Interleukin-18 promoter polymorphism in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which interleukin (IL)-18 plays an important role. However, there are controversial reports on IL-18 promoter polymorphism as an independent marker of RA susceptibility. The aim of present study was to examine the IL-18 promoter polymorphism in patients with RA, and its association with disease susceptibility, activity and severity. We examined 309 patients with RA from a Polish population diagnosed according to the criteria of American College of Rheumatology. An allele-specific polymerase chain reaction was used for analysis of the polymorphisms in positions - 137 and - 607 in promoter region of IL-18 gene. A significantly decreased number of subjects with AC/AC and AG/AG diplotypes was observed among RA patients as compared with healthy controls (OR - 0.51, 95%CI 0.28-0.95, P = 0.045) and (OR - 0.12, 95% CI 0.02-0.97, P = 0.042), respectively. Nevertheless, there was no significant association with disease activity, joint erosions, extra-articular manifestations, rheumatoid factor. Above results suggest that IL-18-137 and - 607 promoter polymorphisms are not the significant factors influencing RA course and severity in a Polish population.     

IL-18与类风湿性关节炎

IL-18是一种多功能的炎性细胞因子，可强烈诱生IFN-γ，加强FasL介导的细胞毒效应，具有重要的免疫调节功能。近年研究发现，IL-18有增强免疫、抗肿瘤等作用，同时也参与某些自身免疫病、变态反应性疾病的发生，如类风湿性关节炎，它通过多种途径诱导IFN-γ产生，在类风湿性关节炎的发病机制中起着重要的作用。     

Tolicizumab在类风湿性关节炎中的应用

类风湿关节炎是以滑膜炎、慢性系统性炎症反应及自身抗体分泌为特点的自身免疫性疾病.已有研究结果表明,过量表达的IL-6在类风湿关节炎起病与进展过程中发挥着重要作用.Tolicizumab是第1个人源性的IL-6受体抗体,通过特异性识别结合IL-6受体而阻断IL-6生物学活性,发挥抑制类风湿关节炎炎症反应的作用.大量临床试...     

NRAMP1 gene polymorphisms in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with HLA-DR genes that share amino acid sequence motif QKRAA/QRRAA from position 70 to 74 in the third hypervariable region of DR1 molecule. The contribution of HLA in RA is however about 37%, suggesting a role for other genes. One such candidate is the gene that encodes natural resistance-associated macrophage protein (NRAMP1), which plays a crucial role in inflammation and tissue destruction. In the present study, we examined the role of NRAMP1 gene polymorphisms in susceptibility to RA. The results show that variation at position 543 in exon 15, which involves substitution of negatively charged aspartic acid (D) by uncharged asparagine (N), and the deletion of TGTG in the 3' UTR may confer protection from development of RA.     

Association of rheumatoid factor production with FcgammaRIIIa polymorphism in Taiwanese rheumatoid arthritis

Fcgamma receptors (FcgammaR) impact upon the development of inflammatory arthritis through immune complex stimulation and proinflammatory cytokine production. FcgammaRIIa, FcgammaRIotaIotaIotaa and FcRgammaIIIb polymorphisms were genotyped in 212 rheumatoid arthritis (RA) patients and 371 healthy control subjects using an allelic-specific polymerase chain reaction (PCR). No significant skewing in the distribution of FcgammaRIIa H/R131, FcgammaRIIIa F/V158 and FcgammaRIIIb NA1/NA2 was found between RA patients and healthy control subjects. However, a significant skewing distribution of the FcgammaRIIIa F/V158 polymorphism was observed between rheumatoid factor (RF)-positive versus RF-negative RA patients (P = 0.01). The low-affinity FcgammaRIIIa F158 allele seems to have a protective role in RF production, in comparison with the FcgammaRIIIa V158 allele (P = 0.004; OR = 0.485; 95% CI: 0.293-0.803). A high frequency of FcgammaRIIIa F/F158 was identified in RA patients with negative RF compared with RF-positive patients (for FF158 versus FV158 + VV158; P = 0.002; OR = 0.372; 95% CI: 0.194-0.713). In addition, no association was found between FcgammaRIIa H/R131, FcgammaRhoIIIa F/V158 and FcgammaRIIIb NA1/NA2 polymorphisms and other clinical parameters. The results of this study suggest that three activating FcgammaRs polymorphisms lack association with RA but FcgammaIIIa F/V158 polymorphism may influence RF production and IgG RF immune complex handling in Taiwanese RA patients.     

地高辛标记人IL-2cDNA探针的制备及临床初步应用

目的：制备ＩＬ－２地高辛标记探针,探讨类风湿关节炎（ｒｈｅｕｍａｔｏｉｄａｒｔｈｒｉｔｉｓ,ＲＡ）患者外周血淋巴细胞ＩＬ－２ｍＲＮＡ的表达情况。方法 采用斑点杂交技术,对６例正常对照和１２例ＲＡ患者进行研究,结果：（１）从ｐＵＣ１２质粒子扩增制备了长度为１ｋｂ和ＩＬ－２ｃＤＮＡ片段,用地高辛标记后制备探针,其敏感性达１ｐｇ同源ＤＮＡ,且特异性较高,（２）１２例ＲＡ患者外周血淋巴细胞ＩＬ－２ｍＲＮＡ     

CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis

Cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms located in the promotor region at positions -318 (C/T) and in exon 1 (49 A/ G) were investigated in 138 Spanish patients (37 men and 101 women) with rheumatoid arthritis and in 305 ethnically-matched healthy controls. When the allelic and genotypic frequencies corresponding to the CTLA4 -318 position were compared, no significant differences between patients and controls were found. However, when the CTLA4 49 A/G polymorphism was analysed, a significant increase of A/G heterozygous individuals among female patients (48.5% vs. 33.8% in controls; P=0.008; OR=2.0) was observed. This increase was absent among males (37.8%, P=NS). Analysis of the CTLA4 49 polymorphism with respect to HLA-DRB1 typing demonstrated a significant increase of A/G heterozygosity in the HLA-DR3-positive patient group compared with HLA-DR3-negative patient group (14/19, 74% vs. 49/119, 41%; P=0.009, OR=4.0). The increase of A/G genotype among HLA-DR3-positive patients was found in both males (4/6, 67%) and females' (10/13, 77%), although statistical differences were only reached in the female group. These results provide new insight into this complex association, confirm previous data from other studies, and suggest that the CTLA4 gene could be involved in the pathogenesis of rheumatoid arthritis.     

Heat shock protein 70 gene polymorphisms in rheumatoid arthritis

A role for heat shock proteins (hsp) in rheumatoid arthritis has been suggested. In addition, the specific binding of human HSP70 protein to QKRAA and RRRAA motifs within the HV3 region of disease-associated DRB1*0401 and DRB1*1001 molecules, respectively, has been proposed as being relevant to rheumatoid arthritis. The purpose of this work was to analyze the influence of HSP70 gene polymorphism on the susceptibility to or severity of rheumatoid arthritis and to investigate the possible contribution of these HSP70 polymorphisms in determining HLA-DRB1*0401/*1001 disease association. The frequencies of the HSP70-1, HSP70-2 and HSP70-hom genotypes were analyzed by PCR-RFLP using BsrBI , Pst I and Nco I enzymes, respectively, in patients with heumatoid arthritis and in healthy controls. No significant differences were observed when HSP70 alleled istribution between the groups under study were compared. Moreover, we did not observe any significant difference in HSP70 allele frequencies between patients positive for HLA-DRB1*0401/*1001 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms do not appear to be relevant in the susceptibility to or severity of rheumatoid arthritis.     

Analysis of two T-cell receptor BV gene segment polymorphisms in caucasoid Brazilian patients with rheumatoid arthritis

Considering the role of T-lymphocytes in rheumatoid arthritis (RA) and a possible involvement of the TCR in the pathology of this disease we analyzed allelic and genotypic frequencies of variants of two TCRBV gene segments (TCRBV3S1 and TCRBV18) in RA. A total of 95 caucasoid South Brazilian RA patients were genotyped for both TCRBV gene segment variants by restriction fragment length polymorphism preceded by PCR (PCR-RFLP) and the obtained frequencies were compared to those from healthy individuals. Allelic frequencies for the TCRBV3S1 gene segment were, respectively, for RA patients and controls, 0.447 and 0.545 (allele 1) and 0.553 and 0.455 (allele 2). Allelic frequencies for the TCRBV18 gene segment were, respectively, for RA patients and controls, 0.824 and 0.806 (allele 1) and 0.176 and 0.194 (allele 2). Neither allelic frequencies nor genotypic frequencies differ among RA and healthy individuals, suggesting that there is not a direct association among the TCRBV allelic variants studied and the development of RA and thus excluding the possibility of use of these gene segment polymorphisms as RA susceptibility markers.     

Tumor necrosis factor locus polymorphisms in rheumatoid arthritis

We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.     

Cross-reactive rheumatoid factors in rheumatoid arthritis with extra-articular disease.

Rheumatoid factors (RF) have been shown to have considerable heterogeneity and bind with IgG as well as with a variety of substances such as nuclear histone, non-histone nuclear protein, nitrophenyl groups or ssDNA. We describe evidence that polyclonal RF cross-reactive with ssDNA (CRRF) are widely distributed in a variety of rheumatic diseases, and that their serum level is significantly higher in rheumatoid arthritis (RA) with extra-articular disease. Although the mechanism of the cross-reactivity is not clear, the presence of CRRF could be a serological feature of a clinical subset of RA. The high prevalence rate of CRRF in RA with extra-articular disease also suggests its pathogenetic role in the extra-articular manifestation of this disease.     

HLA-DRB1*01 and DRB1*04 alleles in Sardinian rheumatoid arthritis patients

In Sardinia, like in other Caucasoid populations, rheumatoid arthritis (RA) is significantly associated with HLA-DR4 and DR1 antigens. To discover which DR4 and DR1 alleles were associated with the disease we selected 22 Sardinian patients affected by RA. Fifty DR4+ and 28 DR1+ healthy individuals coming from the same geographical area were used as controls. In the Sardinian patients only two DRB1*04 alleles were observed: DRB1*0405 in 11 and DRB1*0403 in three patients. The DRB1*0102 allele was observed in two patients and DRB1*0101 in six patients. Hereditary predisposition to RA in Sardinia therefore seems to be almost exclusively associated with the DRB1*0405 and DRB1*0101 alleles which share the 67LLEQRRAA74-85VG86 epitope in the peptide binding groove.     

UBASH3A gene polymorphisms and expression profile in rheumatoid arthritis

Objectives: Recent evidence has demonstrated that UBASH3A play a pivotal role in multiple autoimmune diseases. In this study, we explored the association between UBASH3A gene single-nucleotide polymorphisms (SNPs) and rheumatoid arthritis (RA) in a Chinese Han population. We also comparatively evaluated the UBASH3A expression profile in peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls.

Methods: Four UBASH3A polymorphisms (rs1893592, rs11203203, rs2277798, and rs3788013) were studied in 553 patients with RA and 587 controls in a Chinese population. Genotyping was performed using the Fluidigm 192.24 Dynamic Array Integrated Fluidic Circuit (IFC). For gene expression study, UBASH3A mRNA levels of 30 RA patients and 31 healthy individuals were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Data were analyzed by SPSS 19.0 software.

Results: A significant association between rs1893592 polymorphism and RA was found under all genetic models (all p<.05). We also discovered a significant association between rs3788013 polymorphism and RA in the allele and genotype distributions, as well as the recessive model (all p<.05). Moreover, we found the genotype distribution and allele frequency of rs1893592 were significantly associated with RF phenotype in the RA patients (χ²?=?6.786, p=.034; χ²?=?4.534, p=.033; respectively). We also found the genotype distribution and allele frequency of rs2277798 were significantly associated with anti-CCP phenotype in the RA patients (χ²?=?7.873, p=.020; χ²?=?4.473, p=.034; respectively). However, we did not detect any significant associations between rs11203203 and RA susceptibility and autoantibody profiles (all p>.05). The mRNA expression of UBASH3A was increased in PBMCs of patients with RA when compared to healthy controls (p=.001).

Conclusions: Our observations suggested that the dysregulation of UBASH3A might be associated with the pathogenesis of RA, and UBASH3A gene polymorphisms (rs1893592 and rs3788013) might contribute to RA susceptibility in Chinese Han population.     

Association between polymorphisms in the human chemokine receptor genes CCR2 and CX3CR1 and rheumatoid arthritis

Cell trafficking into the rheumatoid synovium is thought to play an important role in the inflammation seen in rheumatoid arthritis. Chemokine receptors play a central role in this process, and several common variants are known, including the CCR2 variant, CCR2-64I, and two variants of the CX3CR1 gene, V249I and T280M. All three variants result in functional amino acid substitutions. We studied the association of these chemokine receptor variants with susceptibility to and severity of rheumatoid arthritis in two Dutch patient populations; 282 consecutive rheumatoid arthritis patients from a rheumatology outpatient clinic, and a cohort of 101 female rheumatoid arthritis patients, followed closely for a 12-year period, from whom hand and feet X-rays taken at three year intervals were scored and analyzed in this study. Although there was a trend towards increased severity of disease in patients carrying CX3CR1 variants, this was not independent of known risk factors. We found no evidence for a significant independent role for the CCR2 and CX3CR1 variants in the susceptibility to or severity of rheumatoid arthritis.     

Cytotoxic T-lymphocyte antigen-4-CT60 polymorphism in rheumatoid arthritis

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a functional candidate gene with susceptibility to rheumatoid arthritis (RA). The aim of this work was to investigate the possible influence of the recently described CT60A/G dimorphism of the CTLA-4 gene in the susceptibility to RA in Spanish patients. A total of 433 RA patients and 398 control subjects were included in the study. Genotyping of CTLA-4 CT60 was performed using two different methods: polymerase chain reaction restriction fragment length polymorphism system using an amplification-created restriction site and a TaqMan 5'-allelic discrimination assay. In order to validate results obtained by different methods, a quality-control exercise was performed. No significant deviation in the distribution of the alleles or genotypes of the CT60 was found when we compared RA patient and control groups. In addition, no differences in CTLA-4 CT60 genotypic distribution was found when RA patients and controls were stratified by the presence or absence of the shared epitope. In conclusion, our results do not support an association between CT60A/G polymorphism and susceptibility to RA in the Spanish population, although the contribution of other positions located within the 3' region of the CTLA-4 gene to RA susceptibility cannot be discarded.     

Intercellular adhesion molecule-1 polymorphisms in Korean patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by synovial proliferation and the accumulation of inflammatory cells in the affected joints. Intercellular adhesion molecule-1 (ICAM-1) is readily detected in RA synovial tissues and helps recruit inflammatory cells to the joint. ICAM-1 shows genetic polymorphisms at codons 241 (R241G) and 469 (K469E). In order to investigate the association between ICAM-1 gene polymorphisms and RA, we genotyped ICAM-1 R241G and ICAM-1 K469E polymorphisms in 143 Korean patients with RA, and in 138 healthy controls, by using the polymerase chain reaction-restriction fragment length polymorphism method. No polymorphism of R241G was found in Korean subjects. However, the frequency of the K469 allele was found to be significantly lower in RA patients than in healthy controls. Allele frequency of K469 was lower in RA patient group, compared to that in healthy controls, regardless of the shared epitope status. Distribution of K469E allele frequencies was not different whether the patient had rheumatoid factor, radiographic erosion or extra-articular complications. In conclusion, this study shows lower frequency of the ICAM-1 K469E allele in Korean patients with RA than that in healthy controls.     

HTRA1基因单核苷酸多态性与类风湿性关节炎的关联性研究

目的 探讨HTRA1基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)和类风湿性关节炎(rheumatoid arthritis,RA)及其患者血清类风湿因子(rheumatoid factor,RF)、C反应蛋白((C-reactive protein, CRP)之间的相关性.方法 采用Snapshot法测定344例RA患者和288名正常健康人HTRA1基因5个SNPs(rs2014307、rs2248799、rs2300433、rs714816、rs2268356)位点基因型,终点散射比浊法测定RA患者血清RF和CRP水平.结果 RA组HTRA1基因SNPs(rs2014307、rs2248799、rs2300433、rs714816、rs2268356)基因型与正常对照组间差异均无统计学意义(P>0.05),单倍型分析也显示H豫A1基因RA组与正常对照组间差异无统计学意义(P>0.05),RA患者HTRA1基闪SNPs位点(rs2014307、rs2248799、rs714816、rs2268356)不同基因型之间血清RF水平比较差异无统计学意义(P>0.05),而rs2300433位点基因型(AA+AG)组的RF水平明显高于GG组((P<0.05).结论 已分析的与HTRA1基因相关的5个SNPs与中国汉族人种RA遗传易感性不相关,HTRA1基因rs2300433位点不同基因型RA患者体内RF水平有差别,HTRA1基因表达的丝氨酸蛋白酶可能参与了RA患者RF的表达.