Investigation of the Frequency of CRP Gene Polymorphism in Rheumatoid Arthritis and Associations with CRP Level and Clinical Involvements of the Disease

BackgroundPatients with rheumatoid arthritis (RA) and inflammatory polyarthritis (IP) are at increased risk of premature death compared to the general population, with cardiovascular disease (CVD) forming the primary cause. C-reactive...

Additive effect of interleukin-6 and C-reactive protein ( CRP) single nucleotide polymorphism on serum CRP concentration and other cardiovascular risk factors

In this study, we investigated the hypothesis that regulatory T cells (T(reg)) are involved in the immunomodulatory effects of statins on rheumatoid arthritis (RA) patients. The 12-week study cohort consisted of 55 RA patients and 42 control subjects allocated to either a group treated with atorvastatin (AT) (20 mg/day) or a non-AT group. T(reg) numbers, suppressive function, serum inflammatory markers, and disease activity were evaluated before and after the therapy. Furthermore, the effects of AT on the frequency and suppressive function of T(reg) were determined in vitro. Our data revealed that the suppressive function of T(reg) from RA patients significantly decreased compared with that of control subjects. AT significantly reduced erythrosedimentation, C-reactive protein, and disease activity. Concomitantly, T(reg) numbers and suppressive functions were significantly improved by AT. Consistent with the in vivo experiments, AT promoted the generation of T(reg) from primary T cells and enhanced preexisting T(reg) function in vitro. Moreover, we showed that PI3K-Akt-mTOR and ERK signal pathways were involved in the induction of T(reg) by AT. In conclusion, AT significantly increased T(reg) numbers and restored their suppressive function in the RA patients, and this may be relevant in the modulation of uncontrolled inflammation in this disorder.

BackgroundClinical assessment of rheumatoid arthritis (RA) patients may be challenging when objective measures, such as C-reactive protein (CRP), do not show elevated disease activity or when patients have concomitant, non-inflammatory...

BackgroundSingle nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene are implicated in the regulation of the constitutional CRP expression and its response to pro-inflammatory stimuli. Previous reports suggest that...

C-reactive protein (CRP) is an important index for evaluating the disease activity of rheumatoid arthritis (RA). CRP may play a direct role in bone destruction in RA. Studies have demonstrated that serum CRP levels had a close correlation with tissue inflammation scores in patients with RA. In addition, genetic factors play a crucial role in the development of RA. In this study, we aimed to investigate the relationship between the CRP gene variants (rs1205 polymorphism) and the risk of RA in Chinese Han population. 502 RA patients and 581 controls were included in this study. The associations between CRP gene variants and CRP levels and RA risk were investigated. We found that TT/ TT + CT genotype was significantly related with an increased risk of RA (TT vs CC: OR, 1.56, 95%CI, 1.01-2.40, P = 0.045; TT + CT vs CC: OR, 1.30, 95%CI, 1.02-1.65, P = 0.032). In addition, T allele was shown to associate with an elevated risk of RA. After subgroup analysis, we found that rs1205 polymorphism was significantly related with an enhanced risk of RA among females, individuals lower than 60years, and subjects with a BMI > 25kg/m2. Furthermore, data showed that the CRP gene rs1205 polymorphism correlated with CRP and ESR levels. Furthermore, the TT genotype was significantly associated with a reduction of CRP levels compared with CT or CC genotype. To sum up, this study reveals that rs1205 polymorphism of the CRP gene is related with an increased risk of RA and CRP levels in Chinese Han population. Key Points • The CRP gene rs1205 polymorphism is related with a higher risk of RA. • The CRP gene rs1205 polymorphism correlates with CRP and ESR levels. • The TT genotype of rs1205 polymorphism is linked with a reduction of CRP levels.

IntroductionIn many European countries, restrictions exist around the prescription of anti-tumor necrosis factor (anti-TNF) treatments for rheumatoid arthritis (RA). Eligibility and response to treatment is assessed by using the disease activity score 28 (DAS28) algorithm, which incorporates one of two inflammatory markers, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Although DAS28-CRP provides a more reliable measure of disease activity, functional variants exist within the CRP gene that affect basal CRP production.Therefore, we aimed to determine the relation between functional genetic variants at the CRP gene locus and levels of serum CRP in RA patients, and whether these variants, alone or in combination, are correlated with DAS28-CRP and change in DAS28-CRP after anti-TNF treatment.MethodsDNA samples from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) were genotyped for rs1205, rs1800947, and rs3091244 by using either TaqMan or the Sequenom MassARRAY iPLEX system.Estimated haplotypes were constructed for each sample by using the expectation maximization algorithm implemented in the haplo.stats package within the R statistical program.CRP values were log transformed, and the association between single nucleotide polymorphisms (SNPs), haplotypes of SNPs and baseline CRP, baseline DAS28-CRP, and change in DAS28-CRP were evaluated by using linear regression in STATA v.10.ResultsBaseline CRP measurements were available for 599 samples with 442 also having data 6 months after treatment with an anti-TNF. For these 442 samples, the study had > 80% power to detect a clinically meaningful difference of 0.6 DAS28 Units for an allele frequency of 5%. Estimated haplotype frequencies corresponded with previous frequencies reported in the literature. Overall, no significant association was observed between any of the markers investigated and baseline CRP levels. Further, CRP haplotypes did not correlate with baseline CRP (P = 0.593), baseline DAS28-CRP (P = 0.540), or change in DAS28-CRP after treatment with an anti-TNF over a 6-month period (P = 0.302).ConclusionsAlthough CRP genotype may influence baseline CRP levels, in patients with very active disease, no such association was found. This suggests that genetic variation at the CRP locus does not influence DAS28-CRP, which may continue to be used in determining eligibility for and response to anti-TNF treatment, without adjusting for CRP genotype.

To evaluate the prevalence and pattern of arterial calcification in patients with rheumatoid arthritis (RA). Patients with RA are prone to premature atherosclerosis; nonetheless the prevalence and extent of atherosclerosis in different vascular beds and their relationship to each other remain unknown. We studied the distribution and extent of arterial calcification in 85 RA patients and 85 age-and sex-matched controls. Arterial calcification as determined by calcium score (CS) were measured using multi-detector computed tomography in thoracic aorta, coronary and carotid arteries. Compared with controls, RA patients had a significantly higher average CS and prevalence of CS > 0 in aorta, coronary and carotid arteries and overall arteries (all P < 0.05). After adjusting for age and sex, RA patients had a significantly higher relative risk of developing calcification in the aorta [Odds Ratio (OR) = 19.5, 95% Confidence Interval (CI): 8.0-47.6], followed by the carotid arteries (OR = 5.7, 95% CI:1.7-18.7) and coronary arteries (OR = 5.0, 95% CI:2.2-11.1) compared with controls (all P < 0.01). Amongst RA patients aged >60, 90% had diffuse arterial calcification, especially over the thoracic aorta, compared with 55% of controls who had arterial calcification clustered in the coronary arteries (P < 0.05). RA patients with total CS > 0 were older with a higher urea level and C-reactive protein than those without arterial calcification, no factor was found to be independently predictive for arterial calcification (all P > 0.05). Our results demonstrated that RA patients had earlier onset, more diffuse arterial calcification over multiple vascular beds and more preferential involvement of thoracic aorta, rather than coronary artery when compared with control.

Association between C-reactive protein gene haplotypes and C-reactive protein levels in Taiwanese: Interaction with obesity

Recent epidemiological studies have indicated that baseline C-reactive protein (CRP) levels may have value in prediction of cardiovascular risk. Using six tag single-nucleotide polymorphisms (SNPs) selected from our complete list of SNPs on the CRP gene, we investigated the association of CRP genotypes with plasma CRP levels and cardiovascular risk in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study cohort (1,296 Caucasians, 48.5% male, 54.7 +/- 12.8 yr old). There was a significant trend toward association of CRP haplotypes with CRP levels (P = 0.045). SNP analysis indicated a highly significant association of SNP -757 (rs3093059, P = 0.0004) and SNP -286 (rs3091244, P = 0.0065) and a borderline association of SNP -7180 (rs1341665, P = 0.06) with CRP levels. Neither CRP haplotypes nor individual SNP genotypes were associated with intima-media thickness of the common carotid or internal carotid artery or the bifurcation of the carotid arteries. These results indicated a strong impact of local SNPs of the CRP gene on plasma CRP levels, but there was no direct evidence that these genetically controlled CRP elevations by local CRP SNPs contributed to cardiovascular disease phenotypes.

Objectives: Temporomandibular joint (TMJ) involvement in rheumatoid arthritis (RA) patients has been described in the literature; however, its incidence varies greatly. In this study, we aimed to determine the prevalence and clinical characteristics of TMJ involvement in RA patients.Materials and Methods: The present study consisted of 60 individuals with RA. The patients were assigned to two groups, based on TMJ involvement: patients with TMJ involvement and patients without TMJ involvement. We defined TMJ involvement based on the findings of the questionnaires and clinical examination by a rheumatologist. The symptoms and signs were recorded by a single trained dentist.Results: The majority of the participants were women (n=49, 81.66%), with the mean age of 43.9±15.52 years (range: 21-78 years). Thirty-five patients (58.3%) had clinical evidence of TMJ involvement. The levels of C-reactive protein (CRP) and rheumatoid factor (RF) were found to be correlated with TMJ involvement. There was no significant correlation between TMJ involvement and erythrocyte sedimentation rate (ESR), age, gender, treatment duration, and disease duration.Conclusion: The high level of CRP in RA patients with TMJ involvement was reported. TMJ pain was reported in almost half of the patients. There was also a significant correlation between TMJ involvement and RF.

BackgroundC-reactive protein (CRP) levels are used more frequently for determination of disease activity in patients with Ankylosing Spondylitis (AS), but these levels do not necessarily reflect disease activity in each...

Inflammation, metabolism and adipokines: toward a unified theory.

Elevated C-reactive protein (CRP) levels are associated with both prevalent and incident cardiovascular disease. In this study, familial aggregation was estimated, and we tested for association between serum CRP levels and polymorphisms within the CRP and APOE genes in sib-ships with type 2 diabetes mellitus, a population at increased risk for cardiovascular disease. CRP levels were determined in 461 diabetes-affected subjects from 224 sibships from the Diabetes Heart Study (DHS). Heritability estimates of CRP levels were obtained using variance component models. Genetic influence on serum CRP levels by single nucleotide polymorphisms (SNPs) in the CRP and APOE genes was evaluated by association analysis using mixed models. Subjects were Caucasian American (84%) and African-American (16%), 53% female, and had an average age of 62.2 +/- 9.2 years. The median CRP level was 3.3 mg/L (range 0 to 59.3 mg/L), and estimated heritability for CRP was approximately 40%. Estimates of heritability were significantly greater than zero (P < 0.0001) and relatively constant, despite adjustments for important modifiers (age, sex, ethnicity, diabetes duration, statin-use and anti-inflammatory use) of CRP. There was no significant evidence for association of CRP levels with CRP gene SNPs; however, consistent with previous reports, there was significant evidence of association of CRP levels with polymorphisms within the APOE gene. These data indicate CRP levels are significantly influenced by genetic (and/or environmental) factors that are shared within DHS families. While the APOE locus shows evidence of contributing to CRP levels, no evidence of CRP gene polymorphism association with CRP levels was observed.

Pentraxin 3 (PTX3), a soluble pattern recognition molecule, not only acts as a promising indicator reflecting the disease activity of rheumatoid arthritis (RA) patients but exerts essential pathogenic roles in the progression of RA and serves as a potential therapeutic target for RA patients. Our study intends to systematically evaluate the circulating PTX3 levels and their potential influencing factors in RA patients. Articles regarding the circulating PTX3 levels of RA patients were identified in Pubmed, Embase, China National Knowledge Infrastructure (CNKI), and Cochrane databases. Standardized mean difference (SMD) and corresponding 95% confidence intervals (95% CI) were calculated and further illustrated by the forest plot. Egger's regression test and sensitivity analysis were conducted to assess the publication bias and stability of the results, respectively. Twenty articles with 21 individual studies were recruited in our meta-analysis. The overall results revealed that compared to healthy controls, RA patients had significantly higher circulating PTX3 levels (pooled SMD = 0.97, 95% CI: 0.48 to 1.45). Subgroup analyses further demonstrated that compared to healthy controls, RA patients of age ≤ 50 years, 2.6 < disease activity score in 28 joints (DAS28) ≤ 3.2, 3.2 < DAS28 ≤ 5.1, DAS28 > 5.1, C-reactive protein (CRP) levels > 10 mg/L, erythrocyte sedimentation rate (ESR) > 20 mm/h, and disease duration > 5 years had significantly higher circulating PTX3 levels, respectively; whereas RA patients of age > 50 years, DAS28 ≤ 2.6, CRP levels ≤ 10 mg/L, ESR ≤ 20 mm/h and disease duration ≤ 5 years had no significantly altered circulating PTX3 levels, respectively. Additionally, no matter whether the patients were of Caucasian ethnicity or not, circulating PTX3 levels were significantly increased in RA patients. Compared to healthy controls, circulating PTX3 levels are significantly increased in RA patients, which are influenced by age, disease activity, CRP levels, ESR, and disease duration.