Association Study Of NFKB1, SUMO4 And PDCD1 Polymorphisms In Chinese Patients With Psoriasis Vulgaris

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.