Association of CD4 enhancer gene polymorphisms with rheumatoid arthritis in Egyptian female patients

CD4 is a candidate gene in autoimmune diseases, including rheumatoid arthritis (RA). Because the CD4 receptor is crucial for appropriate antigen responses of CD4+ T cells, changes in CD4 expression and CD4+ T-cell activity may influence tolerance or tissue destruction in autoimmune diseases and contribute to their risk. We analyzed two polymorphisms of the CD4 in 172 female Egyptian patients with RA and in 112 matched healthy control. Genotyping of CD4-11743 and CD4-10845 was determined by restriction fragment length polymorphism-polymerase chain reaction (PCR–RFLP). Subjects with the CC genotype of CD4-11743 were significantly more likely to develop RA (OR?=?2.7, P?=?0.03) and more likely to have sever RA (OR?=?2.7, P?=?0.024). Carrier of A allele of CD4-10845 was significantly more likely to develop sever RA (OR?=?3.7, P?=?0.000). CD4-11743 genetic polymorphisms are associated with the susceptibility and severity of RA, and CD4-10845 genetic polymorphisms are associated with the severity of RA.     

The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis

Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.     

Association of PTPN22 with rheumatoid arthritis among South Asians in the UK

OBJECTIVE: To compare the distribution and assess genetic associations of the PTPN22 R620W single-nucleotide polymorphism among South Asian (Asiatic Indian) patients with rheumatoid arthritis (RA) and ethnically matched controls. METHODS: DNA samples from 133 rheumatoid factor-positive South Asian RA patients and 149 control subjects from the East Midlands of the UK were genotyped for PTPN22 R620W polymorphism. Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The PTPN22 *T allele frequency was lower than in the Caucasian populations, but the disease association was significant (odds ratio 5.87, 95% confidence interval 1.68-20.52). Similar association was observed for genotypes containing *T allele. CONCLUSION: Our results suggest that the T variant acts as a susceptibility allele for autoantibody-positive RA among South Asians.     

Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene

OBJECTIVE: The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single-nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell-mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously. METHODS: The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi-square test as implemented in Stata software. RESULTS: There was a significant association between the PTPN22 SNP and RA (P = 1.8 x 10(-8)) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected. CONCLUSION: We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.     

Association of 22 cytokine gene polymorphisms with rheumatoid arthritis in population of ethnic Macedonians

To examine the possible role of 22 cytokine gene polymorphisms in host susceptibility to or protection against RA in Macedonians. In this study, 301 healthy unrelated individuals and 85 patients with RA were studied. Cytokine genotyping was performed by PCR with sequence-specific priming (PCR–SSP) (Heidelberg kit). Results showed susceptible association for four cytokine alleles, six cytokine genotypes, one haplotype, and four combinations of haplotypes, while protective associations were found for four cytokine alleles, three cytokine genotypes, three haplotypes, and only one combination of haplotypes. These results suggest that IL-4 −1098, IL-4 −590, IL-10 −1082, IL-10 −819, IL-2 −330, IL-6 −174, and TNF-α −238 cytokine gene polymorphisms might be significantly associated and affect host susceptibility and/or resistance to RA in Macedonians.     

Association of PTPN22 gene (rs2488457) polymorphism with ulcerative colitis and high levels of PTPN22 mRNA in ulcerative colitis

Purpose

Our aims were to evaluate protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms in ulcerative colitis (UC) and explore PTPN22 mRNA levels in colonic biopsies of UC patients in central China.

Methods

A total of 165 Chinese UC patients and 300 healthy controls were enrolled in this study. PTPN22 ?1123G/C, +1858C/T, and +788G/A polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. PTPN22 mRNA expressions in colonic biopsies and serum C-reactive protein (CRP) levels were determined by quantitative PCR and immunonephelometry, respectively.

Results

The frequency of C carrier was higher in UC patients than in healthy controls (66.7 vs. 53.3 %, P?=?0.005, odds ratios?=?1.75, 95 % CI 1.18–2.60) and associated with extensive colitis (P?=?0.029). PTPN22 mRNA levels were elevated in UC patients than in healthy controls (P?<?0.001). Among UC patients, PTPN22 mRNA expression levels were higher in biopsies of inflamed colonic tissue compared with noninflamed tissue (P?<?0.001) and were correlated with CRP levels (r?=?0.578, P?<?0.001). PTPN22 mRNA expression levels were elevated in extensive colitis compared to proctitis (P?=?0.008) and to left-sided colitis (P?=?0.029) and were higher in moderate and severe disease than in mild disease (P?=?0.005).

Conclusions

Our study showed the potential association between PTPN22 ?1123G/C polymorphism and UC in central China. PTPN22 mRNA levels were highly expressed in UC, especially in active disease, and were correlated with CRP levels, disease location, and disease severity in UC patients.     

Autoimmune thyroid disease in Egyptian patients with rheumatoid arthritis

Aim of the workTo determine the frequency of autoimmune thyroid disease (AITD), anti-thyroglobulin (ATG) and anti-thyroid peroxidase (ATPO) antibodies in Egyptian patients with rheumatoid arthritis (RA).Patients and methods60 RA patients and 60 matched controls were enrolled. Clinical and laboratory data were examined in the patients. The disease activity score (DAS28) and modified health assessment questionnaire (MHAQ) were evaluated. Presence of AITD, ATG and ATPO antibodies were assessed.ResultsThe mean age of the patients was 41 ± 10.5 years, 43 (71.7%) were females and had a disease duration of 8.6 ± 4.1 years. Their mean anti-cyclic citrullinated peptide level was 31.8 ± 33.5 IU/ml), DAS28 (4 ± 1.4) and MHAQ was 1.5 ± 0.5. The thyroid hormones (T3, T4 and thyroid stimulating hormone) were comparable to that of the control. The ATG (80.7 ± 39.3 IU/ml) and ATPO (70.3 ± 39.7 IU/ml) antibodies were significantly increased in RA patients compared to the control (21.5 ± 6.6 IU/ml and 20.5 ± 11.2 IU/ml respectively; p < 0.001). Thyroid dysfunction was present in 38.3% compared to 6.7% in controls (p < 0.001). The frequencies of AITD, ATG and ATPO were higher in patients (23.3%, 26.7% and 33.3% respectively) compared to controls (0%, 3.3% and 6.7%). ATG antibodies, ATPO antibodies and AITD positivity in patients were significantly associated with younger age, female gender, erythrocyte sedimentation rate and DAS28.ConclusionAITD is frequent among patients with RA. Therefore, there is a need of screening of thyroid hormone dysfunction as well as of presence of ATPO and ATG antibodies as markers of AITD in RA patients particularly in young patients, females and those with high disease activity.     

Association of STAT4 with rheumatoid arthritis: a replication study in three European populations

OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.     

Association of hla-drw4 with rheumatoid arthritis in black and white patients

The HLA-A, B, C, and DR antigens were typed in 35 black and 35 white Americans with rheumatoid arthritis. The frequency of HLA-DRw4 was increased in both the black and white patient groups compared to the race-matched control groups. DRw4 was found in 45.7% of the black patients compared to 14.3% of the black controls (corrected P value <0.035) and DRw4 was found in 71.4% of the white patients compared to 40.0% of the white controls (corrected P value <0.035). These data indicate that immunogenetic factors related to DRw4 are important in the development of rheumatoid arthritis in American blacks as well as whites.