Effects of disease modifying agents and dietary intervention on insulin resistance and dyslipidemia in inflammatory arthritis: a pilot study

Patients with rheumatoid arthritis (RA) experience excess cardiovascular disease (CVD). We investigated the effects of disease-modifying antirheumatic drugs (DMARD) and dietary intervention on CVD risk in inflammatory arthritis. Twenty-two patients (17 women; 15 with RA and seven with spondyloarthropathy) who were insulin resistant (n = 20), as determined by the Homeostasis Model Assessment, and/or were dyslipidemic (n = 11) were identified. During the third month after initiation of DMARD therapy, body weight, C-reactive protein (CRP), insulin resistance, and lipids were re-evaluated. Results are expressed as median (interquartile range). DMARD therapy together with dietary intervention was associated with weight loss of 4 kg (0–6.5 kg), a decrease in CRP of 14% (6–36%; P < 0.006), and a reduction in insulin resistance of 36% (26–61%; P < 0.006). Diet compliers (n = 15) experienced decreases of 10% (0–20%) and 3% (0–9%) in total and low-density lipoprotein cholesterol, respectively, as compared with increases of 9% (6–20%; P < 0.05) and 3% (0–9%; P < 0.05) in diet noncompliers. Patients on methotrexate (n = 14) experienced a reduction in CRP of 27 mg/l (6–83 mg/l), as compared with a decrease of 10 mg/l (3.4–13 mg/l; P = 0.04) in patients not on methotrexate. Improved cardiovascular risk with DMARD therapy includes a reduction in insulin resistance. Methotrexate use in RA may improve CVD risk through a marked suppression of the acute phase response. Dietary intervention prevented the increase in total and low-density lipoprotein cholesterol upon acute phase response suppression.     

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

IntroductionWe previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE.MethodsA cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics.ResultsCarotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval) = 1.15 (1.07 to 1.24), P <0.0001, 1.51 (1.05 to 2.17), P = 0.03 and 1.66 (1.00 to 2.73) P = 0.04), respectively). The area under the curve (AUC) of the receiver operating curve (ROC) for the association with plaque was 0.807 (P <0.0001), 0.679 (P = 0.001) and 0.599 (P = 0.08) for age, total cholesterol concentrations and number of synthetic DMARDs used, respectively. The optimal cutoff value in predicting plaque presence for age was 49.5 years with a sensitivity and specificity of 74% and 75%, respectively, and for total cholesterol concentration, it was 5.4 mmol/l with a sensitivity and specificity of 63% and 70%, respectively. The plaque prevalence was 37.5% in patients (n = 80; 55.6%) with age >49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n = 64; 44.4%) with age ≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively.ConclusionsApproximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0576-7) contains supplementary material, which is available to authorized users.     

Elevated Levels of Oxidized Low-Density Lipoprotein Correlate Positively with C-Reactive Protein in Patients with Acute Coronary Syndrome

The relationship between oxidized low-density lipoprotein (Ox-LDL) and C-reactive protein (CRP) in patients with acute coronary syndrome (ACS) is unknown. We, therefore, measured serum levels of Ox-LDL and high-sensitivity (hs)-CRP in 90 ACS patients, 45 stable angina pectoris (SAP) patients, and 66 healthy controls using sandwich ELISA. ACS patients were subdivided into: (1) acute myocardial infarction (AMI; n = 45); (2) unstable angina pectoris (UAP; n = 45) groups. In AMI patients, Ox-LDL (177.5 mmol/l) and hs-CRP (25.40 mg/l) levels were significantly higher (P < 0.01) than in UAP (Ox-LDL:107.5 mmol/l, hs-CRP:10.7 mg/l) and SAP (Ox-LDL:82.3 mmol/l, hs-CRP:2.10 mg/l) patients as well as controls (Ox-LDL:41.4 mmol/l, hs-CRP:1.76 mg/l). Ox-LDL/hs-CRP levels in UAP patients were significantly higher (P < 0.01) than in SAP patients and controls. Importantly, a positive correlation was found between Ox-LDL and CRP (r = 0.622; P < 0.01) levels. Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In conclusion, our data show that Ox-LDL and hs-CRP levels correlate positively in ACS patients, supporting the hypothesis that Ox-LDL and CRP may play a direct role in promoting the inflammatory component of atherosclerosis in these individuals. We suggest that Ox-LDL/CRP elevated levels may serve as markers of the severity of the disease in evaluation and management of ACS patients.     

Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the interleukin-10 (IL-10) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-10 −1082 G/A, −592 C/A, −892 C/T and IL-10.R polymorphisms and RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 16 studies (19 comparisons) involving 2647 RA patients and 3383 controls were considered in the meta-analysis. Meta-analysis of the IL-10 −1082 G/A polymorphism showed no association with RA in the study subjects, or in European or Asian subjects. However, meta-analysis of the −1082 G allele in 4 studies in Hardy–Weinberg equilibrium showed a significant association with RA (OR = 1.217, 95% CI = 1.027–1.442, P = 0.0236). In contrast, meta-analysis of the C allele, the CC genotype, and of the CC versus the AA genotype of the IL-10 −592 C/A polymorphism showed significant associations with RA. The overall ORs of the associations between the C allele and RA were 0.684 and 0.758 (95% CI = 0.494–0.946, P = 0.022; 95% CI = 0.475–1.210, P = 0.045) in all study subjects and Asians. Meta-analysis of the CC + CT versus TT genotype and of the CC versus TT genotype of the IL-10 −892 C/T polymorphism revealed significant associations with RA. The overall OR of the association between the C allele carrier and RA was 0.552 (95% CI = 0.375–0.812, P = 0.003). No association was found between the IL10.R2 alleles and RA. This meta-analysis suggests that the IL-10 −592 C/A polymorphism confers susceptibility to RA in Asians and that the IL-10 −1082 G/A and −892 C/T polymorphisms are associated with RA susceptibility. These findings suggest the IL-10 genes confer susceptibility to RA.     

Plasminogen activator inhibitor-1 4G/5G promoter polymorphism and PAI-1 plasma levels in young patients with ischemic stroke

The 4G/5G polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene, has been associated with arterial disease. In this study, we investigated the association of IS in young patients with CRP and PAI-1 levels and frequency of insertion-deletion polymorphism of PAI-1 gene. The plasma levels of PAI-1 and CRP and the frequency of 4G/5G polymorphism were analyzed in 127 Brazilian young patients that presented IS and in 201 healthy and unrelated control subjects. The levels of CRP (P < 0.001) and PAI-1 (P < 0.001) were significantly higher in patients when compared with control group. Only PAI-1 plasma levels were independently associated with risk of IS (OR 3.40; 95% CI 1.49–7.74; P = 0.001) after adjustments for lifestyles covariates. The 4G/4G genotype was significantly more frequent among control subjects as compared to patients (OR 0.41; 95% CI 0.24–0.68; P < 0.001). Although increased PAI-1 plasma levels are associated with development of IS in Brazilian young patients, they are not influenced by the 4G/5G PAI-1 polymorphism.     

Association of polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis

The decrease of anti-inflammatory cytokine and increase of pro-inflammatory cytokine was observed in rheumatoid arthritis (RA). Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been demonstrated to suppress joint swelling and deformation in RA animal model. Interleukin-18 (IL-18), a widely distributed pro-inflammatory cytokine, induces the production of IFN-γ, activate NK cells, and promote inflammation. Recent studies demonstrated that the serum IL-10 and IL-18 levels may be influenced by genetics and related to susceptibility to several autoimmune diseases. In the present study, using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing techniques, we analyzed the genotype and allele distributions of two single nucleotide polymorphisms (SNP) loci in the promoter region of IL-10 and IL-18 genes (IL-10-592 A/C and IL-18-607 A/C loci, respectively). Our results indicated that IL-10-592 allelic and genotypic frequencies were significantly different between the RA patients and normal subjects (P < 0.05). In addition, significant differences of IL-10-592 allelic and genotypic frequencies were also detected between the patients with or without anti-cyclic citrullinated peptide antibody (anti-CCP) (P < 0.05). In contrast, allelic and genotypic frequencies of IL-18-607 did not show significant difference between RA patients and normal subjects (P > 0.05) or between anti-CCP-positive and anti-CCP-negative RA patients (P > 0.05). Furthermore, ELISA detection of IL-10 and IL-18 serum levels revealed that the genotype of IL-10-592 was associated with IL-10 serum level (P < 0.05), but the genotype and allele frequency of IL-18-607 was not associated with IL-18 serum level (P > 0.05). Taken together, our findings provide new insight for the polymorphism of IL-10 gene in the pathogenesis of RA.     

The <Emphasis Type="Italic">PTPN22</Emphasis>1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden

The PTPN22 1858C/T polymorphism has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have shown that carriage of the T variant (CT or TT) of PTPN22 in combination with anti-cyclic citrullinated peptide (anti-CCP) antibodies highly increases the odds ratio for developing RA. In the present study we analysed the association between the PTPN22 1858C/T polymorphism and early RA in patients from northern Sweden, related the polymorphism to autoantibodies and the HLA-DR shared epitope, and analysed their association with markers for disease activity and progression. The inception cohort includes individuals who also donated samples before disease onset. A case–control study was performed in patients (n = 505; 342 females and 163 males) with early RA (mean duration of symptoms = 6.3 months) and in population-based matched controls (n = 970) from northern Sweden. Genotyping of the PTPN22 1858C/T polymorphism was performed using a TaqMan instrument. HLA-shared epitope alleles were identified using PCR sequence-specific primers. Anti-CCP2 antibodies were determined using enzyme-linked immunoassays. Disease activity (that is, the number of swollen and tender joints, the global visual analogue scale, and the erythrocyte sedimentation rate) was followed on a regular basis (that is, at baseline and after 6, 12, 18 and 24 months). Both the 1858T allele and the carriage of T were associated with RA (χ² = 23.84, P = 0.000001, odds ratio = 1.69, 95% confidence interval = 1.36–2.11; and χ² = 22.68, P = 0.000002, odds ratio = 1.79, 95% confidence interval = 1.40–2.29, respectively). Association of the 1858T variant with RA was confined to seropositive disease. Carriage of 1858T and the presence of anti-CCP antibodies was independently associated with disease onset at an earlier age (P < 0.05 and P < 0.01, respectively), while the combination of both resulted in an even earlier age at onset. Smoking was identified as a risk factor independent of the 1858T variant and anti-CCP antibodies.     

Association between the CTLA-4 +49 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to explore whether the cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 A/G polymorphism confers susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between CTLA-4 +49 A/G polymorphism and RA using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) an additive model. A total of 19 studies, 5,752 RA patients and 5,508 controls, encompassing 9 Caucasian, 8 Asian, 1 Mexican, and 1 Tunisian population were included in this meta-analysis. Ethnicity-specific meta-analysis was performed on Caucasian and Asian populations. Meta-analysis of the CTLA-4 +49 A/G polymorphism revealed an association between RA and the CTLA-4 +49 G allele in all 11,260 study subjects (odds ratio (OR) 1.118, 95% confidence interval (CI) 1.033–1.210, P = 0.005). Stratification by ethnicity showed an association between the CTLA-4 +49 G allele and RA in Asians (OR 1.164, 95% CI 1.056–1.283, P = 0.002), but no evidence of an association in Caucasians (OR 1.085, 95% CI 0.973–1.209, P = 0.431). Furthermore, associations were found between RA and the CTLA-4 +49 A/G polymorphism in Asians using the dominant and additive models, but not using the recessive model. On the other hand, no association was found between RA and the CTLA-4 +49 A/G polymorphism using the recessive, dominant, or additive models in Caucasians. This meta-analysis demonstrates that the CTLA-4 +49 A/G polymorphism confers susceptibility to RA in Asians, but not in Caucasians.     

Meta-analysis of the association of CTLA-4 exon-1 +49A/G polymorphism with rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a highly suspected candidate gene for RA susceptibility. However, association studies on the polymorphism of CTLA-4 exon-1 +49A/G in RA have shown conflicting results. Therefore, we performed a meta-analysis to better assess the purported association. In order to look for ethnic effect, we performed subgroup meta-analysis in populations of European descent and Asian descent. Meta-regression analysis was also performed to explore the possible heterogeneity between the two subgroups. Ten studies (11 comparisons) with the CTLA-4 exon-1 +49A/G genotyping on 2,315 patients with RA and 2,536 controls were selected for our meta-analysis. Overall, the fixed-effects odds ratio (OR) for the G versus A allele was 1.11 (P=0.02, 95% confidence interval (CI) 1.02–1.21), with no between-study heterogeneity. Subgroup and meta-regression analysis according to the ethnicity (European or Asian) demonstrated different scenarios concerning the CTLA-4 exon-1 +49A/G polymorphism’s role in RA susceptibility for the two different subgroups. No effect of G on susceptibility was seen in European descent (five comparisons; OR=1.04, P=0.30, 95% CI 0.95–1.19; no significant between-study heterogeneity). However, there is a significant association in Asian descent under both fixed [OR=1.21, 95% CI (1.06–1.39), P=0.005] and random-effect models [OR=1.19, 95% CI (1.01–1.42), P=0.04]. Meta-regression analysis also supports the heterogeneity between the two subgroups (P=0.082). We also explored the role of this polymorphism on RA risk under other various interested genetic contrasts. These results further support that this polymorphism could not be a risk factor for Europeans. Interestingly, we find that in Asians the G allele has a greater tendency to cause RA in a recessive genetic model. However, sensitivity analysis showed that the combined result of Asian populations was unstable. In conclusion, our meta-analysis results suggest that CTLA-4 exon-1 +49G allele would not be a risk factor for RA in Europeans but might play a role in RA susceptibility for Asians.Shizhong Han and Yao Li have contributed equally to this paper.     

Sex difference in the regulation of plasma high density lipoprotein cholesterol by genetic and environmental factors

Association between high density lipoprotein (HDL) cholesterol concentration and restriction fragment length polymorphisms at the cholesteryl ester transfer protein (CETP) gene locus was studied in a random population-based cohort of 526 Caucasian subjects (259 men, mean age 50.9 years, and 267 women, mean age 51.8 years). HDL cholesterol concentration was adjusted for age, body mass index, alcohol consumption, smoking and plasma triglyceride and low density lipoprotein cholesterol levels. In females, the HDL cholesterol levels were associated withTagIB polymorphism (1.46 mmol/1 in the B1B1 genotype, 1.56 mmol/l in B 1B2 and 1.72 mmol/1 in B2B2,P = 0.0001 for the trend). In contrast, this was not observed in men (1.24, 1.20, 1.27 mmol/l, NS). The association was seen even in women who were current smokers (1.41, 1.56, 1.75 mmol/l,n = 72,P = 0.007), but not in male smokers (1.26, 1.19, 1.14 mmol/l,n = 102, NS). In male non-smokers the association was weak (1.22, 1.20, 1.32 mmol/l,n = 157,P = 0.05). In postmenopausal women not receiving hormone replacement therapy (n = 108), the association continued to be present, although weaker (1.50, 1.58, 1.70 mmol/l,P = 0.06). CETP activity (n = 101) tended to be lower in subjects with the 132132 genotype. In conclusion, a clear-cut sex difference was observed in the genotype effect on plasma HDL cholesterol levels. The slight attenuation of the gene dosage effect after menopause suggests that the gender difference may be, at least in part, due to sex hormones. A genetic subgroup (men with the 132132 genotype) particularly susceptible to the HDL cholesterol decreasing effect of smoking could be demonstrated.Part of this work was presented at the 67th Scientific Sessions of the American Heart Association, Dallas, Texas, USA, 14–17 November, 1994     

Synovial fluid and plasma selenium, copper, zinc, and iron concentrations in patients with rheumatoid arthritis and osteoarthritis

In recent years, a great number of studies have investigated the possible role of trace elements in the etiology and pathogenesis of rheumatoid arthritis (RA) and osteoartritis (OA). We studied synovial fluid and plasma concentrations of selenium (Se), zinc (Zn), copper (Cu), and iron (Fe) in patients with RA and OA and compared them with sex- and age-matched healthy subjects. Plasma albumin levels were measured as an index of nutritional status. Plasma Se, Cu, and Zn concentrations were determined by atomic absorption spectrophotometry and Fe concentrations were determined by the colorimetric method. Although plasma and synovial fluid Se concentration were found to be significantly lower (p<0.05, and p<0.05, respectively), Cu concentrations were significantly higher in patients with RA than those of healthy subjects and OA (p<0.05 and p<0.05, respectively). There were no significant differences in plasma and synovial fluid Zn concentrations and albumin levels among three groups (p>0.05). On the other hand, synovial fluid Cu and Fe concentrations were significantly higher in patients with OA than those of healthy subjects (p<0.05). There was a significantly positive correlation between synovial fluid Se−Cu values and Zn−Fe values in patients with RA. Our results showed that synovial fluid and plasma trace element concentrations, excluding Zn, change in inflammatory RA, but not in OA. These alterations in trace element concentrations in inflammatory Ra might be a result on the changes of the immunoregulatory cytokines.     

Expression of MDC/CCL22 and its receptor CCR4 in rheumatoid arthritis,psoriatic arthritis and osteoarthritis

The pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) involves an abnormal chemokine regulation. The chemokine receptor CCR4 is necessary for T cell migration to the skin. We, therefore, studied if CCR4 and its ligand macrophage-derived chemokine (MDC/CCL22) could participate in spreading the disease between skin and joints by examining RA, PsA and osteoarthritis (OA) patients. In synovial fluid from RA and PsA patients we observed a significantly higher MDC/CCL22 level compared to OA patients. Additionally, the MDC/CCL22 protein was found to be elevated in RA and PsA plasma compared to OA and healthy volunteers. Flow cytometry revealed that most CD4⁺CCR4⁺ lymphocytes also co-expressed CD45RO. Neither the MDC/CCL22 level nor the expression of CCR4 correlated to CRP. Immunohistochemistry of the RA and OA synovial membrane demonstrated CCR4 to be expressed by mononuclear cells and endothelial cells. Our results show that MDC/CCL22 is present within the synovial membrane of RA and OA patients and in high amount in the synovial fluid of patients with RA and PsA. This will enable migration of CCR4 expressing memory cells supporting that MDC/CCR4 could play a role in attracting skin specific memory T cells to the joints.     

Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis

Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1β, TNF-α, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.     

The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis update

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the PTPN22 C1858T polymorphism involving eighteen studies, which in total contained 20344 RA patients and 21828 controls. Meta-analysis revealed an association between the PTPN22 C1858T polymorphism T allele and RA in all subjects (odds ratio [OR] = 1.637, 95% confidence interval [CI] = 1.514–1.770, P < 0.001). After stratification by ethnicity, analysis indicated that the PTPN22 C1858T polymorphism T allele was significantly associated with RA in Europeans and Non-Europeans (OR = 1.587, 95% CI = 1.486–1.696, P < 0.001; OR = 1.748, 95% CI = 1.274–2.398, P < 0.001). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and -negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF. In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.     

Role of tissue plasminogen activator and plasminogen activator inhibitor polymorphism in myocardial infarction

A case–control association study on 229 Myocardial Infarction (MI) patients and 217 healthy controls was carried out to determine the role of tissue-plasminogen activator (t-PA) (Alu-repeat insertion (I)/deletion (D)) and plasminogen activator inhibitor (PAI-1) (4G/5G insertion/deletion) polymorphisms with MI in the Pakistani population. In MI patients the genotype distribution of the PAI-1 gene was not found to be different when compared with the unaffected controls (P > 0.05, χ² = 1.03). The risk allele 4G was also not associated with MI (P > 0.05, χ² = 0.46, odds ratio (OR) = 1.1 (95% confidence interval (CI) = 0.84–1.43), P > 0.05). Similarly, the genotype frequencies of t-PA I/I, I/D and D/D were not different from the unaffected controls (P > 0.05, χ² = 1.60), and the risk allele “I” was not found to be associated with MI (P > 0.05, χ² = 1.35, OR = 0.86 (95% CI = 0.66–1.11), P > 0.05). However, when the data were distributed along the lines of gender a significant association of the 4G/4G PAI-1 genotype was observed with only the female MI patients (P < 0.05, z-test = 2.21). When the combined genotypes of both the polymorphisms were analyzed, a significant association of MI was observed with the homozygous DD/4G4G genotype (P < 0.01, z-test = 2.61), which was specifically because of the female samples (P = 0.01, z-test = 2.53). In addition smoking (P < 0.001, χ² = 13.52, OR = 3.45 (95% CI = 1.77–6.94)), diabetes (P < 0.001, χ² = 22.45, OR = 8.89 (95% CI = 2.96–29.95)), hypertension (OR = 7.76 (95% CI = 2.88–22.68), P < 0.001) family history (P < 0.001, χ² = 13.72, OR = 3.7 (95% CI = 1.71–8.18)) and lower HDL levels (P < 0.05) were found to be significantly associated with the disease. In conclusion the PAI-1 gene polymorphism was found to have a gender specific role in the female MI patients.     

Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls

Introduction  

Both genetic and environmental factors contribute to rheumatoid arthritis (RA), a common and complex autoimmune disease. As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. This study was initiated to investigate the association between defined genetic markers and RA in a Slovak population. In contrast to recent studies, we included intensively-characterized osteoarthritis (OA) patients as controls.     

Matrix metalloproteinases MMP-3 and MMP-1 levels in sera and synovial fluids in patients with rheumatoid arthritis and osteoarthritis

OBJECTIVES: To investigate whether serum levels of matrix metalloproteinases (MMP-3, stromelysin) and (MMP-1, collagenase) are specifically elevated in joint disease as rheumatoid arthritis (RA) compared to osteoarthritis (OA), and to assess how these markers reflect the clinical activity of RA compared to circulating cytokine as tumor necrosis factor-alpha (TNF-alpha) as well as established variables as [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)]. SUBJECTS AND METHODS: This study included 22 patients with RA, 10 patients with OA and 10 healthy control subjects matched for age and sex. Patients with superimposed infection were excluded. Serum levels of MMP-3, MMP-1, TNF-alpha and CRP were assayed. Synovial fluid (SF) levels of MMP-3 and MMP-1 were also assayed. RESULTS: Serum levels of TNF-alpha and CRP in RA patients were significantly higher than normal subjects. Serum MMP-1 was significantly elevated in patients with RA and OA, compared to healthy controls but there were no significant differences between patients with RA and those with OA. Serum MMP-3 levels did not differ between OA patients and normal sera. However, RA patients displayed significantly elevated levels of this enzyme, compared to OA and control sera. Levels of MMP-3 and MMP-1 in the SF of RA patients were significantly higher than in OA fluids. CRP, ESR, TNF-alpha and MMP-3 correlated significantly with the swollen joint count. The strongest positive correlations existed between rheumatoid activity as assessed by the levels of CRP and circulating levels of MMP-3. Similar correlations between TNF-alpha concentration and CRP, MMP-1 and MMP-3 were observed in RA patients. Serum levels of MMP-3 correlated significantly with serum concentrations of MMP-1 in RA patients (r = 0.487, p < 0.05). There was close correlation between serum and SF concentrations of MMP-3 in RA patients (r = 0.619, p < 0.01). In the same patients there was highly significant correlation between SF concentrations of MMP-3 and MMP-1 (r = 0.732, p < 0.001). CONCLUSIONS: Our data suggested that elevated MMP-3 levels reflected disease activity of RA better than cytokine levels. However, MMP-3 levels do not exceed the association of CRP with clinical activity.     

Associations between vitamin D receptor polymorphisms and susceptibility to rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis

The aim of this study was to determine whether the vitamin D receptor (VDR) polymorphisms confer susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematous (SLE). A meta-analysis was conducted on the associations between the BsmI, TaqI, FokI, and ApaI polymorphisms of VDR and RA or SLE using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) additive model. A total of ten studies, six RA and four SLE studies, were considered in the meta-analysis. Meta-analysis of the VDR BsmI and TaqI polymorphisms showed no association between RA in all subjects, or in European or Asian subjects. In contrast, meta-analysis of the F allele, the FF genotype, and the FF vs. the ff genotype of the FokI polymorphism showed significant associations with RA in Europeans. The overall OR of the association between the F allele and RA was 1.502 (95% CI = 1.158–1.949, P = 0.002). Meta-analysis of the B allele, BB + Bb genotype, and BB genotype (additive model) of the BsmI polymorphism showed significant associations with SLE and LN in Asians. The overall ORs of the associations between the B allele and SLE and LN were 3.584 (95% CI = 1.407–9.130, P = 0.007) and 3.652 (95% CI = 1.347–9.902, P = 0.011). This meta-analysis demonstrates that the VDR FokI polymorphism may confer susceptibility to RA in Europeans. Furthermore, associations were found between the VDR BsmI polymorphism and susceptibilities to SLE and LN in Asians.