Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) + 49 A&gt;G gene polymorphism in Egyptian cases with rheumatoid arthritis

doi:10.1016/j.gene.2014.12.046

Gene

Volume 558, Issue 1, 1 March 2015, Pages 103-107

https://doi.org/10.1016/j.gene.2014.12.046 Get rights and content

Highlights

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The gene encoding CTLA-4 + 49 A>G has been reported to be associated with to RA in several populations.
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The CTLA-4 + 49 G allele was significantly associated with RA susceptibility in Egyptian cases.
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The CTLA-4 + 49 G allele was significantly associated with functional disability of RA in Egyptian cases.

Abstract

Background

The gene encoding cytotoxic T lymphocyte associated antigen-4 (CTLA-4) has been reported to be associated with rheumatoid arthritis (RA) in several ethnic populations. The aim of this work is to assess the association of this polymorphism with the susceptibility, activity and functional disability of RA in Egyptian subjects.

Subjects and methods

This study included 112 unrelated RA Egyptian patients who were compared to 122 healthy controls from the same locality. For all subjects, DNA was genotyped for CTLA-4 + 49 A>G (rs231775) polymorphism using the PCR-RFLP technique. Antibodies to cyclic citrullinated peptides (anti-CCP) were measured by enzyme-linked immunosorbent assay (ELISA).

Results

The frequency of the CTLA-4 G allele was significantly higher among cases compared to controls (37.1% vs. 23.4%, OR = 1.93; 95% CI = 1.29–2.89, p = 0.002). Also, the frequency of CTLA-4 + 49 G allele carriage (AG+GG genotypes) was significantly higher among cases with RA compared to controls (61.6% vs. 41.8%, OR = 2.23, 95% CI = 1.32–3.77, p = 0.003). Logistic regression analysis showed that cases positive to the G allele (GA+GG genotypes) had less frequency of rheumatoid deformities and also a lower DAS28-CRP score, yet with a higher visual analogue scale (VAS) i.e. more functional disability than other cases.

Conclusions

CTLA-4 + 49 G allele carriage was associated with increased susceptibility and functional disability of RA in Egyptian patients.

Introduction

Rheumatoid arthritis (RA) is a common autoimmune disorder affecting approximately 1% of the adult population worldwide. It might result into persistent inflammation and destruction of synovial joints with subsequent changes in joint integrity (Harris, 1990). Population and family studies have suggested that genetic factors are major determinants of the susceptibility to RA (Ollier and Thomson, 1992, Goëb et al., 2008). Human leukocyte antigen (HLA) class II genes were portrayed as being the most powerful genetic factors linked to RA identified to date (Urayama et al., 2013, Wordsworth and Bell, 1991). However, this association is speculated to account for only one-third of genetic susceptibility, therefore non-HLA genes should be also considered (Urayama et al., 2013, Deighton et al., 1989). One of the best examples of a non-MHC common susceptibility allele for autoimmunity was represented in the polymorphism pertinent to the cytotoxic T lymphocyte associated antigen-4 (CTLA-4; also known as CD152) gene (Muñoz-Valle et al., 2010, Li et al., 2014). CTLA-4 molecule is expressed on activated T cells and has structural homologue of CD28. It is a second receptor of the co-stimulating factors B7-1 (CD80) and B7-2 (CD86) (Kristiansen et al., 2000, Harper et al., 1991). The CTLA-4 ligation engaging the T-cell antigen receptor appears to play a critical role in increasing and maintaining the T-cell response (Tivol et al., 1996). Thus the CTLA-4 gene is a strong candidate gene for autoimmune diseases including RA (Muñoz-Valle et al., 2010, Li et al., 2014, Tang and Zhou, 2013, Barton et al., 2000, Yanagawa et al., 2000). The CTLA-4 gene has three exons in addition to the leader sequence in the 5′ region and is mapped to the 2q33 chromosome. One of the most studied polymorphisms in the CTLA-4 gene is the + 49 A>G (rs231775) transition, which leads to alanine to threonine amino acid substitution in codon 17 of the leader peptide (A17T) (Harper et al., 1991, Donner et al., 1997). It has been reported that the CTLA-4 + 49 A>G polymorphism might influence the inhibitory function of CTLA-4 by reducing the cell surface expression (Muñoz-Valle et al., 2010, Barton et al., 2000). Knowing that the allelic frequencies of genes often differ substantially between populations; we were interested to test for the association of this seemingly important polymorphism; CTLA-4 + 49 A>G with RA in Egyptian cases.

Section snippets

Subjects and methods

This work is a case controlled study involving 112 RA patients (93 females and 19 males) with an age mean ± SD of 47.6 ± 10.1 years, in addition to a control sample of 122 healthy unrelated blood donors (99 females and 23 males) with an age mean ± SD of 42.3 ± 10.3 years. Patients were typically fulfilling the classification criteria set by the American College of Rheumatology (ACR) for RA (Arnett et al., 1988). They were recruited from the Rheumatology and Rehabilitation Department; Mansoura University

Results

The demographic and clinical data of the RA patients are shown in Table 1. It was noted that 38 cases (33.9%) had a positive family history of RA while 50 cases (44.6%) had a positive parental consanguinity. Analysis of laboratory markers revealed that 105 cases (93.8%) were positive for anti-cyclic citrullinated peptide (anti-CCP) while 83 cases (74.1%) were positive for rheumatoid factor (RF).

The genotypic and allelic frequencies of the CTLA-4 + 49 A>G gene SNP in RA patients and controls are

Discussion

Knowing that RA is mainly predisposed to by genetic and immune mechanisms involving the CD4 + T cells (Perricone et al., 2011), this work was planned to analyze CTLA-4 + 49 A>G polymorphism in Egyptian patients. To our knowledge, this is the first study probing into this association among Egyptian RA cases. High CTLA-4 + 49 G allele carriage (AG+GG genotypes) was significantly noted among Egyptian cases with RA coping with the dominant model of inheritance. Regarding the activity and disability of

Conflict of interest

The authors declare that they have no conflict of interest related to this work.

Acknowledgment

The authors are grateful for the faculty members of Rheumatology Department, Mansoura University Hospitals, Egypt for their help in selecting cases under the study.

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Cited by (21)

Association of CTLA-4 (+49A/G) polymorphism and susceptibility of developing rheumatoid arthritis in an Iraqi Arab population
2022, Human Gene
Citation Excerpt :
The +49A/G polymorphism (rs231775) located in exon 1 of the CTLA-4 gene has been poorly reported to be possibly related to RA as a genetic risk factor. The non-synonymous substitution in the 17 amino acids caused by rs231775 exhibits an inhibitory effect on CTLA-4 function via reducing cell surface expression (Tang and Zhou, 2013; Elshazli et al., 2015; Fattah et al., 2017; Aslam et al., 2020). Although the association between the occurrence of RA among carriers of rs231775 has been studied before, the data are still limited and inconclusive (Lei et al., 2005; Benhatchi et al., 2011; Li et al., 2014; Zhou et al., 2021).
The gene responsible for encoding the protein of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has been found to be associated with rheumatoid arthritis (RA) in different ethnic populations. But the association of +49A/G CTLA-4 polymorphism with susceptibility of RA among Iraqi Arab populations has not yet been determined.
One hundred and seventy-eight patients were examined, 67 of them were males (mean age 54.71 ± 10.4 years), while 167 were examined for the control group, of whom 64 were males and the rest were females. CTLA-4 DNA genotyping was carried on to determine the +49 A/G (rs231775) polymorphism using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Enzyme-linked immunosorbent assay (ELISA) was also applied here to measure the antibodies level for cyclic citrullinated peptides (anti-CCP) and Rheumatoid factor (RF).
The frequency of AG and GG genotypes in CTLA-4 + 49 were significantly higher among RA patients in comparing with controls (55.61% vs 42.51%, OR = 2.18, 95% CI = 1.62–3.79, P = 0.003) and (20.22% vs 10.77%, OR = 2.61, 95% CI = 1.31–6.46, P = 0.002) respectively. G allele frequency was also significantly higher among RA cases (52.24% vs. 31.73%, OR = 3.02; 95% CI = 1.61–7.39, P = 0.001). The frequencies of the AA genotype and A allele, however, were significantly lower in cases than controls (24.15% vs 46.70%, P = 0.001) and (47.75% vs 68.26%, P = 0.001) respectively. Moreover, the levels of Anti-CCP and RF were raised significantly among RA patients than controls (P = 0.0001), but none of these parameters were correlated with genotypes of CTLA-4.
Carries of CTLA-4 + 49 AG and GG alleles were at a high risk of developing functional disability of RA, unlike the AA allele carriers.
Association of CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant with the risk of hepatocellular carcinoma and gastric cancer: A meta-analysis and meta-regression
2022, Meta Gene
Citation Excerpt :
In addition, disease prognosis is fairly dependent on individual characteristics as regards their genetic susceptibility, inflammatory response, and immunity factors (Hayashi and Di Bisceglie, 2005; El-Mesery et al., 2017; El-Mowafy et al., 2017; Robinson et al., 2017). One of the important immune factors is the immunosuppressive protein named cytotoxic T-lymphocyte associated protein 4 (CTLA4) which is a key element of the immunoglobulin categories and is considered as an inhibitory cytokine of T-lymphocytes (Elshazli et al., 2015; Alghamdi et al., 2021). The CTLA4 gene is positioned at chromosome number 2 (2q33.2) and is comprised of four exons and three introns.
Various reports have examined the contribution of the CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant with different cancerous disorders. This meta-analysis was executed to further probe into the involvement of this missense variant with the susceptibility for hepatocellular carcinoma (HCC) and gastric cancer (GC).
Following a wide-based scrutinized search of the internet done by three independent researchers for the contribution of the CTLA4 c.49A > G (rs231775; p.Thr17Ala) variant with the cancer risk up to February 2021, only 16 case-control studies were found relevant and usable to the analysis out of 575 total retrieved reports. Multiple genetic models were checked for the proposed association through the computation of the odds ratio (OR) in addition to their 95% confidence intervals (95%CIs). Stratification and regression analysis was also carried out for the analyzed reports based on their geographical distributions, genotyping techniques, source of cancer-free controls, genetic equilibrium within cancer-free controls, and quality score. In addition, trial sequential analysis (TSA) was applied to test for the adequacy of the total sample size.
This meta-analysis has included 4320 HCC and GC patients in conjunction with 6601 cancer-free controls. This work disclosed a significant association for the CTLA4 c.49A > G (rs231775; p.Thr17Ala) variant with HCC among overall subjects tested by the recessive model [OR = 1.235, 95% CI = 1.050–1.453, P-value = 0.011]. Similarly, an elevated risk of GC was noticed associated with this variant within the overall subjects tested by the allelic model [OR = 1.225, 95% CI = 1.070–1.401, P-value = 0.003], and dominant model [OR = 1.352, 95% CI = 1.081–1.691, P-value = 0.008]. Furthermore, the stratification analysis showed a verification of correlation for this variant with HCC in Asian subjects under the recessive model, while the association was observed to be significant with GC in Asian and Caucasian patients under the dominant model. TSA confirmed that this work had significant findings noting that the collective Z-curve spanned the examining borderlines prior to attaining sample size confirming the acceptability of the study sample size.
The CTLA4 c.49A > G (rs231775; p.Thr17Ala) gene variant could be considered as an actual risk factor for the susceptibility of HCC and GC warranting efficient and adequate genetic counseling for this gene variant carriers.
Genetic association of interleukin-4 VNTR polymorphism with susceptibility to rheumatoid arthritis in South Gujarat population
2021, Gene Reports
Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease, which causes swelling and severe pain within joints. The variable number tandem repeats (VNTR) polymorphism of interleukin-4 (IL4) gene has been associated with autoimmune diseases including RA. The study investigated the association of IL4 VNTR (IVS3; R1 > R2) polymorphism with RA susceptibility in South Gujarat population of India. Polymerase chain reaction (PCR) method was used for genotyping of IL4 VNTR polymorphism in 302 RA patients and 334 controls and ELISA was used for estimation of plasma IL-4 levels. The genotype and allele frequencies of the polymorphism were significantly differed between RA patients and control population (p < 0.0001), suggesting that IL4 VNTR polymorphism is associated with RA susceptibility in South Gujarat population. The susceptible ‘R2’ allele was prevalent in RA group as compared to the control group (79.4% vs 64.00%; p < 0.0001). Moreover, both the genotype and allele frequencies were significantly differed between severe and mild RA patients (p = 0.0039 & p = 0.0005 respectively). The plasma IL-4 levels (p = 0.0216) and genotype-phenotype correlation revealed significant increased IL-4 levels for R2R2 genotype in RA patients compared to controls (p = 0.0265). The IL-4 levels were significantly higher in R2R2 genotype when compared to R1R1 and R1R2 genotypes in RA patients (p = 0.007 & p = 0.03 respectively). Furthermore, IL-4 levels were significantly increased in severe RA patients compared to mild (p = 0.0293). Both, IL-4 levels and R2R2 genotypes were positively correlated with rheumatoid factor (r = 0.49, p = 0.0009 & r = 0.41, p = 0.035 respectively). Overall, the study for the first time suggests that IL4 VNTR R2 allele may be associated with susceptibility to RA in South Gujarat population and it is likely to play a role in increased IL-4 levels thereby contributing to RA pathogenesis.
Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis
2021, International Immunopharmacology
Citation Excerpt :
In addition, two studies in the United Kingdom proposed that CTLA-4 (+49 A/G) is related to RA susceptibility [29,30], while two other studies in the United Kingdom suggested that there is no association between them [31,32]. Except for above nine studies, five other studies believed that CTLA-4 (+49 A/G) was associated with RA susceptibility [33–37], and ten studies showed no correlation [38–47]. Furthermore, in the relevant studies of SLE, most of the results indicated that CTLA-4 (+49 A/G) is not related to SLE munity [46–59], but some papers believed that it is [60–65].
In recent years, more and more studies have been focusing on the association between Cytotoxic T lymphocyte antigen-4 (CTLA-4) (+49 A/G) gene polymorphism and autoimmune diseases. However, the results of previous studies are still controversial. The meta-analysis is aiming at determining the association in CTLA-4 (+49 A/G) gene rs231775 polymorphism and ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE).
We searched PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) up to November 2020, use random or fixed-effect models to perform meta-analysis to compare alleles and other genetic models, including homozygous, heterozygous, recessive and dominant models. The odds ratio (OR) with a 95% confidence interval (95% CI) was used to assess the correlation between CTLA-4 (+49 A/G) gene polymorphism and the genetic affectability of AS, RA, and SLE. Meanwhile, we used sequential trial analysis (TSA) to analyze the reliability of the results. Finally, we searched the relevant data of genome-wide association studies (GWAS) to further verify the accuracy of the experimental results.
47 studies with 11,893 cases and 12,032 healthy controls were included. The rs231775 G allele was relevant to high risk of autoimmune disease over all people (P < 0.05). The G allele of rs231775 was significantly related to RA susceptibility (P < 0.05), but not with AS or SLE. Subgroup analysis by ethnicity indicated that rs231775 G allele was closely related to RA in Caucasian populations and Mongolian populations (P < 0.05). A strong connection within rs231775 G allele and AS affectability was uncovered in Caucasian populations (P < 0.05). The analysis of the TSA shows that the meta-analysis can draw the conclusion.
CTLA-4 (+49 A/G) gene rs231775 G allele increases the risk of autoimmune diseases in Caucasian populations. And it also increases the risk of RA in Caucasian and Mongolian populations. More sample size and more elaborately designed studies are needed to elucidate the relationship in CTLA-4 (+49 A/G) gene rs231775 G allele and autoimmune diseases, especially AS, SLE.
Association of AIRE (rs2075876), but not CTLA4 (rs231775) polymorphisms with systemic lupus erythematosus
2021, Gene
The AIRE (rs2075876) and CTLA4 (rs231775) variants have a crucial function in controlling the negative selection and suppression of T lymphocytes. Numerous reports studied the association of AIRE and CTLA4 variants with different autoimmune disorders, but with inconclusive conclusions. The main purpose of this work is to evaluate the association of these two variants with SLE susceptibility among Egyptian patients.
A total of 247 participants (100 SLE patients and 147 healthy controls) were enrolled in this case-controlled study. The genomic DNA of these dual variants was genotyped using the TaqMan genotyping method.
The AIRE (rs2075876) variant conferred protection against developing SLE disease under allelic [A allele vs. G allele; OR = 0.16, 95%CI = 0.09–0.28], and dominant [GA + AA vs. GG; OR = 0.14, 95%CI = 0.05–0.34] models. Moreover, patients with AIRE rs2075876 (A/A) genotype revealed a statistically significant with lower levels of complement 3 (p-value = 0.007). Nonetheless, the CTLA4 (rs231775) variant was not associated with increased risk of SLE under all genetic association models (p-value > 0.05). However, CTLA4 rs231775 (G/G) genotype observed significant difference with recurrent infection and hematuria.
Our findings indicated that the AIRE (rs2075876) variant conferred protection against developing SLE disease, but not the CTLA4 (rs231775) variant.
Signal peptide missense variant in cancer-brake gene CTLA4 and breast cancer outcomes
2020, Gene
Citation Excerpt :
The prevalence of breast carcinoma in Egypt is rising significantly year by year with unclear etiology (Abou-El-Naga et al., 2018). Cytotoxic T-lymphocyte associated protein 4 (CTLA4; OMIM number: 123890, also known as CD152) is a immunosuppressive cytokine of the immunoglobulin superfamily that executes an inhibitory signal on T-lymphocyte immune responses (Magistrelli et al., 1999; Elshazli et al., 2015). CTLA4 protein comprises of three different segments, a V domain with a transmembrane domain in addition to a cytoplasmic tail (Ling et al., 1999).
The cancer-brake gene CTLA4 has a vital function in suppressing the immune responses of activated T lymphocytes. Numerous reports explored the impact of various CTLA4 variants with the predisposition for malignancies but with unconvincing findings. Hence, this study is designed to assess the association of CTLA4 (c.49A>G, rs231775) variant with the outcome of breast carcinoma.
A total of 272 participants (93 BC patients and 179 cancer-free healthy volunteers) were enrolled. Genomic DNA for all participants was genotyped for CTLA4 (c.49A>G) variant via TaqMan genotyping assay. Patients with A/G genotype conferred protection against developing BC under heterozygote comparison (OR = 0.56, 95%CI = 0.31–0.98) as well dominant model (OR = 0.55, 95%CI = 0.32–0.97). AG/GG genotypes were anchored with an increased risk of nodal infiltration (OR = 2.90, 95%CI = 1.03–8.17, P = 0.037), metastasis (OR = 4.46, 95%CI = 1.18–16.8, P = 0.019), advanced clinical stage (OR = 6.54, 95%CI = 2.06–20.75, P < 0.001), recurrence (OR = 5.2, 95%CI = 1.73–15.7, P = 0.001), and shorter survival (OR = 2.54, 95%CI = 1.08–5.99, P = 0.032). In addition, functional enrichment analysis revealed the key role of CTLA4 in cancer immunosurveillance. Our findings indicated that the CTLA4 c.49A>G variant might have prognostic as well diagnostic impact in breast cancer.

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Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) + 49 A>G gene polymorphism in Egyptian cases with rheumatoid arthritis

Highlights

Abstract

Background

Subjects and methods

Results

Conclusions

Introduction

Section snippets

Subjects and methods

Results

Discussion

Conflict of interest

Acknowledgment

Clin. Chim. Acta

Rheum. Dis. Clin. N. Am.

Autoimmun. Rev.

Best Pract. Res. Clin. Rheumatol.

Curr. Opin. Immunol.

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum.

A single nucleotide polymorphism in exon 1 of cytotoxic T-lymphocyte-associated-4(CTLA-4) is not associated with rheumatoid arthritis

Rheumatology (Oxford)

Haplotype analysis in simplex families and novel analytic approaches in a case–control cohort reveal no evidence of association of the CTLA-4 gene with rheumatoid arthritis

Arthritis Rheum.

CTLA4 exon1 A49G polymorphism in Slovak patients with rheumatoid arthritis and Hashimoto thyroiditis—results and the review of the literature

Clin. Rheumatol.

Confirmation of STAT4, IL2/IL21, and CTLA4 polymorphisms in rheumatoid arthritis

Arthritis Rheum.

The contribution of HLA to rheumatoid arthritis

Clin. Genet.

Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease

J. Clin. Endocrinol. Metab.

Cross-cultural adaptation and validation of an Arabic Health Assessment Questionnaire for use in rheumatoid arthritis patients

Joint Bone Spine

Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population

World J. Gastroenterol.

Measurement of patient outcome in arthritis

Arthritis Rheum.

Contribution of PTPN22 1858T, TNFRII 196R and HLA-shared epitope alleles with rheumatoid factor and anti-citrullinated protein antibodies to very early rheumatoid arthritis diagnosis

Rheumatology (Oxford)

CTLA4 polymorphisms in Spanish patients with rheumatoid arthritis

Tissue Antigens

HLA-DQB1 CAR1/CAR2, TNFa IR2/IR4 and CTLA-4 polymorphisms in Tunisian patients with rheumatoid arthritis and Sjögren's syndrome

Rheumatology (Oxford)

CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location

J. Immunol.