NFKB1、SUMO4和PDCD1基因多态性与银屑病的相关性研究
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摘要
银屑病(俗称牛皮癣)是一种病情顽固、易反复、治疗困难的常见皮肤病,严重影响着大约1-3%的世界人口的日常生活和心身健康。尽管其确切病因尚不完全清楚,但目前越来越多的证据表明,银屑病的发生是携带着遗传易感基因的个体,在感染、创伤等因素作用下,激发了机体的细胞免疫应答,出现了CD4+T细胞介导的自身免疫紊乱。本实验立足于银屑病的遗传发病机制与免疫发病机制交汇点,瞄定了与银屑病的免疫学发病机制密切相关的三个分子NF-κB、SUMO4和PDCD1,从单核苷酸多态性角度探索它们与银屑病发病的相关性。下面简要介绍一下本项研究瞄定的三个分子。
NF-κB(nuclear factor-κB)是一种重要的真核细胞转录因子,位于活化T细胞信号转导通路的末端,它作为关键的桥梁,连接着活化的T细胞和银屑病相关分子的转录,如TNF-α、IL-8、IL-12和细胞周期蛋白D等。有研究表明银屑病患者皮损处有大量活化形式的NF-κB,当银屑病病情好转,皮疹平复时,伴随着皮疹区活化形式的NF-κB明显减少。因此,NF-κB的任何异常都很可能导致银屑病的发生或银屑病病情的加重。
转录因子NF-κB由NFKB1基因编码,在NFKB1基因的启动子区,存在着-94位ATTG四个碱基的插入与缺失多态性,相应的有三种NFKB1基因型:纯合子WW(insert/insert)、DD(delete/delete)和杂合子WD。Karban AS等研究发现NFKB1 D等位基因能增加自身免疫性疾病—溃疡性结肠炎患病的危险性,功能研究表明NFKB1 D等位基因具有降低NFKB1基因启动子启动基因转录的活性。那么,由此推断,此多态性位点很可能是自身免疫性疾病—银屑病的发病危险因素,研究NFKB1-94 ATTG多态性与寻常型银屑病发病的相关性将是非常有意义的切入点。
SUMO4蛋白(Small ubiquitin-related modifier),位于细胞质中,是转录因子NF-κB活化的负性调控分子。SUMO4蛋白由位于染色体6q25的SUMO4基因编码。SUMO4基因中有编号rs237025、由G突变到A的单核苷酸多态性(Single nucleotide polymorphism, SNP),此SNP位点的基因突变导致sumo4蛋白质肽链中的第55位氨基酸由缬氨酸替换蛋氨酸(M55V)。有研究表明SUMO4蛋白的M55V替换与1型糖尿病的发病密切相关,SNP位点的功能研究表明,M55V替换能使NF-κB蛋白转录活性提高5.5倍。由此我们推测,作为NF-κB活化的负性调控分子,SUMO4 rs237025多态性可能是银屑病潜在的发病危险因素。
PDCD1(programmed cell death 1)也称作程序性细胞死亡,是分布在细胞表面的抑制性免疫受体, PDCD1分子通过下调PKCθ的信号转导通路,抑制其下游的转录因子NF-κB的活化。PDCD1是位于细胞膜上,SUMO4上游的NF-κB的活化负性调控分子。PDCD1分子的异常及其编码基因的多态性,可能是通过下游的转录因子NF-κB或其它的环节促进了银屑病的发生,或者是加重银屑病的病情。依据文献资料,我们选择了PDCD1基因的三个SNPs位点进行研究:位于启动子区的PD1.1,位于外显子5上的PD1.5和PD1.9位点。
基于NF-κB与银屑病发病的紧密相关性,以及SUMO4和PDCD1分子对NF-κB活化的负性调控作用,我们提出了如下假说,即NFKB1基因、SUMO4基因和PDCD1基因的基因多态性可能是银屑病患病的危险因素,或者加重了银屑病的病情,或者与银屑病的某种临床表型相关,并在本实验中予以验证。
实验目的:分析NFKB1基因、SUMO4基因和PDCD1基因的基因多态性与中国寻常型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。
实验方法:采用性别、年龄相匹配的病例-对照研究方法,收集519例寻常型银屑病患者和541例正常对照的外周血,提基因组DNA,用聚合酶链式反应-限制性片断长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法鉴定NFKB1、SUMO4和PDCD1基因上的基因多态性,用SAS软件进行统计学分析,探讨分别位于三个基因上的五个基因多态性位点与寻常型银屑病发病的相关性。依据患者的性别、发病年龄、家族史和PASI评分对患者进行分组,用分层分析的统计方法,进一步研究基因多态性的遗传背景与银屑病的上述临床表型之间的相关性。
实验结果
1.首次进行了NFKB1-94ins/del ATTG多态性与寻常型银屑病的相关性研究,发现NFKB1 WW基因型是危险基因型,携带NFKB1-94ins/del ATTG WW基因型的个体患银屑病的危险性增加1.57倍,校正OR =1.57,95% CI =1.10-2.24。
2.研究基因多态性与银屑病临床表型的相关性,本实验对NFKB1-94ins/del ATTG多态性位点进行了联合基因型的分层分析,以NFKB1WD+DD基因型为参照,Logistic回归分析发现携带NFKB1WW基因型可增加下列各组寻常型银屑病的患病危险性:年龄≤40、PASI评分>20、男性患者与无家族史的银屑病患者。
3.本实验首次研究了SUMO4基因的功能性SNP位点rs237025与银屑病的相关性,结果表明SUMO4基因的AA、GA、GG基因型和G、A等位基因均与银屑病的发病无相关性,提示SUMO4 rs237025多态性位点与中国寻常型银屑病的易感性无关。
4.本实验首次研究了PDCD1基因与银屑病发病的相关性,发现PD1.1GG基因型有增加银屑病患病危险性的趋势,校正OR =1.30,95% CI =0.93-1.83;PD1.5的TT、TC、CC基因型和T、C等位基因与银屑病的发病无显著相关性;PD1.9CC基因型使寻常型银屑病患病危险性增加了1.4倍,校正OR =1.40, 95% CI =1.00-1.95。
5.对PDCD1基因的多态性位点进行联合基因型分析,以PD1.1AG+AA/PD1.9TC+TT为参照, Logistic回归分析发现PD1.1GG/PD1.9CC联合基因型使寻常型银屑病患病危险性增加了1.54倍,提示PD1.1GG和PD1.9CC基因型的致病性具有联合效应。
6. PDCD1基因的三个多态性位点间存在着连锁不平衡,据此通过软件构建出八种单倍体等位基因,分别为ATT、GTT、ATC、ACT、GCT、ACC、GTC、GCC。Logistic回归分析发现,单倍体等位基因与银屑病的易感性有随着危险等位基因数目的增多而增高的趋势,具有三个危险等位基因的GCC单倍体等位基因使寻常型银屑病的患病危险性增高了3.78倍。
7.在PDCD1基因的三个SNPs中,我们进一步分析了个体所携带的危险等位基因数目与银屑病易感性的相关性,发现携带5-6个危险等位基因的个体患寻常型银屑病的危险性高于携带0-4个危险等位基因的个体,校正OR =1.43,95% CI =1.05-1.94。
实验结论
本研究表明SUMO4 rs237025多态性与中国寻常型银屑病的患病危险性无关。携带NFKB1 WW基因型个体患银屑病的危险性增加1.57倍,同时与发病年龄≤40岁的早发型、PASI评分>20的银屑病临床表型相关。在PDCD1基因的SNPs中,PD1.5多态性位点与银屑病的发病无显著相关性,携带PD1.1GG基因型与PD1.9CC基因型有增加银屑病患病危险性的趋势,具有三个危险等位基因的GCC单倍体等位基因使寻常型银屑病的患病危险性增高3.78倍。总之,本研究表明银屑病的发病与NFKB1基因和PDCD1基因的基因多态性相关,支持银屑病发病的免疫学说与遗传学说。
Psoriasis is a common dermatological disorder, affecting approximately 1% to 3% of the general population. Although the pathogenesis of psoriasis has not been definitively understood, recent evidence suggests that the CD4-positive T-lymphocytes paly an important role in the pathogenesis and progression of psoriasis under a polygenic inheritance background. Considering the crossing of immunopathogenesis and genetic background for psoriasis etiology, the present study selected NFKB1, SUMO4 and PDCD1 gene,assessed the associations between psoriasis and the five single nucleotide polymorphisms respectively in the three genes. Then, I concisely introduce the selected three genes.
Nuclear factor kappa-beta (NF-κB) is a critical transcription factor modulating the expression of many genes involved in the pathogenesis of psoriasis. Located at the signaling pathway terminal of the activated T cells, NF-κB acts as a key bridge which links the activated Th1 cells with the transcription of many crucial genes involved in the pathogenesis of psoriasis, 第四军医大学博士学位论文such as TNF-α, IL-8, IL-12 and cyclin D. Furthermore, the increased expression of NF-κB in the involved synovial membranes and lesions has been demonstrated in the psoriatic patients. Therefore, the dysfunction of NF-κB may contribute to the formation or aggravation of psoriasis.
NF-κB protein is encoded by the NFKB1 gene. In the promoter region of NFKB1, there is a -94ATTG 4 base insert/delete (-94W/D) polymorphism site, which consists of three genotypes: wild homozygous WW (ins/ins), variant homozygous DD (del /del) and heterozygous WD (ins/del). A previous study by Karban AS et al has found that the D allele could increase the risk of ulcerative colitis and decrease the NFKB1 promoter activity in vitro. To date, we have not seen any published paper regarding the association between this promoter polymorphism in NFKB1 and psoriasis vulgaris. Therefore, it is worthwhile to investigate whether this promoter polymorphism in NFKB1 is also associated with the etiology of psoriasis vulgaris, a newly defined autoimmune disease.
Small ubiquitin-related modifier (SUMO) is a negative regulator of NF-κB in the upstream of NF-κB signaling pathway. The 94 amino acid SUMO4 protein is encoded by SUMO4 gene located at chromosome 6q25. A rs237025 A>G single nucleotide polymorphism (SNP) has been detected in SUMO4 gene. This SNP locates in the coding region of SUMO4 gene and corresponds the substitution of a methionine with a valine residue (M55V). Studies have verified that the substitution (M55V) of SUMO4 is strongly associated with type1 diabetes. Functional research has manifested that the M55V substitution results in 5.5 times greater NF-κB transcriptional activity. As both type1 diabetes and psoriasis are autoimmune-related diseases, the pathogenesis of them might result from the same SUMO4 rs237025 A>G SNP.
Programmed cell death 1(PDCD1)is another negative regulator of NF-κB which located at the cell surface. By down-regulating the PKCθcell signaling pathway, PDCD1 inhibits the activation of NF-κB. Thus the SNPs in PDCD1 gene might contribute to the pathogenesis of psoriasis or worsen the patients’clinical symptoms. According to the published papers, we selected three SNPs in the PDCD1 gene to study their associations with psoriasis vulgaris risk. PD1.1 is in the promoter resion. PD1.5 and PD1.9 are all locating at the extron 5. Therefore, on the basis of the key role of NF-κB in the pathogenesis of psoriasis and the negative regulation of SUMO4 and PDCD1 on NF-κB, we investigated the association between psoriasis and five SNPs separately in the three genes by a hospital-based, case-control study.
Objective: To investigated the association of five SNPs in NFKB1, SUMO4 and PDCD1 gene with psoriasis vulgaris susceptibility in the Chinese.
Methods: In a hospital-based case-control study, 519 psoriasis patients and 541 controls were enrolled in frequency matching by the age and sex. Genotyping for the five polymorphisms was conducted using polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) method. The Chi-square test was used to evaluate the differences in the frequency distributions of selected demographic variables, each of the alleles and genotypes of the five polymorphisms between patients with psoriasis vuagaris and individuals in the control group. As the age of onset, sex, family history and PASI score are the different clinical characteristics of psoriasis, the associations between the combined-genotypes and the risk of psoriasis in different subgroups were also evaluated.
Results:
1. A significantly increased psoriasis risk was associated with the NFKB1 WW genotype. Individuals with the NFKB1 WW genotype had 1.57 fold psoriasis risk (adjusted OR =1.57, 95% CI =1.10-2.24).
2. The NFKB1 WW genotype frequency was also statistically higher in the psoriatic subgroups of onset age≤40, PASI>20, male patients and sporadic patients than in controls.
3. No associations of the SUMO4 rs237025 A>G polymorphism with the susceptibility of psoriasis was found in the present study.
4. Individuals with the PD1.1 GG genotype had the tendency of increased psoriasis risk (adjusted OR =1.30, 95% CI =0.93-1.83);The TT, TC, CC genotypes and T, C alleles in the PD1.5 polymorphism did not show any association with the susceptibility of psoriasis. Individuals with the PD1.9 CC genotype had 1.4 fold psoriasis risk (adjusted OR =1.40, 95% CI =1.00-1.95).
5. We performed a combined genotype analysis for the PD1.1 and PD1.9 SNPs in the PDCD1 gene. When the individuals with the PD1.1AG+AA/PD1.9TC+TT genotype was used as the reference, individuals with the PD1.1GG/PD1.9CC combined genotype had 1.54 fold psoriasis risk, which illustrate that the PD1.1GG and PD1.9CC genotype have joint effect for psoriasis risk.
6. We detected linkage disequilibrium among the three PDCD1 SNPs. By Phase software, we constructed eight haplotypes for the three SNPs: ATT, GTT, ATC, ACT, GCT, ACC, GTC and GCC. The GCC haplotype genotype with 3 risk alleles was associated with 3.78 fold psoriasis risk compared to that with 0 risk alleles.
7. When the combined genotype containing 0–4 PDCD1 risk alleles was used as the reference, a significantly higher risk was associate with the combined genotypes containing 5–6 PDCD1 risk alleles (adjusted OR=1.43; 95% CI=1.05-1.94)
In conclusion: As far as we know, this is the first association study between NFKB1, SUMO4 and PDCD1 polymorphisms and the psoriasis vulgaris in the Chinese population. Larger, population-based studies are needed to confirm these findings.
NF-κB(nuclear factor-κB)是一种重要的真核细胞转录因子,位于活化T细胞信号转导通路的末端,它作为关键的桥梁,连接着活化的T细胞和银屑病相关分子的转录,如TNF-α、IL-8、IL-12和细胞周期蛋白D等。有研究表明银屑病患者皮损处有大量活化形式的NF-κB,当银屑病病情好转,皮疹平复时,伴随着皮疹区活化形式的NF-κB明显减少。因此,NF-κB的任何异常都很可能导致银屑病的发生或银屑病病情的加重。
转录因子NF-κB由NFKB1基因编码,在NFKB1基因的启动子区,存在着-94位ATTG四个碱基的插入与缺失多态性,相应的有三种NFKB1基因型:纯合子WW(insert/insert)、DD(delete/delete)和杂合子WD。Karban AS等研究发现NFKB1 D等位基因能增加自身免疫性疾病—溃疡性结肠炎患病的危险性,功能研究表明NFKB1 D等位基因具有降低NFKB1基因启动子启动基因转录的活性。那么,由此推断,此多态性位点很可能是自身免疫性疾病—银屑病的发病危险因素,研究NFKB1-94 ATTG多态性与寻常型银屑病发病的相关性将是非常有意义的切入点。
SUMO4蛋白(Small ubiquitin-related modifier),位于细胞质中,是转录因子NF-κB活化的负性调控分子。SUMO4蛋白由位于染色体6q25的SUMO4基因编码。SUMO4基因中有编号rs237025、由G突变到A的单核苷酸多态性(Single nucleotide polymorphism, SNP),此SNP位点的基因突变导致sumo4蛋白质肽链中的第55位氨基酸由缬氨酸替换蛋氨酸(M55V)。有研究表明SUMO4蛋白的M55V替换与1型糖尿病的发病密切相关,SNP位点的功能研究表明,M55V替换能使NF-κB蛋白转录活性提高5.5倍。由此我们推测,作为NF-κB活化的负性调控分子,SUMO4 rs237025多态性可能是银屑病潜在的发病危险因素。
PDCD1(programmed cell death 1)也称作程序性细胞死亡,是分布在细胞表面的抑制性免疫受体, PDCD1分子通过下调PKCθ的信号转导通路,抑制其下游的转录因子NF-κB的活化。PDCD1是位于细胞膜上,SUMO4上游的NF-κB的活化负性调控分子。PDCD1分子的异常及其编码基因的多态性,可能是通过下游的转录因子NF-κB或其它的环节促进了银屑病的发生,或者是加重银屑病的病情。依据文献资料,我们选择了PDCD1基因的三个SNPs位点进行研究:位于启动子区的PD1.1,位于外显子5上的PD1.5和PD1.9位点。
基于NF-κB与银屑病发病的紧密相关性,以及SUMO4和PDCD1分子对NF-κB活化的负性调控作用,我们提出了如下假说,即NFKB1基因、SUMO4基因和PDCD1基因的基因多态性可能是银屑病患病的危险因素,或者加重了银屑病的病情,或者与银屑病的某种临床表型相关,并在本实验中予以验证。
实验目的:分析NFKB1基因、SUMO4基因和PDCD1基因的基因多态性与中国寻常型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。
实验方法:采用性别、年龄相匹配的病例-对照研究方法,收集519例寻常型银屑病患者和541例正常对照的外周血,提基因组DNA,用聚合酶链式反应-限制性片断长度多态性(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)方法鉴定NFKB1、SUMO4和PDCD1基因上的基因多态性,用SAS软件进行统计学分析,探讨分别位于三个基因上的五个基因多态性位点与寻常型银屑病发病的相关性。依据患者的性别、发病年龄、家族史和PASI评分对患者进行分组,用分层分析的统计方法,进一步研究基因多态性的遗传背景与银屑病的上述临床表型之间的相关性。
实验结果
1.首次进行了NFKB1-94ins/del ATTG多态性与寻常型银屑病的相关性研究,发现NFKB1 WW基因型是危险基因型,携带NFKB1-94ins/del ATTG WW基因型的个体患银屑病的危险性增加1.57倍,校正OR =1.57,95% CI =1.10-2.24。
2.研究基因多态性与银屑病临床表型的相关性,本实验对NFKB1-94ins/del ATTG多态性位点进行了联合基因型的分层分析,以NFKB1WD+DD基因型为参照,Logistic回归分析发现携带NFKB1WW基因型可增加下列各组寻常型银屑病的患病危险性:年龄≤40、PASI评分>20、男性患者与无家族史的银屑病患者。
3.本实验首次研究了SUMO4基因的功能性SNP位点rs237025与银屑病的相关性,结果表明SUMO4基因的AA、GA、GG基因型和G、A等位基因均与银屑病的发病无相关性,提示SUMO4 rs237025多态性位点与中国寻常型银屑病的易感性无关。
4.本实验首次研究了PDCD1基因与银屑病发病的相关性,发现PD1.1GG基因型有增加银屑病患病危险性的趋势,校正OR =1.30,95% CI =0.93-1.83;PD1.5的TT、TC、CC基因型和T、C等位基因与银屑病的发病无显著相关性;PD1.9CC基因型使寻常型银屑病患病危险性增加了1.4倍,校正OR =1.40, 95% CI =1.00-1.95。
5.对PDCD1基因的多态性位点进行联合基因型分析,以PD1.1AG+AA/PD1.9TC+TT为参照, Logistic回归分析发现PD1.1GG/PD1.9CC联合基因型使寻常型银屑病患病危险性增加了1.54倍,提示PD1.1GG和PD1.9CC基因型的致病性具有联合效应。
6. PDCD1基因的三个多态性位点间存在着连锁不平衡,据此通过软件构建出八种单倍体等位基因,分别为ATT、GTT、ATC、ACT、GCT、ACC、GTC、GCC。Logistic回归分析发现,单倍体等位基因与银屑病的易感性有随着危险等位基因数目的增多而增高的趋势,具有三个危险等位基因的GCC单倍体等位基因使寻常型银屑病的患病危险性增高了3.78倍。
7.在PDCD1基因的三个SNPs中,我们进一步分析了个体所携带的危险等位基因数目与银屑病易感性的相关性,发现携带5-6个危险等位基因的个体患寻常型银屑病的危险性高于携带0-4个危险等位基因的个体,校正OR =1.43,95% CI =1.05-1.94。
实验结论
本研究表明SUMO4 rs237025多态性与中国寻常型银屑病的患病危险性无关。携带NFKB1 WW基因型个体患银屑病的危险性增加1.57倍,同时与发病年龄≤40岁的早发型、PASI评分>20的银屑病临床表型相关。在PDCD1基因的SNPs中,PD1.5多态性位点与银屑病的发病无显著相关性,携带PD1.1GG基因型与PD1.9CC基因型有增加银屑病患病危险性的趋势,具有三个危险等位基因的GCC单倍体等位基因使寻常型银屑病的患病危险性增高3.78倍。总之,本研究表明银屑病的发病与NFKB1基因和PDCD1基因的基因多态性相关,支持银屑病发病的免疫学说与遗传学说。
Psoriasis is a common dermatological disorder, affecting approximately 1% to 3% of the general population. Although the pathogenesis of psoriasis has not been definitively understood, recent evidence suggests that the CD4-positive T-lymphocytes paly an important role in the pathogenesis and progression of psoriasis under a polygenic inheritance background. Considering the crossing of immunopathogenesis and genetic background for psoriasis etiology, the present study selected NFKB1, SUMO4 and PDCD1 gene,assessed the associations between psoriasis and the five single nucleotide polymorphisms respectively in the three genes. Then, I concisely introduce the selected three genes.
Nuclear factor kappa-beta (NF-κB) is a critical transcription factor modulating the expression of many genes involved in the pathogenesis of psoriasis. Located at the signaling pathway terminal of the activated T cells, NF-κB acts as a key bridge which links the activated Th1 cells with the transcription of many crucial genes involved in the pathogenesis of psoriasis, 第四军医大学博士学位论文such as TNF-α, IL-8, IL-12 and cyclin D. Furthermore, the increased expression of NF-κB in the involved synovial membranes and lesions has been demonstrated in the psoriatic patients. Therefore, the dysfunction of NF-κB may contribute to the formation or aggravation of psoriasis.
NF-κB protein is encoded by the NFKB1 gene. In the promoter region of NFKB1, there is a -94ATTG 4 base insert/delete (-94W/D) polymorphism site, which consists of three genotypes: wild homozygous WW (ins/ins), variant homozygous DD (del /del) and heterozygous WD (ins/del). A previous study by Karban AS et al has found that the D allele could increase the risk of ulcerative colitis and decrease the NFKB1 promoter activity in vitro. To date, we have not seen any published paper regarding the association between this promoter polymorphism in NFKB1 and psoriasis vulgaris. Therefore, it is worthwhile to investigate whether this promoter polymorphism in NFKB1 is also associated with the etiology of psoriasis vulgaris, a newly defined autoimmune disease.
Small ubiquitin-related modifier (SUMO) is a negative regulator of NF-κB in the upstream of NF-κB signaling pathway. The 94 amino acid SUMO4 protein is encoded by SUMO4 gene located at chromosome 6q25. A rs237025 A>G single nucleotide polymorphism (SNP) has been detected in SUMO4 gene. This SNP locates in the coding region of SUMO4 gene and corresponds the substitution of a methionine with a valine residue (M55V). Studies have verified that the substitution (M55V) of SUMO4 is strongly associated with type1 diabetes. Functional research has manifested that the M55V substitution results in 5.5 times greater NF-κB transcriptional activity. As both type1 diabetes and psoriasis are autoimmune-related diseases, the pathogenesis of them might result from the same SUMO4 rs237025 A>G SNP.
Programmed cell death 1(PDCD1)is another negative regulator of NF-κB which located at the cell surface. By down-regulating the PKCθcell signaling pathway, PDCD1 inhibits the activation of NF-κB. Thus the SNPs in PDCD1 gene might contribute to the pathogenesis of psoriasis or worsen the patients’clinical symptoms. According to the published papers, we selected three SNPs in the PDCD1 gene to study their associations with psoriasis vulgaris risk. PD1.1 is in the promoter resion. PD1.5 and PD1.9 are all locating at the extron 5. Therefore, on the basis of the key role of NF-κB in the pathogenesis of psoriasis and the negative regulation of SUMO4 and PDCD1 on NF-κB, we investigated the association between psoriasis and five SNPs separately in the three genes by a hospital-based, case-control study.
Objective: To investigated the association of five SNPs in NFKB1, SUMO4 and PDCD1 gene with psoriasis vulgaris susceptibility in the Chinese.
Methods: In a hospital-based case-control study, 519 psoriasis patients and 541 controls were enrolled in frequency matching by the age and sex. Genotyping for the five polymorphisms was conducted using polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) method. The Chi-square test was used to evaluate the differences in the frequency distributions of selected demographic variables, each of the alleles and genotypes of the five polymorphisms between patients with psoriasis vuagaris and individuals in the control group. As the age of onset, sex, family history and PASI score are the different clinical characteristics of psoriasis, the associations between the combined-genotypes and the risk of psoriasis in different subgroups were also evaluated.
Results:
1. A significantly increased psoriasis risk was associated with the NFKB1 WW genotype. Individuals with the NFKB1 WW genotype had 1.57 fold psoriasis risk (adjusted OR =1.57, 95% CI =1.10-2.24).
2. The NFKB1 WW genotype frequency was also statistically higher in the psoriatic subgroups of onset age≤40, PASI>20, male patients and sporadic patients than in controls.
3. No associations of the SUMO4 rs237025 A>G polymorphism with the susceptibility of psoriasis was found in the present study.
4. Individuals with the PD1.1 GG genotype had the tendency of increased psoriasis risk (adjusted OR =1.30, 95% CI =0.93-1.83);The TT, TC, CC genotypes and T, C alleles in the PD1.5 polymorphism did not show any association with the susceptibility of psoriasis. Individuals with the PD1.9 CC genotype had 1.4 fold psoriasis risk (adjusted OR =1.40, 95% CI =1.00-1.95).
5. We performed a combined genotype analysis for the PD1.1 and PD1.9 SNPs in the PDCD1 gene. When the individuals with the PD1.1AG+AA/PD1.9TC+TT genotype was used as the reference, individuals with the PD1.1GG/PD1.9CC combined genotype had 1.54 fold psoriasis risk, which illustrate that the PD1.1GG and PD1.9CC genotype have joint effect for psoriasis risk.
6. We detected linkage disequilibrium among the three PDCD1 SNPs. By Phase software, we constructed eight haplotypes for the three SNPs: ATT, GTT, ATC, ACT, GCT, ACC, GTC and GCC. The GCC haplotype genotype with 3 risk alleles was associated with 3.78 fold psoriasis risk compared to that with 0 risk alleles.
7. When the combined genotype containing 0–4 PDCD1 risk alleles was used as the reference, a significantly higher risk was associate with the combined genotypes containing 5–6 PDCD1 risk alleles (adjusted OR=1.43; 95% CI=1.05-1.94)
In conclusion: As far as we know, this is the first association study between NFKB1, SUMO4 and PDCD1 polymorphisms and the psoriasis vulgaris in the Chinese population. Larger, population-based studies are needed to confirm these findings.
引文
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