The −590 IL-4 promoter polymorphism in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The aim of the present study was to evaluate the –590 IL-4 promoter polymorphism in patients with RA and its association with disease activity and severity. We enrolled 94 patients with RA diagnosed according to the criteria of the American College of Rheumatology. Polymerase chain reaction amplification was used for analysis of the polymorphism at position –590 of the promoter of the IL-4 gene. The distribution of IL-4 genotypes in RA patients did not differ from control subjects. Nevertheless, the active form of RA was more frequently diagnosed in patients with T allele (genotypes CT and TT) as compared with homozygous CC patients. Moreover, in carriers of the T allele, parameters of disease activity (DAS 28 score, ESR, number of swollen and tender joints) were significantly increased. We suggest that the IL-4 –590 promoter polymorphism may be a genetic risk factor for RA severity.     

Allelic frequency of the MCP-1 promoter −2518 polymorphism in the Turkish population and in Turkish patients with juvenile rheumatoid arthritis

Although genetic and environmental factors contribute to the pathogenesis of juvenile rheumathoid arthritis (JRA), the etiology and pathogenesis remain controversial. The objective of this study was to investigate genotypic and allelic frequencies of monocyte chemoattractant protein-1 (MCP-1) gene −2518 (G/A) polymorphism in the healthy Turkish population and patients with JRA. Genomic DNA was collected from 66 JRA patients and 150 healthy individuals. To evaluate the association of the −2518 (G/A) MCP-1 gene polymorphism with the outcome of JRA, we analyzed the types of JRA and the score on the childhood health assessment questionnaire (C-HAQ score). In the healthy Turkish population, the frequencies of A and G alleles were 71 and 29%, respectively. No significant difference was observed between the JRA patients and healthy subjects in the distribution allelic and genotypic frequencies of the −2518 (G/A) MCP-1 gene polymorphism (p>0.05). However, the AG genotype was found to be higher and the AA genotype was found to be lower in the patients with systemic type JRA compared to those with the other types of JRA (p=0.019). When the JRA patients were evaluated according to the C-HAQ score, we found that the −2518 (G/A) MCP-1 gene polymorphism did not relate the prognosis (p>0.05). AG genotype was found to be higher in the systemic type of JRA. The results indicate that MCP-1 gene polymorphism might slightly associate with patients with systemic JRA. Further studies are needed to elucidate the role of this polymorphism in the pathogenesis of JRA in various populations because this polymorphism has a functional significance and an ethnic difference.     

The −383A>C TNFRI polymorphism is associated with soluble levels and clinical activity in rheumatoid arthritis

Tumor necrosis factor-α (TNF-α) plays a central role in inflammation, and it has been directly implicated in the pathogenesis of rheumatoid arthritis (RA). TNF-α activity is mediated through TNFRI and TNFRII cell surface receptors, which act as physiological attenuators of TNF-α activity. We recruited 190 RA patients and 190 healthy subjects (HS) in order to associate the −383A>C TNFRI polymorphism with sTNFRI levels and DAS28 score in RA. In results, sTNFRI levels were higher in RA patients than HS (P = 0.04). The −383A>C TNFRI polymorphism did not show significant differences in both studied groups. However, in the RA group the sTNFRI levels were significantly elevated (P = 0.004) in A/A genotype carriers. In addition, the A/A genotype carriers had the higher DAS28 score than A/C genotype (P = 0.02). These data suggest that −383A>C TNFRI polymorphism is not a susceptibility marker in RA, whereas the increased levels of sTNFRI could reflect the clinical activity in RA patients.     

The −844 G/A <Emphasis Type="Italic">PAI-1</Emphasis> polymorphism is associated with mRNA expression in rheumatoid arthritis

We assessed whether the −844 G/A polymorphism and mRNA expression of plasminogen activator inhibitor 1 (PAI-1) gene are associated with rheumatoid arthritis (RA). Demographic data, hematological, biochemical parameters, disease activity–disability indexes, −844 G/A genotypes and mRNA expression levels of the PAI-1 gene were determined in 50 RA patients and 50 healthy subjects (HS). Non-significant differences in genotype and allele frequencies related to −844 G/A polymorphism in RA versus HS, were found. High mRNA expression of the PAI-1 gene, was demonstrated in RA versus HS (P < 0.05). In addition, A/A genotype carriers showed increase of PAI-1 mRNA expression (3.1-fold) respect to G/G and G/A genotypes in RA patients (P < 0.05). Our finding suggest an association of A/A −844 PAI-1 genotype with high PAI-1 mRNA expression in RA patients.     

Genetic polymorphism of 3′ untranslated region of zeta-chain associated protein kinase 70 kDa in southern Taiwanese patients with rheumatoid arthritis

Clinical Rheumatology - T cell activation participates in the pathogenesis of rheumatoid arthritis (RA), and the signaling molecule zeta-chain-associated protein kinase 70&nbsp;kDa (ZAP-70)...     

Tumour necrosis factor a −308 promoter polymorphism in patients with rheumatoid arthritis

There are controversial reports that TNF-a promoter polymorphism may be an independent marker of susceptibility to rheumatoid arthritis (RA). We used Polymerase chain reaction amplification and Restriction fragment length polymorphism for analysis of the polymorphism at position -308 in promoter of TNF-α gene in 34 patients with RA and 30 healthy individuals. Distribution of TNF-genotypes in RA patients did not differ from that in controls. Moreover, there was apparent association between the -308 TNF-α polymorphism and erosions in hand x-Ray was found (P value = 0.043). We suggest that TNF-α -308 promoter polymorphism is not a genetic risk factor for RA susceptibility but may be associated with radiographic damage in rheumatoid patients. All work was funded by the Chancellor for Research of Mashhad University of Medical Science.     

Monocyte chemoattractant protein-1 ?2518 polymorphism is not associated with diabetic retinopathy in Japanese type 2 diabetes

To clarify whether polymorphism of monocyte chemoattractant protein-1 (MCP-1) were related to diabetic retinopathy (DR), we performed a case–control study in 175 Japanese type 2 diabetic patients participating in a multi-center research protocol. Genetic analysis was performed using a fluorescent allele-specific DNA primer assay system. DR was diagnosed in a masked manner by an independent ophthalmologist using fundus photographs and was classified as non-diabetic retinopathy (NDR), non-proliferative retinopathy (NPDR), and proliferative retinopathy (PDR). The results showed that the genotype frequencies of the MCP-1 gene at position ?2518 were not significantly different among patients with NDR, NPDR and PDR. Multivariate logistic regression analyses showed that significant associations were observed between DR and age, diabetes duration, systolic pressure, and HbA₁c, but not polymorphisms of the MCP-1 gene at position ?2518. In conclusion, the present study demonstrated no association between polymorphism of MCP-1 gene at position ?2518 and DR in Japanese type 2 diabetic patients.     

The −374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients

Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the −374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications.Methods The AGER −374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin.Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER −374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE −374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p<0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA_1c values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02).Conclusions/interpretation Our results show an association between the AGER −374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA_1c-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.     

Interleukin 8 gene 2767 A/G polymorphism is associated with increased risk of nephritis in children with Henoch–Schönlein purpura

The objective of this study is to investigate the association between IL-8 gene 2767 G/A polymorphism and clinical features, kidney involvement and prognosis in childhood Henoch Schnölein purpura (HSP). A total of 115 patients with HSP (59 male, 56 female) were included in the study with age at diagnosis between 2 and 17 years (8.0 ± 3.0). Hundred and eight healthy adults were included in the study as controls. The patients had been followed up for kidney involvement for at least 6 months and in average 8.2 ± 7.5 months. Interleukin 8 (IL–8) gene 2767 G/A polymorphism was studied by PCR–RFLP method. Frequency of the “A” allele was 0.37 in the patient group, whereas it was 0.36 in the control group. The difference was not statistically significant (P = 0.696). No association was detected between the IL-8 gene G/A polymorphism and the clinical, laboratory, and demographic data related to the patients with HSP. Kidney involvement was more common in those with the G/A polymorphism of the IL-8 gene. While a 0.44 frequency of the “A” allele was detected in those with kidney involvement, this rate was 0.29 in those with no kidney involvement (P = 0.046). Follow-up of those with the “A” allele revealed higher proteinuria (P = 0.023, odds ratio 0.176, 95% CI 0.034–0.917) and higher creatinine levels (P = 0.049, odds ratio 0.024, 95% CI 0.036–0.094). These results suggest that the kidney involvement is more common in patients with the “A” allele, and degree of proteinuria and creatinine levels is higher in these patients at follow-up.     

Tumor necrosis factor alpha −308 polymorphism is associated with rheumatoid arthritis in Han population of Eastern China

The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) in tumor necrosis factor alpha (TNFα) promoter with rheumatoid arthritis (RA) in Chinese Han population. Six SNPs at positions −238, −244, −308, −376, −857, −863 within TNFα promoter were genotyped in 367 unrelated RA patients and 271 healthy controls, using direct DNA sequencing method. Allelic, genotypic, and haplotypic associations of these SNPs with RA were examined. The frequencies of TNFα −308A allele and the haplotype GACC (in order of −238, −308, −857, −863) were significantly lower in RA patients when compared with healthy controls (P = 0.0046, P = 0.0045, respectively) but TNFα −308 polymorphism was not related to the clinical manifestations of RA patients. These results implied that TNFα gene itself or a gene in linkage disequilibrium with it might be associated with RA in Han population of Eastern China. R. Chen, M. Fang, Q. Cai are equally contributed to the work.     

Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab in Japanese patients with rheumatoid arthritis

Objectives: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis.

Methods: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients’ charts.

Results: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p?=?0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p?=?0.01).

Conclusions: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.     

The new antirheumatic drug KE-298 suppresses monocyte chemoattractant protein (MCP)-1 and RANTES production in rats with adjuvant-induced arthritis and in IL-1β-stimulated synoviocytes of patients with rheumatoid arthritis

We analyzed the effects of the new antirheumatic drug KE-298 on monocyte chemoattractant protein (MCP)-1 and regulated on activation normal T-cell expressed and secreted (RANTES) production in rats with adjuvant-induced arthritis and in interleukin (IL)-1beta-stimulated rheumatoid arthritis (RA) synoviocytes. In rats with adjuvant-induced arthritis, the enhanced production of MCP-1 and RANTES and the development of arthritis were suppressed by oral treatment with 100 mg/kg per day of KE-298 for 18 days. Furthermore, KE-298 (10-100 microg/ml) suppressed MCP-1 and RANTES production by IL-1beta-stimulated RA synoviocytes through inhibition of NF-kappaB and AP-1 activation. These results suggest that the inhibitory effect of KE-298 on MCP-1 and RANTES production might partly explain its efficacy in rats with adjuvant-induced arthritis and in patients with RA.     

No relationship of −627 interleukin-10 promoter polymorphism in Chinese patients with rheumatoid arthritis

Abstrtact The aim of this study was to examine whether –627 interleukin-10 (IL-10) promoter polymorphism is a marker of susceptibility to or severity of rheumatoid arthritis (RA) in Chinese patients in Taiwan. The study included 198 Chinese patients with RA. One hundred unrelated healthy individuals living in central Taiwan served as the control subjects. The relationship between IL-10 gene polymorphism and clinical manifestations of RA was evaluated. For the genotype, allelic frequency, and carriage rate of IL-10 polymorphism, there were no statistically significant differences found between patients and controls. Furthermore, we did not detect any association of IL-10 genotype with rheumatoid factor (RF), extra-articular involvement, or bone erosion in the RA patients. The lack of association of –627 IL-10 gene polymorphism with RA and the clinical findings in our study implies that the IL-10 gene polymorphism cannot serve as a candidate gene marker for screening RA patients.     

The PNPLA3 rs738409 C > G polymorphism is associated with the risk of progression to cirrhosis in NAFLD patients

Background and aims: The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C?>?G single nucleotide polymorphism (SNP) has been associated with steatosis and fibrosis in previous NAFLD populations in which cirrhotic patients were very poorly represented. Since not all NAFLD with fibrosis evolve to cirrhosis, we investigated the specific risk of cirrhosis conferred in NAFLD patients by carrying this SNP. Methods: Three groups were studied: patients with NASH-cirrhosis; patients with biopsy-proven non-cirrhotic NAFLD; healthy subjects undergoing medicine check-ups. Epidemiological, anthropometric, and clinical data were collected, and the SNP was analyzed by pyrosequencing. Results: Sixty-one patients with NASH-cirrhosis, 60 with non-cirrhotic NAFLD, and 125 healthy controls were included. Frequency of the PNPLA3 minor (G) allele was increased in patients with NASH-cirrhosis compared with non-cirrhotic NAFLD and controls (allele frequency: 0.598 versus 0.367 versus 0.2, respectively, p?p?Conclusions: In NAFLD patients, carriage of the PNPLA3G allele, and particularly of the GG genotype, is significantly associated with the risk of cirrhotic evolution. If confirmed in larger series, these results would suggest that most of NASH cases require the contribution of an altered PNPLA3 function to progress until cirrhosis.     

Association of the ?1082 G/A promoter polymorphism of interleukin-10 gene with the autoantibodies production in patients with rheumatoid arthritis

Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate the downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory; for example, the activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of the IL-10 gene may contribute to the regulation of autoantibodies production. To examine the putative association between the −1082 G/A polymorphism in the promoter region of the IL-10 gene and the susceptibility to disease onset and severity of RA, a total of 144 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. Radiographic progression of RA was scored according to the Sharp/van der Heijde method. Serum levels of rheumatoid factors (RFs) were measured by enzyme-linked immunosorbent assay. Polymerase chain reaction amplification was used for the analysis of the promoter polymorphism of the IL-10 gene. We observed significant differences in genotype distribution of the −1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (P _g = 0.006), IgA RF (P _g = 0.05), and IgG RF (P _g = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association between the −1082 G/A polymorphism in the IL-10 gene promoter and the production of RFs in RA patients.     

A novel genetic polymorphism of inducible nitric oxide synthase is associated with an increased risk of gastric cancer

AIM:Inducible nitric oxide synthase(iNOS)plays a central role in the pathway of reactive oxygen and nitrogen species metabolism when Helicobacter pylori(H pylori)infection occurs in humans,iNOS Ser~(608)Leu allele,a novel genetic polymorphism(C/T)occurring within exon 16 of the iNOS reductase domain,may have a dramatic effect on the enzymatic activity.The aim of this study was to determine whether iNOS C/T polymorphism was associated with increased susceptibility to gastric cancer. METHODS:We conducted a population based case-control study in a high gastric cancer incidence area,Yangzhong, China.Questionnaires from 93 patients with intestinal type gastric cancer(IGC),50 with gastric cardia cancer(GCC) and 246 healthy controls were obtained between 1997 and 1998,and iNOS genotyping was carried out.Odds ratios (ORs),interaction index(γ),and 95% confidence intervals for the combined effects of iNOS genotype and H pylori infection,cigarette smoking or alcohol drinking were estimated. RESULTS:The frequency of(CT -TT)genotypes was higher in cases than in control group(24.48% vs23.17%),but the difference was not statistically significant.After adjusting for age and gender,past cigarette smokers with(CT TT) genotypes had a significantly increased risk of IGC(OR=3.62, 95% CI:1.23-10.64),while past alcohol drinkers with (CT TT)genotypes had a significantly increased risk of GCC(OR=3.33,95% CI:1.14-9.67).H pylori CagA negative subjects with(CT TT)genotypes had a significantly increased risk of both IGC and GCC(OR=2.19 and 3.52,respectively). CONCLUSION:iNOS Ser~(608)Leu allele may be a potential determinant of susceptibility to cigarette -alcohol induced gastric cancer,but larger studies are needed to confirm the observations.     

The Fcγ receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia

Objective

A gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fcγ receptor IIa (FcγRIIa). The R allele is associated with increased binding of CRP and enhanced activation of monocytes. FcγRIIa is also expressed on endothelial cells, and we hypothesized this polymorphism would be associated with alterations of endothelial function.

Methods

Genomic DNA was extracted and allele-specific PCR reactions were used to determine the FcγRIIa H131R polymorphism in 78 hypercholesterolaemic subjects. Using strain gauge plethysmography, forearm blood flow (FBF) responses were determined to intra-arterial infusion of acetylcholine (ACH), for endothelium-dependent vasodilatation (EDV), to nitroprusside (NP), for endothelium-independent vasodilatation (EIV), to NG-monomethyl-l-arginine (l-NMMA), for basal NO activity, and to ACH in the presence of l-NMMA, to assess the contribution of NO release to EDV.

Results

Homozygous carriers of the H allele (n = 30) had significantly better EDV than homozygous carriers of the R allele (n = 15), while heterozygotes showed an intermediate phenotype (n = 33) (e.g. % increase of FBF to ACH 48 μg/min: 527 ± 359% in H/H versus 452 ± 262% in H/R versus 332 ± 413% in R/R, p = 0.0012 by 2-way ANOVA). EIV and basal NO activity were not affected by genotype, and co-infusion of l-NMMA abolished the differences in EDV.

Conclusions

The R allele of the FcγRIIa polymorphism is associated with impaired EDV and reduced NO activity during endothelial cell stimulation. These data suggest that the functional effects of the FcγRIIa H131R gene polymorphism previously observed in vitro translate into clinically relevant alterations of endothelial function in vivo.