J.G., The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol, 2002. 46(1): p. 1-23; quiz 23-6.
27. Sugiyama, H., R. Gyulai, E. Toichi, E. Garaczi, S. Shimada, S.R. Stevens, T.S. McCormick, and K.D. Cooper, Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol, 2005. 174(1): p. 164-73.
28. Lan, R.Y., A.A. Ansari, Z.X. Lian, and M.E. Gershwin, Regulatory T cells: development, function and role in autoimmunity. Autoimmun Rev, 2005. 4(6): p. 351-63.
29. Walsh, S.R. and N.H. Shear, Psoriasis and the new biologic agents: interrupting a T-AP dance. CMAJ, 2004. 170(13): p. 1933-41.
30. Prinz, J.C., Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol, 2001. 26(4): p. 326-32.
31. Jablonska, S. and S. Majewski, On the immunopathogenesis of psoriasis. Arch Dermatol, 2001. 137(2): p. 229-31.
32. Guenther, L.C. and J.P. Ortonne, Pathophysiology of psoriasis: science behind therapy. J Cutan Med Surg, 2002. 6(3 Suppl): p. 2-7.
33. Fearon, U. and D.J. Veale, Pathogenesis of psoriatic arthritis. Clin Exp Dermatol, 2001. 26(4): p. 333-7.
34. 满孝勇,郑敏.银屑病发病的遗传与免疫机制.中华皮肤科杂志;2006, 39(4)238-240
35. Raza, N., M. Usman, and A. Hameed, Chronic plaque psoriasis: streptococcus pyogenes throat carriage rate and therapeutic response to oral antibiotics in comparison with oral methotrexate. J Coll Physicians Surg Pak, 2007. 17(12): p. 717-20.
36. Guilhou, J.J. and C. Girard, [Psoriasis]. Rev Prat, 2006. 56(19): p. 2153-8.
37. Simopoulos, A.P., Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr, 2002. 21(6): p. 495-505.
38. Wolters, M., [The significance of diet and associated factors in psoriasis]. Hautarzt, 2006. 57(11): p. 999-1004.
39. Wolters, M., Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol, 2005. 153(4): p. 706-14.
40. Higgins, E., Alcohol, smoking and psoriasis. Clin Exp Dermatol, 2000. 25(2): p. 107-10.
41. Farber, E.M., G. Rein, and S.W. Lanigan, Stress and psoriasis. Psychoneuroimmunologic mechanisms. Int J Dermatol, 1991. 30(1): p. 8-12.
42. 何平平,张学军.银屑病易感基因研究进展.国外医学遗传学分册;2001,24 (6)318-321
43. Orru, S., E. Giuressi, C. Carcassi, M. Casula, and L. Contu, Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN). Am J Hum Genet, 2005. 76(1): p. 164-71.
44. Speckman, R.A., J.A. Wright Daw, C. Helms, S. Duan, L. Cao, P. Taillon-Miller, P.Y. Kwok, A. Menter, and A.M. Bowcock, Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoriasis susceptibility. Hum Genet, 2003. 112(1): p. 34-41.
45. Capon, F., S. Semprini, S. Chimenti, G. Fabrizi, G. Zambruno, S. Murgia, C. Carcassi, M. Fazio, R. Mingarelli, B. Dallapiccola, and G. Novelli, Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. J Invest Dermatol, 2001. 116(5): p. 728-30.
46. Gonzaga, H.F., E.A. Torres, M.M. Alchorne, and M. Gerbase-Delima, Both psoriasis and benign migratory glossitis are associated with HLA-Cw6. Br J Dermatol, 1996. 135(3): p. 368-70.
47. 王 岩,翟 宁,宋芳吉. 银屑病的 HLA 等位基因及非 HLA 基因相关性研究进展.中国麻风皮肤病杂志.2005,21(6)460-462
48. Mallon, E., M. Bunce, F. Wojnarowska, and K. Welsh, HLA-CW*0602 is a susceptibility factor in type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics. J Invest Dermatol, 1997. 109(2): p. 183-6.
49. 范星,张学军,杨森.银屑病易感基因最新研究进展.国外医学皮肤性病学分册;2005,31(6) 364-366
50. Hattersley, A.T. and M.I. McCarthy, What makes a good genetic association study? Lancet, 2005. 366(9493): p. 1315-23.
51. Chang, Y.T., H.N. Liu, Y.M. Shiao, M.W. Lin, D.D. Lee, M.T. Liu, W.J. Wang, S. Wu, C.Y. Lai, and S.F. Tsai, A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis. Br J Dermatol, 2005. 153(1): p. 90-6.
52. Chang, Y.T., C.T. Chou, Y.M. Shiao, M.W. Lin, C.W. Yu, C.C. Chen, C.H. Huang, D.D. Lee, H.N. Liu, W.J. Wang, and S.F. Tsai, Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes. Br J Dermatol, 2006. 155(4): p. 663-9.
53. Capon, F., M.H. Allen, M. Ameen, A.D. Burden, D. Tillman, J.N. Barker, and R.C. Trembath, A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet, 2004. 13(20): p. 2361-8.
54. Jenisch, S., S. Koch, T. Henseler, R.P. Nair, J.T. Elder, C.E. Watts, E. Westphal, J.J. Voorhees, E. Christophers, and M. Kronke, Corneodesmosin gene polymorphism demonstrates strong linkage disequilibrium with HLA and association with psoriasis vulgaris. TissueAntigens, 1999. 54(5): p. 439-49.
55. Asumalahti, K., T. Laitinen, R. Itkonen-Vatjus, M.L. Lokki, S. Suomela, E. Snellman, U. Saarialho-Kere, and J. Kere, A candidate gene for psoriasis near HLA-C, HCR (Pg8), is highly polymorphic with a disease-associated susceptibility allele. Hum Mol Genet, 2000. 9(10): p. 1533-42.
56. Asumalahti, K., C. Veal, T. Laitinen, S. Suomela, M. Allen, O. Elomaa, M. Moser, R. de Cid, S. Ripatti, I. Vorechovsky, J.A. Marcusson, H. Nakagawa, C. Lazaro, X. Estivill, F. Capon, G. Novelli, U. Saarialho-Kere, J. Barker, R. Trembath, and J. Kere, Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus. Hum Mol Genet, 2002. 11(5): p. 589-97.
57. Kaluza, W., E. Reuss, S. Grossmann, R. Hug, R.E. Schopf, P.R. Galle, E. Maerker-Hermann, and T. Hoehler, Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol, 2000. 114(6): p. 1180-3.
58. Reich, K., R. Mossner, I.R. Konig, G. Westphal, A. Ziegler, and C. Neumann, 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. J Invest Dermatol, 2002. 118(1): p. 155-63.
59. Tsunemi, Y., H. Saeki, K. Nakamura, T. Sekiya, K. Hirai, H. Fujita, N. Asano, M. Kishimoto, Y. Tanida, T. Kakinuma, H. Mitsui, Y. Tada, M. Wakugawa, H. Torii, M. Komine, A. Asahina, and K. Tamaki, Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci, 2002. 30(2): p. 161-6.
60. Cargill, M., S.J. Schrodi, M. Chang, V.E. Garcia, R. Brandon, K.P. Callis, N. Matsunami, K.G. Ardlie, D. Civello, J.J. Catanese, D.U. Leong, J.M. Panko, L.B. McAllister, C.B. Hansen, J. Papenfuss, S.M. Prescott, T.J. White, M.F. Leppert, G.G. Krueger, and A.B. Begovich, 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(2): p. 273-90.
61. Krueger, G.G., R.G. Langley, C. Leonardi, N. Yeilding, C. Guzzo, Y. Wang, L.T. Dooley, and M. Lebwohl, A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med, 2007. 356(6): p. 580-92.
62. Donn, R.P., D. Plant, F. Jury, H.L. Richards, J. Worthington, D.W. Ray, and C.E. Griffiths, Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis. J Invest Dermatol, 2004. 123(3): p. 484-7.
63. Plant, D., H.S. Young, R.E. Watson, J. Worthington, and C.E. Griffiths, The CX3CL1-CX3CR1 system and psoriasis. Exp Dermatol, 2006. 15(11): p. 900-3.
64. Chang, Y.C., W.M. Wu, C.H. Chen, S.H. Lee, H.S. Hong, and L.A. Hsu, Association between the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene and risk for psoriasis in a Chinese population in Taiwan. Br J Dermatol, 2007. 156(4): p. 642-5.
65. Young, H.S., A.M. Summers, M. Bhushan, P.E. Brenchley, and C.E. Griffiths, Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. J Invest Dermatol, 2004. 122(1): p. 209-15.
66. Halsall, J.A., J.E. Osborne, J.H. Pringle, and P.E. Hutchinson, Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics, 2005.15(5): p. 349-55.
67. Vasku, V., J. Bienertova Vasku, M. Pavkova Goldbergova, and A. Vasku, Three retinoid X receptor gene polymorphisms in plaque psoriasis and psoriasis guttata. Dermatology, 2007. 214(2): p. 118-24.
68. Yamada, R. and K. Ymamoto, Recent findings on genes associated with inflammatory disease. Mutat Res, 2005. 573(1-2): p. 136-51.
69. Helms, C., L. Cao, J.G. Krueger, E.M. Wijsman, F. Chamian, D. Gordon, M. Heffernan, J.A. Daw, J. Robarge, J. Ott, P.Y. Kwok, A. Menter, and A.M. Bowcock, A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet, 2003. 35(4): p. 349-56.
70. Prokunina, L., C. Castillejo-Lopez, F. Oberg, I. Gunnarsson, L. Berg, V. Magnusson, A.J. Brookes, D. Tentler, H. Kristjansdottir, G. Grondal, A.I. Bolstad, E. Svenungsson, I. Lundberg, G. Sturfelt, A. Jonssen, L. Truedsson, G. Lima, J. Alcocer-Varela, R. Jonsson, U.B. Gyllensten, J.B. Harley, D. Alarcon-Segovia, K. Steinsson, and M.E. Alarcon-Riquelme, A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet, 2002. 32(4): p. 666-9.
71. Capon, F., C. Helms, C.D. Veal, D. Tillman, A.D. Burden, J.N. Barker, A.M. Bowcock, and R.C. Trembath, Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J Med Genet, 2004. 41(6): p. 459-60.
72. Holm, S.J., L.M. Carlen, L. Mallbris, M. Stahle-Backdahl, and K.P. O'Brien, Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Exp Dermatol, 2003. 12(4): p. 435-44.
73. Foerster, J., I. Nolte, S. Schweiger, C. Ehlert, M. Bruinenberg, K. Spaar, G.van der Steege, M. Mulder, V. Kalscheuer, B. Moser, Z. Kijas, P. Seeman, M. Stander, W. Sterry, and G. te Meerman, Evaluation of the IRF-2 gene as a candidate for PSORS3. J Invest Dermatol, 2004. 122(1): p. 61-4.
74. Rahman, P., S. Bartlett, F. Siannis, F.J. Pellett, V.T. Farewell, L. Peddle, C.T. Schentag, C.A. Alderdice, S. Hamilton, M. Khraishi, Y. Tobin, D. Hefferton, and D.D. Gladman, CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am J Hum Genet, 2003. 73(3): p. 677-81.
75. Giardina, E., G. Novelli, A. Costanzo, S. Nistico, C. Bulli, C. Sinibaldi, M.L. Sorgi, S. Chimenti, F. Pallone, E. Taccari, and P. Borgiani, Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. J Invest Dermatol, 2004. 122(5): p. 1106-7.
76. Hensen, P., K. Asadullah, C. Windemuth, F. Ruschendorf, U. Huffmeier, M. Stander, M. Schmitt-Egenolf, T.F. Wienker, A. Reis, and H. Traupe, Interleukin-10 promoter polymorphism IL10.G and familial early onset psoriasis. Br J Dermatol, 2003. 149(2): p. 381-5.
77. Kingo, K., S. Koks, T. Nikopensius, H. Silm, and E. Vasar, Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis. Genes Immun, 2004. 5(2): p. 117-21.
78. Koks, S., K. Kingo, R. Ratsep, M. Karelson, H. Silm, and E. Vasar, Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes Immun, 2004. 5(8): p. 662-7.
79. Wang, L., L. Yang, L. Gao, T.W. Gao, W. Li, and Y.F. Liu, A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with psoriasis. Int J Immunogenet, 2008. 35(1): p. 45-9.
80. Li, H., L. Gao, Z. Shen, C.Y. Li, K. Li, M. Li, Y.J. Lv, C.X. Li, T.W. Gao, and Y.F. Liu, Association study of NFKB1 and SUMO4 polymorphisms in Chinese patients with psoriasis vulgaris. Arch Dermatol Res, 2008.
81. Collins, F.S., L.D. Brooks, and A. Chakravarti, A DNA polymorphism discovery resource for research on human genetic variation. Genome Res, 1998. 8(12): p. 1229-31.
82. Wang, D.G., J.B. Fan, C.J. Siao, A. Berno, P. Young, R. Sapolsky, G. Ghandour, N. Perkins, E. Winchester, J. Spencer, L. Kruglyak, L. Stein, L. Hsie, T. Topaloglou, E. Hubbell, E. Robinson, M. Mittmann, M.S. Morris, N. Shen, D. Kilburn, J. Rioux, C. Nusbaum, S. Rozen, T.J. Hudson, R. Lipshutz, M. Chee, and E.S. Lander, Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science, 1998. 280(5366): p. 1077-82.
83. Reich, D.E., S.F. Schaffner, M.J. Daly, G. McVean, J.C. Mullikin, J.M. Higgins, D.J. Richter, E.S. Lander, and D. Altshuler, Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet, 2002. 32(1): p. 135-42.
84. Brookes, A.J., The essence of SNPs. Gene, 1999. 234(2): p. 177-86.
85. Sachidanandam, R., D. Weissman, S.C. Schmidt, J.M. Kakol, L.D. Stein, G. Marth, S. Sherry, J.C. Mullikin, B.J. Mortimore, D.L. Willey, S.E. Hunt, C.G. Cole, P.C. Coggill, C.M. Rice, Z. Ning, J. Rogers, D.R. Bentley, P.Y. Kwok, E.R. Mardis, R.T. Yeh, B. Schultz, L. Cook, R. Davenport, M. Dante, L. Fulton, L. Hillier, R.H. Waterston, J.D. McPherson, B. Gilman, S. Schaffner, W.J. Van Etten, D. Reich, J. Higgins, M.J. Daly, B. Blumenstiel, J. Baldwin, N. Stange-Thomann, M.C. Zody, L. Linton, E.S. Lander, and D. Altshuler, A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature, 2001. 409(6822): p. 928-33.
86. Lai, E., Application of SNP technologies in medicine: lessons learned and future challenges. Genome Res, 2001. 11(6): p. 927-9.
87. Mullikin, J.C., S.E. Hunt, C.G. Cole, B.J. Mortimore, C.M. Rice, J. Burton, L.H. Matthews, R. Pavitt, R.W. Plumb, S.K. Sims, R.M. Ainscough, J. Attwood, J.M. Bailey, K. Barlow, R.M. Bruskiewich, P.N. Butcher, N.P. Carter, Y. Chen, C.M. Clee, P.C. Coggill, J. Davies, R.M. Davies, E. Dawson, M.D. Francis, A.A. Joy, R.G. Lamble, C.F. Langford, J. Macarthy, V. Mall, A. Moreland, E.K. Overton-Larty, M.T. Ross, L.C. Smith, C.A. Steward, J.E. Sulston, E.J. Tinsley, K.J. Turney, D.L. Willey, G.D. Wilson, A.A. McMurray, I. Dunham, J. Rogers, and D.R. Bentley, An SNP map of human chromosome 22. Nature, 2000. 407(6803): p. 516-20.
88. Lyamichev, V., A.L. Mast, J.G. Hall, J.R. Prudent, M.W. Kaiser, T. Takova, R.W. Kwiatkowski, T.J. Sander, M. de Arruda, D.A. Arco, B.P. Neri, and M.A. Brow, Polymorphism identification and quantitative detection of genomic DNA by invasive cleavage of oligonucleotide probes. Nat Biotechnol, 1999. 17(3): p. 292-6.
89. Cha, R.S., H. Zarbl, P. Keohavong, and W.G. Thilly, Mismatch amplification mutation assay (MAMA): application to the c-H-ras gene. PCR Methods Appl, 1992. 2(1): p. 14-20.
90. Kohara, Y., H. Noda, K. Okano, and H. Kambara, DNA probes on beads arrayed in a capillary, 'Bead-array', exhibited high hybridization performance. Nucleic Acids Res, 2002. 30(16): p. e87.
91. Taylor, J.D., D. Briley, Q. Nguyen, K. Long, M.A. Iannone, M.S. Li, F. Ye, A. Afshari, E. Lai, M. Wagner, J. Chen, and M.P. Weiner, Flow cytometric platform for high-throughput single nucleotide polymorphism analysis. Biotechniques, 2001. 30(3): p. 661-6, 668-9.
92. Sanger, F. and A.R. Coulson, A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. J Mol Biol, 1975. 94(3): p. 441-8.
93. Hung, R.J., J. Hall, P. Brennan, and P. Boffetta, Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol, 2005. 162(10): p. 925-42.
94. 张忆,初少莉,施静艺等. 血管紧张素原基因多态性与高血压血尿醛酮水平相关. Molecular Cardiology of China; 2006, 6 (4) 212 - 217.
95. 李义, 吴国栋, 左瑾等. 应用单核苷酸多态性技术筛查 2 - 型糖尿病易感基因. 中国医学科学院学报; 2005, 27 (3) 274 - 276.
96. Tabor, H.K., N.J. Risch, and R.M. Myers, Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet, 2002. 3(5): p. 391-7.
97. Schubert, L.A., E. Jeffery, Y. Zhang, F. Ramsdell, and S.F. Ziegler, Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem, 2001. 276(40): p. 37672-9.
98. Hori, S., T. Nomura, and S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003. 299(5609): p. 1057-61.
99. O'Garra, A. and P. Vieira, Twenty-first century Foxp3. Nat Immunol, 2003. 4(4): p. 304-6.
100. Khattri, R., D. Kasprowicz, T. Cox, M. Mortrud, M.W. Appleby, M.E. Brunkow, S.F. Ziegler, and F. Ramsdell, The amount of scurfin protein determines peripheral T cell number and responsiveness. J Immunol, 2001. 167(11): p. 6312-20.
101. Brunkow, M.E., E.W. Jeffery, K.A. Hjerrild, B. Paeper, L.B. Clark, S.A. Yasayko, J.E. Wilkinson, D. Galas, S.F. Ziegler, and F. Ramsdell, Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001. 27(1): p. 68-73.
102. Bennett, C.L., M.E. Brunkow, F. Ramsdell, K.C. O'Briant, Q. Zhu, R.L. Fuleihan, A.O. Shigeoka, H.D. Ochs, and P.F. Chance, A rare polyadenylation signal mutation of the FOXP3 gene(AAUAAA-->AAUGAA) leads to the IPEX syndrome. Immunogenetics, 2001. 53(6): p. 435-9.
103. Chatila, T.A., F. Blaeser, N. Ho, H.M. Lederman, C. Voulgaropoulos, C. Helms, and A.M. Bowcock, JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest, 2000. 106(12): p. R75-81.
104. Cookson, W.O. and M.F. Moffatt, Genetics of asthma and allergic disease. Hum Mol Genet, 2000. 9(16): p. 2359-64.
105. Field, L.L., Genetic linkage and association studies of Type I diabetes: challenges and rewards. Diabetologia, 2002. 45(1): p. 21-35.
106. de Kleer, I.M., L.R. Wedderburn, L.S. Taams, A. Patel, H. Varsani, M. Klein, W. de Jager, G. Pugayung, F. Giannoni, G. Rijkers, S. Albani, W. Kuis, and B. Prakken, CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol, 2004. 172(10): p. 6435-43.
107. Bassuny, W.M., K. Ihara, Y. Sasaki, R. Kuromaru, H. Kohno, N. Matsuura, and T. Hara, A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes. Immunogenetics, 2003. 55(3): p. 149-56.
108. Polanczyk, M.J., B.D. Carson, S. Subramanian, M. Afentoulis, A.A. Vandenbark, S.F. Ziegler, and H. Offner, Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol, 2004. 173(4): p. 2227-30.
109. Park, O., I. Grishina, P.S. Leung, M.E. Gershwin, and T. Prindiville, Analysis of the Foxp3/scurfin gene in Crohn's disease. Ann N Y Acad Sci, 2005. 1051: p. 218-28.
110. Suda, T., T. Takahashi, P. Golstein, and S. Nagata, Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factorfamily. Cell, 1993. 75(6): p. 1169-78.
111. Bohana-Kashtan, O. and C.I. Civin, Fas ligand as a tool for immunosuppression and generation of immune tolerance. Stem Cells, 2004. 22(6): p. 908-24.
112. Takahashi, T., M. Tanaka, J. Inazawa, T. Abe, T. Suda, and S. Nagata, Human Fas ligand: gene structure, chromosomal location and species specificity. Int Immunol, 1994. 6(10): p. 1567-74.
113. Orlinick, J.R., A.K. Vaishnaw, and K.B. Elkon, Structure and function of Fas/Fas ligand. Int Rev Immunol, 1999. 18(4): p. 293-308.
114. Ross, M.J., S. Martinka, V.D. D'Agati, and L.A. Bruggeman, NF-kappaB regulates Fas-mediated apoptosis in HIV-associated nephropathy. J Am Soc Nephrol, 2005. 16(8): p. 2403-11.
115. Kroemer, G. and H. de The, Arsenic trioxide, a novel mitochondriotoxic anticancer agent? J Natl Cancer Inst, 1999. 91(9): p. 743-5.
116. Bettinardi, A., D. Brugnoni, E. Quiros-Roldan, A. Malagoli, S. La Grutta, A. Correra, and L.D. Notarangelo, Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood, 1997. 89(3): p. 902-9.
117. Drappa, J., A.K. Vaishnaw, K.E. Sullivan, J.L. Chu, and K.B. Elkon, Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med, 1996. 335(22): p. 1643-9.
118. Fisher, G.H., F.J. Rosenberg, S.E. Straus, J.K. Dale, L.A. Middleton, A.Y. Lin, W. Strober, M.J. Lenardo, and J.M. Puck, Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell, 1995. 81(6): p. 935-46.
119. Holzelova, E., C. Vonarbourg, M.C. Stolzenberg, P.D. Arkwright, F. Selz, A.M. Prieur, S. Blanche, J. Bartunkova, E. Vilmer, A. Fischer, F. Le Deist,and F. Rieux-Laucat, Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med, 2004. 351(14): p. 1409-18.
120. Krammer, P.H., CD95's deadly mission in the immune system. Nature, 2000. 407(6805): p. 789-95.
121. Rieux-Laucat, F., F. Le Deist, C. Hivroz, I.A. Roberts, K.M. Debatin, A. Fischer, and J.P. de Villartay, Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science, 1995. 268(5215): p. 1347-9.
122. Sneller, M.C., S.E. Straus, E.S. Jaffe, J.S. Jaffe, T.A. Fleisher, M. Stetler-Stevenson, and W. Strober, A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease. J Clin Invest, 1992. 90(2): p. 334-41.
123. Wu, J., J. Wilson, J. He, L. Xiang, P.H. Schur, and J.D. Mountz, Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest, 1996. 98(5): p. 1107-13.
124. 陈晋广,任小丽. 银屑病角质形成细胞凋亡与 Fas/ FasL 表达的关系. 浙江临床医学;2007,9 (11) 1465-1466.
125. Takahashi, H., A. Manabe, A. Ishida-Yamamoto, Y. Hashimoto, and H. Iizuka, Aberrant expression of apoptosis-related molecules in psoriatic epidermis. J Dermatol Sci, 2002. 28(3): p. 187-97.
126. Norris, D.A., J.B. Travers, and D.Y. Leung, Lymphocyte activation in the pathogenesis of psoriasis. J Invest Dermatol, 1997. 109(1): p. 1-4.
127. Gilhar, A., R. Yaniv, B. Assy, S. Serafimovich, Y. Ullmann, and R.S. Kalish, Fas pulls the trigger on psoriasis. Am J Pathol, 2006. 168(1): p. 170-5.
128. Nickoloff, B.J., T. Wrone-Smith, B. Bonish, and S.A. Porcelli, Response of murine and normal human skin to injection of allogeneic blood-derived psoriatic immunocytes: detection of T cells expressing receptors typicallypresent on natural killer cells, including CD94, CD158, and CD161. Arch Dermatol, 1999. 135(5): p. 546-52.
129. Nickoloff, B.J., B. Bonish, B.B. Huang, and S.A. Porcelli, Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci, 2000. 24(3): p. 212-25.
130. Gilhar, A., Y. Ullmann, H. Kerner, B. Assy, R. Shalaginov, S. Serafimovich, and R.S. Kalish, Psoriasis is mediated by a cutaneous defect triggered by activated immunocytes: induction of psoriasis by cells with natural killer receptors. J Invest Dermatol, 2002. 119(2): p. 384-91.
131. Chaudhari, U., P. Romano, L.D. Mulcahy, L.T. Dooley, D.G. Baker, and A.B. Gottlieb, Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet, 2001. 357(9271): p. 1842-7.
132. Leonardi, C.L., J.L. Powers, R.T. Matheson, B.S. Goffe, R. Zitnik, A. Wang, and A.B. Gottlieb, Etanercept as monotherapy in patients with psoriasis. N Engl J Med, 2003. 349(21): p. 2014-22.
133. Qin, J.Z., P. Bacon, V. Chaturvedi, and B.J. Nickoloff, Role of NF-kappaB activity in apoptotic response of keratinocytes mediated by interferon-gamma, tumor necrosis factor-alpha, and tumor-necrosis-factor-related apoptosis-inducing ligand. J Invest Dermatol, 2001. 117(4): p. 898-907.
134. Biancone, L., A.D. Martino, V. Orlandi, P.G. Conaldi, A. Toniolo, and G. Camussi, Development of inflammatory angiogenesis by local stimulation of Fas in vivo. J Exp Med, 1997. 186(1): p. 147-52.
135. Huang, Q.R., S.M. Teutsch, M.M. Buhler, B.H. Bennetts, R.N. Heard, N. Manolios, and G.J. Stewart, Evaluation of the apo-1/Fas promoter mva I polymorphism in multiple sclerosis. Mult Scler, 2000. 6(1): p. 14-8.
136. van Veen, T., N.F. Kalkers, J.B. Crusius, L. van Winsen, F. Barkhof, P.J. Jongen, A.S. Pena, C.H. Polman, and B.M. Uitdehaag, The FAS-670 polymorphism influences susceptibility to multiple sclerosis. J Neuroimmunol, 2002. 128(1-2): p. 95-100.
137. Huang, Q.R., V. Danis, M. Lassere, J. Edmonds, and N. Manolios, Evaluation of a new Apo-1/Fas promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus patients. Rheumatology (Oxford), 1999. 38(7): p. 645-51.
138. Kanemitsu, S., K. Ihara, A. Saifddin, T. Otsuka, T. Takeuchi, J. Nagayama, M. Kuwano, and T. Hara, A functional polymorphism in fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus. J Rheumatol, 2002. 29(6): p. 1183-8.
139. Lee, Y.H., J.D. Ji, J. Sohn, and G.G. Song, Polymorphsims of CTLA-4 exon 1 +49, CTLA-4 promoter -318 and Fas promoter -670 in spondyloarthropathies. Clin Rheumatol, 2001. 20(6): p. 420-2.
140. Sibley, K., S. Rollinson, J.M. Allan, A.G. Smith, G.R. Law, P.L. Roddam, C.F. Skibola, M.T. Smith, and G.J. Morgan, Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res, 2003. 63(15): p. 4327-30.
141. Wu, J., C. Metz, X. Xu, R. Abe, A.W. Gibson, J.C. Edberg, J. Cooke, F. Xie, G.S. Cooper, and R.P. Kimberly, A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol, 2003. 170(1): p. 132-8.
142. Stuck, B.J., M.A. Pani, F. Besrour, M. Segni, M. Krause, K.H. Usadel, and K. Badenhoop, Fas ligand gene polymorphisms are not associated with Hashimoto's thyroiditis and Graves' disease. Hum Immunol, 2003. 64(2): p. 285-9.
143. Pinti, M., L. Troiano, M. Nasi, L. Moretti, E. Monterastelli, A. Mazzacani, C. Mussi, P. Ventura, F. Olivieri, C. Franceschi, G. Salvioli, and A. Cossarizza, Genetic polymorphisms of Fas (CD95) and FasL (CD178) in human longevity: studies on centenarians. Cell Death Differ, 2002. 9(4): p. 431-8.
144. Bertocci, B., V. Miggiano, M. Da Prada, Z. Dembic, H.W. Lahm, and P. Malherbe, Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proc Natl Acad Sci U S A, 1991. 88(4): p. 1416-20.
145. Grossman, M.H., B.S. Emanuel, and M.L. Budarf, Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1----q11.2. Genomics, 1992. 12(4): p. 822-5.
146. Karayiorgou, M., M. Altemus, B.L. Galke, D. Goldman, D.L. Murphy, J. Ott, and J.A. Gogos, Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A, 1997. 94(9): p. 4572-5.
147. Dimon-Gadal, S., P. Gerbaud, P. Therond, J. Guibourdenche, W.B. Anderson, D. Evain-Brion, and F. Raynaud, Increased oxidative damage to fibroblasts in skin with and without lesions in psoriasis. J Invest Dermatol, 2000. 114(5): p. 984-9.
148. Shilov, V.N. and V.I. Sergienko, Oxidative stress in keratinocytes as an etiopathogenetic factor of psoriasis. Bull Exp Biol Med, 2000. 129(4): p. 309-13.
149. Erdal, M.E., U. Tursen, T.I. Kaya, A. Kanik, E. Derici, and G. Ikizoglu, Association between Cathechol-O-Metyltransferase polymorphism and psoriasis. Int J Dermatol, 2004. 43(4): p. 312-4.
150. de Rie, M.A., A.Y. Goedkoop, and J.D. Bos, Overview of psoriasis. Dermatol Ther, 2004. 17(5): p. 341-9.
151. Kwok, P.Y., Methods for genotyping single nucleotide polymorphisms. Annu Rev Genomics Hum Genet, 2001. 2: p. 235-58.
152. Chen, X. and P.F. Sullivan, Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput. Pharmacogenomics J, 2003. 3(2): p. 77-96.
153. Feuilhade de Chauvin, M., New diagnostic techniques. J Eur Acad Dermatol Venereol, 2005. 19 Suppl 1: p. 20-4.
154. Marchand, S., P. Hajdari, P. Hackman, B. Udd, and I. Richard, Touch-down method for high-performance sequencing of polymerase chain reaction products. Anal Biochem, 2003. 315(2): p. 270-2.
155. Bovenschen, H.J., I.M. van Vlijmen-Willems, P.C. van de Kerkhof, and P.E. van Erp, Identification of lesional CD4+ CD25+ Foxp3+ regulatory T cells in Psoriasis. Dermatology, 2006. 213(2): p. 111-7.
156. Wrone-Smith, T. and B.J. Nickoloff, Dermal injection of immunocytes induces psoriasis. J Clin Invest, 1996. 98(8): p. 1878-87.
157. Gilhar, A., M. David, Y. Ullmann, T. Berkutski, and R.S. Kalish, T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice. J Invest Dermatol, 1997. 109(3): p. 283-8.
158. de Boer, O.J., C.M. van der Loos, P. Teeling, A.C. van der Wal, and M.B. Teunissen, Immunohistochemical analysis of regulatory T cell markers FOXP3 and GITR on CD4+CD25+ T cells in normal skin and inflammatory dermatoses. J Histochem Cytochem, 2007. 55(9): p. 891-8.
159. Bos, J.D. and M.A. De Rie, The pathogenesis of psoriasis: immunological facts and speculations. Immunol Today, 1999. 20(1): p. 40-6.
160. Boehncke, W.H., D. Dressel, T.M. Zollner, and R. Kaufmann, Pulling the trigger on psoriasis. Nature, 1996. 379(6568): p. 777.
161. Lin, W., D. Haribhai, L.M. Relland, N. Truong, M.R. Carlson, C.B. Williams, and T.A. Chatila, Regulatory T cell development in the absence of functional Foxp3. Nat Immunol, 2007. 8(4): p. 359-68.
162. Nieves, D.S., R.P. Phipps, S.J. Pollock, H.D. Ochs, Q. Zhu, G.A. Scott, C.K. Ryan, I. Kobayashi, T.M. Rossi, and L.A. Goldsmith, Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol, 2004. 140(4): p. 466-72.
163. Li, C., D. Larson, Z. Zhang, Z. Liu, S.S. Strom, J.E. Gershenwald, V.G. Prieto, J.E. Lee, M.I. Ross, P.F. Mansfield, J.N. Cormier, M. Duvic, E.A. Grimm, and Q. Wei, Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma. Pharmacogenet Genomics, 2006. 16(4): p. 253-63.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |