Association of 86 bp variable number of tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL1RN) with susceptibility and clinical activity in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. Several studies have reported a variable number of tandem repeat (VNTR) 86 bp (rs2234663) in the intron 2 of IL1RN gene with RA risk. The present study was designed to determine the frequencies of this polymorphism in patients with RA and control subjects (CS) and its association with RA in a western Mexican population. An analytical cross-sectional study was performed, in which 350 patients with RA and 307 CS were included. The identification of IL1RN VNTR polymorphism was carried out by polymerase chain reaction (PCR), and genotypes were associated with clinical variables (DAS28 and CRP). The presence of A1/A2 genotype was associated with RA risk (p = 0.03, OR = 1.45, 95% CI = 1.02–2.05). Also, results indicate that the presence of heterozygote genotypes which include A2 was associated with RA risk (p = 0.01, OR = 1.5, 95% CI = 1.07–2.11). Patients carrier of A2/A2 genotype have a higher score of DAS28 (5.64 [4.49–6.70]). A-/A- has higher level of CRP (2.30 [0.62–9.10]) in comparison with A2/A- (1.06 [0.37–2.82]). A1/A2 genotype was associated with susceptibility to RA in a western Mexican population. The presence of the A2/A2 genotype in RA is associated with increased disease activity.     

A meta-analysis of the association of IL-6 −174 G/C and −572 G/C polymorphisms with systemic lupus erythematosus risk

The results from previous studies on association of IL-6 ?174 G/C and ?572 G/C polymorphisms with the risk of systemic lupus erythematosus (SLE) remained inconsistent. Therefore, a meta-analysis was performed to assess the association between these two polymorphisms and SLE susceptibility. A literature-based search was conducted to identify all relevant studies. Pooled data were estimated by fixed- and random-effects models when appropriate. Nine publications were included in the meta-analysis, seven for ?174 G/C polymorphism and three for ?572 G/C polymorphism. The results indicated that IL-6 ?174 G/C polymorphism was significantly associated with SLE risk for recessive model and allele analysis in overall populations (OR 1.64, 95 % CI 1.10–2.45, P = 0.016; and 1.34, 1.05–1.72, P = 0.019, respectively, for recessive model and allele analysis) or in Caucasians (OR 1.37, 95 % CI 1.04–1.82, P = 0.027; and 1.27, 1.04–1.54, P = 0.018, respectively, for recessive model and allele analysis). Also, significant association between IL-6 ?572 G/C polymorphism and SLE was found under recessive model (OR 1.49, 95 % CI 1.10–2.01, P = 0.009), but not under dominant model and allele analysis (OR 1.05, 95 % CI 0.77–1.43, P = 0.750; and 1.21, 1.00–1.48, P = 0.054, respectively, for dominant model and allele analysis). Additionally, our meta-analysis showed that IL-6 ?174 G/C polymorphism was significantly associated with discoid skin lesions (P < 0.05). The present study indicates that IL-6 ?174 G/C and ?572 G/C polymorphisms could be candidates for susceptibility to SLE. Furthermore, a large number of studies should be performed to explore the association of IL-6 polymorphisms with the risk and clinical characteristics of SLE patients in different ethnics.     

Associations of the TNF-alpha -308 G/A, IL6 -174 G/C and AdipoQ 45 T/G polymorphisms with inflammatory and metabolic responses to lifestyle intervention in Brazilians at high cardiometabolic risk

Background

Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals.

Method

32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements.

Results

Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R?=?0.49, p?=?0.011) and protein (R?=?0.51, p?=?0.004) expression, as well as with circulating adiponectin levels (R?=?0.46, 0?=?0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R?=??0.61, 0?=?0.003) and adipocyte cell size (R?=??0.40, p?=?0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals.

Conclusions

In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.     

Association between interleukin- 1β- 511( C/T) gene polymorphism and early diabetic kidney disease

<正>Objective To investigate the association between interleukin(IL)-1β-511(C/T)gene polymorphism and early diabetic kidney disease(EDKD)in Han population in Luzhou.Methods A total of 548 patients with type 2diabetes(T2DM)were enrolled in this study and divided into two groups:T2DM with normal albuminuria group(NA group,n=286)and T2DM with micro-albuminuria group(MA group,n=262).327 healthy subjects were     

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.     

Clinical significance of serum interleukin-6 and −174 G/C promoter polymorphism in Rheumatoid arthritis patients

Aim of the workTo evaluate the clinical significance of serum levels of interleukin-6 (IL-6) and ?174 G/C promoter polymorphism in Rheumatoid arthritis (RA) patients.Patients and methodsWe studied 37 RA patients and 10 age and gender matched healthy controls. Demographic, clinical and serological data were prospectively evaluated. Disease activity score (DAS28) and Health Assessment Questionnaire (HAQ) were assessed. Serum IL-6 level was measured and promoter (?174G/C) genotyped.ResultsSerum IL-6 levels were significantly higher in RA patients compared to control (p = 0.04), especially those with CC promoter polymorphism. Twenty-four patients had GG IL-6 (?174 G/C) gene promoter polymorphism, 11 were GC and 2 CC. Nine controls were GG and 1 GC. In patients with more advanced polymorphism (?174 CC) there was a significantly increased functional impairment (HAQ score) (p = 0.029) and platelet count (p = 0.049). In those with GG genotype, there was a significant correlation between IL-6 and Morning stiffness duration (r = 0.44,p = 0.03), while those with GC genotype had a significant negative correlation of the IL-6 level with the parameters of disease activity and the DAS28 (r = ?0.69,p = 0.019). None of the studied parameters would predict the IL-6 promoter polymorphism.ConclusionSerum IL-6 levels and ?174 G/C promoter polymorphism were higher in RA patients than in healthy controls. The inverse relation of IL-6 with the DAS28 in those with an increased IL-6 promoter polymorphism may confirm its increased involvement in the pathogenesis of RA and in the increased disease activity which may point to the need for considering of anti-IL-6 agents in their management plan.     

Could the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) be a valid measure of disease activity in patients with psoriatic arthritis?

Objective

To determine whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) could be a valid indicator of disease activity in psoriatic arthritis (PsA).

Methods

Patients with PsA identified from a disease‐register and case‐note review answered a questionnaire by mail (n = 133); some patients (n = 86) consented to examination. In a second sample of 47 consecutive clinic attendees with PsA, logistic regression examined the independent contribution of BASDAI to disease activity, as judged by treatment decisions at that time.

Results

BASDAI correlated highly with patient perception of disease activity (r = 0.739) and there was no significant effect of the pattern of disease (axial or peripheral) on this relationship. However, only physician perception of disease activity was significantly associated with high or low disease activity (odds ratio 18.4, 95% confidence interval 2.9–118.3). BASDAI, patient perception, and erythrocyte sedimentation rate failed to contribute significantly to the model.

Conclusion

BASDAI performs similarly for axial and peripheral PsA but does not correlate well with external indicators of disease activity, such as treatment decisions.

     

Could the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) be a valid measure of disease activity in patients with psoriatic arthritis?

OBJECTIVE: To determine whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) could be a valid indicator of disease activity in psoriatic arthritis (PsA). METHODS: Patients with PsA identified from a disease-register and case-note review answered a questionnaire by mail (n = 133); some patients (n = 86) consented to examination. In a second sample of 47 consecutive clinic attendees with PsA, logistic regression examined the independent contribution of BASDAI to disease activity, as judged by treatment decisions at that time. RESULTS: BASDAI correlated highly with patient perception of disease activity (r = 0.739) and there was no significant effect of the pattern of disease (axial or peripheral) on this relationship. However, only physician perception of disease activity was significantly associated with high or low disease activity (odds ratio 18.4, 95% confidence interval 2.9-118.3). BASDAI, patient perception, and erythrocyte sedimentation rate failed to contribute significantly to the model. CONCLUSION: BASDAI performs similarly for axial and peripheral PsA but does not correlate well with external indicators of disease activity, such as treatment decisions.     

Association of FAS (TNFRSF6)-670 gene polymorphism with villous atrophy in coeliac disease

AIM:To investigate the association of FAS gene polymorphismwith coeliac disease (CD) development.METHODS:FAS-G670A gene polymorphism,located in agamma interferon activation site,was studied in 146 unrelatedCD patients and 203 healthy ethnically matched controls.Therestriction fragment length polymorphism (RFLP) method wasused to identify FAS-G670A gene polymorphism.RESULTS:No significant difference was found in genotypefrequency between CD cases and controls.In controls,however,the frequency of the GGgenotype was significantlyhigher in women (26.5%) than in men (12.8%) (OR=2.44,95% CI 1.15-5.20,P=0.020) and it was also higher in menwith CD than controls (OR=2.60,95% CI 0.96-7.05,P=0.061).The GG genotype frequency was significantly higher inpatients with most severe villous atrophy (Marsh Ⅲc lesions)(OR=3.74,95% CI 1.19-11.82,P=0.025).A significantlyless proportion of men suffered from Marsh Ⅲc lesions thanwomen (OR=0,20,95% CI 0.06-0.68,P=0.01).The risk ofhaving severe villous atrophy increased with the additiveeffect of the Gallele in women (P=0.027 for trend,age andgender adjusted).CONCLUSION:FAS-G670A gene polymorphism is associatedwith the severity of villous atrophy in CD.Female gender isalso associated with the severity of villous atrophy.     

Association between ‘interleukin’ 10 gene (IL10) polymorphisms and systemic sclerosis with interstitial lung involvement

Systemic sclerosis (SSc), also termed as “scleroderma”, is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities and immune dysfunction. Extracellular matrix (ECM) production by fibroblasts in SSc is modulated and regulated by cytokines. Since IL10 has antiinflamatory properties and, contributes to the fibrotic processes in SSc, we analyzed IL-10 gene polymorphisms including −1082 G/A, −819 C/T and −592C/A in 45 systemic sclerosis patients with lung involvement and 150 healthy control using ARMS-PCR. While no association was found between SSc and −819C/T, −592C/A polymorphism, −1082 G/A allele frequency in SSc patients was higher than that in control and significant association was found between SSc and −1082 G/A (Pc: <0.000, OR: 2.85 95% CI: 1.74–4.63). In addition significant difference was found between the frequencies of the IL-10 GCC, ACC haplotypes (Pc: <0.000, OR: 2.85, 95% CI: 1.74–4.63; Pc: 0.012, O.R: 1.56, 95% CI: 1.09–2.23, respectively), GCC⁺/GCC⁺, GCC⁻/GCC⁻ genotypes (Pc: 0.002, OR: 5.07, 95% CI: 1.82–14.21; Pc: <0.000, O.R: 4.00, 95% CI: 1.87–8.98, respectively) and SSc. Our findings suggest that IL-10 1082 G/A alleles or haplotypes containing these alleles may play role in SSc susceptibility.     

In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24?weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline

We aimed to evaluate the efficacy of tocilizumab in patients with rheumatoid arthritis (RA), using the clinical disease activity index (CDAI), and to determine the baseline variables associated with CDAI remission. Fifty-eight patients with active RA were enrolled. We tried to evaluate whether baseline variables were associated with CDAI remission at 24?weeks. Twenty-two of the 58 patients (37.9%) had received tumor necrosis factor (TNF) inhibitors. The continuation rate of tocilizumab at 24?weeks was 87.9%. The seropositivity rates of IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline were both 91.4%. The rate of CDAI remission at 24?weeks was 20.7%. We selected baseline variables including age, gender, duration of disease, concomitant use of glucocorticoids, concomitant use of methotrexate (MTX), previous anti-TNF therapy, titer of anti-CCP antibodies (high or low toward median), titer of IgM-RF (high or low toward median), and CDAI, and found that a high titer of IgM-RF was the only variable to be associated with CDAI remission, according to univariate and logistic regression analyses. This is a new finding, and may be specific to tocilizumab as compared with previous observations in anti-TNF therapy.     

A longitudinal study of the effect of disease activity and clinical damage on physical function over the course of psoriatic arthritis: Does the effect change over time?

OBJECTIVE: To investigate whether there are differential effects of disease activity and damage on physical functioning as measured by the Health Assessment Questionnaire (HAQ) over the course of psoriatic arthritis (PsA). METHODS: Between June 1993 and March 2005, 382 patients attending the University of Toronto PsA clinic had completed > or =2 HAQs on an annual basis. At the time of each HAQ assessment, clinical and laboratory measures of disease activity and damage were recorded. Generalized linear mixed-effects models were used to investigate the longitudinal relationship between disease activity, damage, and the HAQ score. To avoid floor effects that would arise in a single mixed-effects model, we adopted a 2-part model. RESULTS: The number of actively inflamed joints (measure of disease activity) and the number of clinically deformed joints (measure of damage) were positively and significantly related to the HAQ score. Furthermore, interaction terms for illness duration with the number of actively inflamed joints were statistically significant, with or without inclusion of the erythrocyte sedimentation rate and morning stiffness in the model (P = 0.029 and P < 0.001, respectively). The positive effects of actively inflamed joints on the level of the HAQ score decreased over increasing duration of PsA. There was less evidence to suggest that the positive effect of joint damage on the HAQ score increased over time. CONCLUSION: Our results support the view that the influence of disease activity on HAQ scores declines with increased disease duration. We could not demonstrate strong evidence that the effect of clinical damage increases over the course of illness.     

A longitudinal study of the effect of disease activity and clinical damage on physical function over the course of psoriatic arthritis: Does the effect change over time?

Objective

To investigate whether there are differential effects of disease activity and damage on physical functioning as measured by the Health Assessment Questionnaire (HAQ) over the course of psoriatic arthritis (PsA).

Methods

Between June 1993 and March 2005, 382 patients attending the University of Toronto PsA clinic had completed ≥2 HAQs on an annual basis. At the time of each HAQ assessment, clinical and laboratory measures of disease activity and damage were recorded. Generalized linear mixed‐effects models were used to investigate the longitudinal relationship between disease activity, damage, and the HAQ score. To avoid floor effects that would arise in a single mixed‐effects model, we adopted a 2‐part model.

Results

The number of actively inflamed joints (measure of disease activity) and the number of clinically deformed joints (measure of damage) were positively and significantly related to the HAQ score. Furthermore, interaction terms for illness duration with the number of actively inflamed joints were statistically significant, with or without inclusion of the erythrocyte sedimentation rate and morning stiffness in the model (P = 0.029 and P < 0.001, respectively). The positive effects of actively inflamed joints on the level of the HAQ score decreased over increasing duration of PsA. There was less evidence to suggest that the positive effect of joint damage on the HAQ score increased over time.

Conclusion

Our results support the view that the influence of disease activity on HAQ scores declines with increased disease duration. We could not demonstrate strong evidence that the effect of clinical damage increases over the course of illness.

     

What does "active disease" mean? patient and parent perceptions of disease activity in the systemic arthritis form of juvenile idiopathic arthritis (SO-JIA)

OBJECTIVE: The systemic onset form of juvenile idiopathic arthritis (SO-JIA) is a very serious chronic illness of childhood. At present, there is no specific tool to measure disease activity for SO-JIA. Our long-term goal is to develop a disease activity measure for SO-JIA using a consensus (Delphi) approach. In preparation for the development of this measure, we interviewed both patients and their parents. We sought to elicit specific items reflecting their perceptions of active disease that may be considered for inclusion in a disease activity measure for SO-JIA. METHODS: SO-JIA patients followed at The Hospital for Sick Children and their parents were chosen by purposive sampling. A trained research coordinator interviewed all participants using open-ended questions to elicit aspects of disease activity (defined as reversible manifestations of disease) of relevance to families. A list of these aspects was then generated and organized by categories to allow item reduction. RESULTS: Fourteen patients (eight females) with a mean age of 11.8 yr (mean disease duration 5.2 yr) and their parents were interviewed. A total of 292 items were generated, with an average of 11 items generated per interview. Arthralgia, ambulation difficulties, rash, decreased energy level and fever were the most common items mentioned by patients and their parents. Mood disturbances, decreased activity levels, arthritis severity and decreased school attendance were also common items identified as relevant aspects of disease activity. CONCLUSION: This study has allowed us to include patient and parent perspectives in preparation for developing a disease activity measure for SO-JIA. The resulting items will be added to future physician surveys in the further development and validation of a disease activity measure for SO-JIA.     

Impact of interleukin 6 promoter polymorphisms (−174 G > C, −572 G > C and −597 G > A) on plasma IL-6 levels and their influence on the development of DVT: a study from India

ABSTRACT

Objectives: To evaluate the association of interleukin 6 (IL-6) levels with deep vein thrombosis (DVT) and to assess the impact of IL-6 promoter polymorphisms (?174G?>?C, ?572G?>?C and ?597G?>?A) on its plasma levels and their influence in the development of DVT in India.

Methods: One hundred DVT patients and 100 age and sex-matched healthy controls were study subjects. IL-6 polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism. IL-6 levels were detected by enzyme-linked immunosorbent assay.

Results: Significantly raised IL-6 levels were observed in patients as compared to controls. (Patients: 13.73?±?6.30?pg/ml, Controls: 11.83?±?4.47?pg/ml, p?=?0.014). The prevalence of C allele of ?572G?>?C polymorphism was significantly higher in patients than controls (Patients: 39.5%, Controls: 27.5%, p?=?0.011, χ²=6.463). Subjects with GC and CC genotype had significantly higher IL-6 levels than GG genotype (p=<0.001). Patients with GC and CC genotype increased the DVT risk by 1.39 fold (OR^a: 1.39, CI: 0.74–2.62) and 2.69 fold (OR^a: 2.42, CI: 1.08–6.70), respectively. IL-6 ?174G?>?C and ?597G?>?A polymorphisms were not associated with raised IL-6 levels and nor with thrombotic risk (?174G?>?C: p?=?0.823 χ²=0.369; ?597G?>?A: p?=?0.678 χ²=1.08).

Conclusion: Our study emphasizes the importance of ?572G?>?C polymorphism in increasing IL-6 levels, thereby showing its significant role in DVT in India. IL-6 ?174G?>?C and ?597G?>?A were neither associated with raised plasma IL-6 levels nor with thrombotic risk. Thus ?572G?>?C polymorphism detection may be one of the connecting links between IL-6 and thrombotic risk in Indian DVT patients.     

Functional FCGR3A 158 V/F and IL-6 −174 C/G polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis: a meta-analysis

The aim of this study was to investigate whether the Fc gamma receptor 3A (FCGR3A) 158 V/F and interleukin-6 (IL-6) promoter ?174 G/C polymorphisms can predict the response to biologic-based therapy in patients with rheumatoid arthritis (RA). We conducted a meta-analysis of studies on the association between the FCGR3A V/F polymorphism or the IL-6 ?174 C/G polymorphism and non-responsiveness to biologic therapy in RA patients. A total of 10 studies involving 1,427 patients were considered. These studies consisted of seven studies on the FCGR3A polymorphism and three studies on the IL-6 polymorphism. Meta-analysis showed no association between the FCGR3A VV+VF genotype and non-responders to biologic therapy [odds ratio (OR) 0.881, 95 % confidence interval (CI) 0.505–1.537, p = 0.655]. However, stratification by biologic type indicated an association between the FCGR3A VV+VF genotype and non-responders to rituximab (OR 0.566, 95 % CI 0.373–0.857, p = 0.007), but no association was found in non-responders to tumor necrosis factor (TNF)-blockers (OR 1.337, 95 % CI 0.869–2.056, p = 0.186). Meta-analysis revealed no association between the IL-6 CC+CG genotype and non-responders to the biologics (OR 3.233, 95 % CI 0.766–13.64, p = 0.110). However, an association was found between the IL-6 CC+CG genotype and non-responders to anti-TNF therapy (OR 8.030, 95 % CI 1.807–33.68, p = 0.006). This meta-analysis demonstrates that FCGR3A V allele carriers show a better response to rituximab, and individuals carrying the IL-6 ?174 C allele show a poorer response to anti-TNF therapy for RA. Genotyping for these polymorphisms may be a useful tool for predicting the response to biologics with respect to personalized medicine.