The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT)13, (GT)20, and (GT)24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14+ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P=0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14+ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats.     

Association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and nontuberculous mycobacterial lung disease in a Korean population

This study evaluated the association between the guanine-thymine (GT) repeat polymorphism in intron II of the Toll-like receptor 2 (TLR2) gene and lung disease caused by nontuberculous mycobacteria (NTM). Polymerase chain reaction and gene scans were used to determine the numbers of GT repeats for 193 patients with the nodular bronchiectatic form of NTM lung disease, including 110 patients with Mycobacterium avium-intracellulare (MAC) infection, 82 patients with Mycobacterium abscessus infection, and 1 patient with co-infection of both organisms. These values were compared with the results for 191 controls. Genotypes with shorter GT repeats were more common among patients with NTM lung disease (50.8 vs 37.7%, p = 0.01). In the subgroup analysis, genotypes that included S alleles were more common in the patients with MAC lung disease (53.6%, p = 0.01, OR, 1.91; 95% CI, 1.16, 3.16) than in healthy controls, whereas this difference was not statistically significant in patients with M. abscessus lung disease (47.6%, p = 0.13). In conclusion, these results suggest that the GT repeat microsatellite polymorphisms in intron II of the human TLR2 gene contribute to the development of NTM lung disease, especially MAC lung disease, in a Korean population.     

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles (P < 0.001; odds ratio (OR) = 2.32; 95% confidence interval (CI) = 1.57–3.42) and fewer L alleles (P = 0.02; OR = 0.66; 95% CI = 0.46–0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR = 2.05, 95% CI = 1.26–3.34), and this association was influenced by the presence of APOE ?4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.     

IgG rheumatoid factors and anti-nuclear antibodies in rheumatoid vasculitis.

We studied the distribution and characteristics of circulating rheumatoid factors (RF) and anti-nuclear antibodies (ANA) in 30 rheumatoid arthritis (RA) patients who had polyarthritis alone (group I), 28 RA patients with polyarthritis and extra-articular disease (group II), 28 RA patients with systemic vasculitis (group III) and 60 healthy matched controls. IgG RF occurred more frequently and in higher serum titres in group III (100%) than RA patients in group I (40%), or in group II (18%) or in normal controls (5.8%). The serum titre of IgM RF was higher in vasculitis patients than in other RA patients. ANA were found in 74% of all RA patients and although the frequency did not differ in the three patient groups, the serum titre was significantly higher in the vasculitis group. Antibodies to extractable nuclear antigen were found only in group III (18.7%). Antibodies to histones were also more prevalent in group III than in the other RA groups. The serological abnormalities in rheumatoid vasculitis differed quantitatively as well as qualitatively from other RA patients.     

HLA-DRB1 alleles encoding the "shared epitope" are associated with susceptibility to developing rheumatoid arthritis whereas HLA-DRB1 alleles encoding an aspartic acid at position 70 of the beta-chain are protective in Mexican Mestizos

The risk to develop rheumatoid arthritis (RA) has been associated with the presence of HLA-DRB1 alleles encoding the "shared epitope" (SE). Additionally, HLA-DRB1 alleles encoding an aspartic acid at position 70 (D70+ ) have been associated with protection against the development of RA. In this study we tested the association between either SE or D70+ and rheumatoid arthritis in Mexican Mestizos. We included 84 unrelated Mexican Mestizos patients with RA and 99 unrelated healthy controls. The HLA-typing was performed by PCR-SSO and PCR-SSP. We used the chi-squared test to detect differences in proportions of individuals carrying at least one SE or D70+ between patients and controls. We found that the proportion of individuals carrying at least one HLA-DRB1 allele encoding the SE was significantly increased in RA cases as compared to controls (p(c) = 0.0004, OR = 4.1, 95% CI = 2.2-7.7). The most frequently occurring allele was HLA-DRB1*0404 (0.161 vs 0.045). Moreover, we observed a significantly increased proportion of HLA-DRB1 SE+ cases with RF titers above the median (p = 0.005). Conversely, the proportion of individuals carrying at least one HLA-DRB1 allele encoding the D70+ was significantly decreased (p(c) = 0.004, OR = 0.4, 95% CI 0.2-0.7) among RA patients compared with controls. In conclusion, the SE is associated with RA in Mexican Mestizos as well as with the highest titers of RF.     

Intercellular adhesion molecule-1 polymorphisms in Korean patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by synovial proliferation and the accumulation of inflammatory cells in the affected joints. Intercellular adhesion molecule-1 (ICAM-1) is readily detected in RA synovial tissues and helps recruit inflammatory cells to the joint. ICAM-1 shows genetic polymorphisms at codons 241 (R241G) and 469 (K469E). In order to investigate the association between ICAM-1 gene polymorphisms and RA, we genotyped ICAM-1 R241G and ICAM-1 K469E polymorphisms in 143 Korean patients with RA, and in 138 healthy controls, by using the polymerase chain reaction-restriction fragment length polymorphism method. No polymorphism of R241G was found in Korean subjects. However, the frequency of the K469 allele was found to be significantly lower in RA patients than in healthy controls. Allele frequency of K469 was lower in RA patient group, compared to that in healthy controls, regardless of the shared epitope status. Distribution of K469E allele frequencies was not different whether the patient had rheumatoid factor, radiographic erosion or extra-articular complications. In conclusion, this study shows lower frequency of the ICAM-1 K469E allele in Korean patients with RA than that in healthy controls.     

Localization of Circulating Immune Complexes from Patients with Rheumatoid Arthritis in Murine Spleen Germinal Centres

In previous studies we have demonstrated high levels of rheumatoid factor (RF) and large-size (greater than 22S) circulating immune complexes (CIC) in the serum of rheumatoid arthritis (RA) patients with extra-articular disease. These findings were paralleled by a concurrent increase in the level of RF-associated cross-reactive idiotypes (CRI) and an apparent diversification of the RF repertoire detected in the serum of the same patients. In the present study we examine the ability of CICs to activate the complement system in vivo, and its possible influence on expanding the RF repertoire in RA patients with extra-articular disease. Activation of complement by CICs is the key for germinal centre localization and long-term retention of such complexes on the surface of follicular dendritic cells (FDC), and so provides a source for the selection of cells with high affinity receptors for IgG and leads to the establishment of immunological memory. CICs containing different immunoglobulin isotypes and from different patients localized in mouse spleen germinal centres. However, intense localization was mainly seen for IgG-containing complexes from the serum of patients with large-size (greater than 22S) IgG-IgM RF complexes. The ability of these complexes to localize in mouse spleen germinal centres was related to activation of the complement system via the classical pathway in the patients' sera. Localization of IgG complexes was significantly (P less than 0.05) higher in sera from RA patients with extra-articular disease than those with articular disease alone. This study demonstrates the ability of large-size (greater than 22S) IgG-IgM RF complexes to activate complement, and suggests a possible role for such complexes in modulating the immune response to IgG in RA patients with extra-articular disease.     

Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer

Factors underlying genetic predisposition for development of sporadic colorectal cancer are largely unknown. The fact that this cancer is more common in patients suffering from inflammatory bowel disease raises the question of the relationship between chronic inflammation and cancer. Toll-like receptors 2 (TLR2) and 4 (TLR4) are critical in initiating innate immune response and inflammation toward various bacteria commonly found in the intestine. Recent evidence about the association of polymorphisms in these genes with ulcerative colitis and Crohn's disease, as well as other inflammatory conditions, was the basis for our investigation of their role in sporadic colorectal cancer. We assessed genotype and allele frequencies of TLR2 GT microsatelite polymorphism, TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms in 89 colorectal cancer patients and 88 age- and sex-matched controls. The frequency of TLR2 GT microsatelite alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p = 0.001, respectively), while the frequency of the allele with 31 GT repeats was increased (p = 0.0147) in patients. The mutant allele Asp299Gly of TLR4 gene was slightly more frequent in colorectal cancer patients (p = 0.0269). In conclusion, we report an association of microsatelite GT polymorphisms of TLR2 gene and Asp299Gly polymorphism of the TLR4 gene with sporadic colorectal cancer among Croatians.     

Association of the CTLA4 3' untranslated region polymorphism with the susceptibility to rheumatoid arthritis

Cytotoxic T-lymphocyte antigen 4 (CTLA4) gene polymorphism located in the 3' untranslated region (UTR) was investigated in 141 Spanish patients (38 men and 103 women) with rheumatoid arthritis (RA) and in 194 ethnically-matched healthy controls. Twenty alleles having different numbers of (AT) repeats (from 7 to 32) were found in this population. (AT)7 and (AT)16 were the most frequent alleles, and accounted for almost two-thirds of the allelic frequency in the control population. Consequently, alleles were assigned as L (large: 16 or more AT repeats) or S (short: less than 16 AT repeats). When the L/S distribution in patients and controls were compared, an increase of L alleles was observed among patients (49.9% vs. 39.7%; p = 0.02; p(c) = 0.04, odds ratio [OR] = 1.46; 95% confidence interval [CI], 1.06-2.01). Hence, the frequency of S alleles was decreased among patients (51.1% vs. 60.3%; p = 0.02; p(c) = 0.04; OR = 0.69; 95%CI, 0.50-0.95). Moreover, a statistically significant decrease in the frequency of S/S individuals was observed among RA patients (27.7% versus 40.7%; p = 0.01; p(c) = 0.03; OR = 0.56; 95%CI, 0.34-0.91). These differences were irrespective of the HLA "shared epitope" (SE) status, and were observed similarly among SE+ as well as among SE- patients. After combining these data with other reported previously by us, from studies of CTLA4 49 (A/G) and -318 (C/T) polymorphisms, we conclude that the strongest association between CTLA4 gene polymorphisms and RA susceptibility occurs with the 3' UTR polymorphism.     

Association of rheumatoid factor production with FcgammaRIIIa polymorphism in Taiwanese rheumatoid arthritis

Fcgamma receptors (FcgammaR) impact upon the development of inflammatory arthritis through immune complex stimulation and proinflammatory cytokine production. FcgammaRIIa, FcgammaRIotaIotaIotaa and FcRgammaIIIb polymorphisms were genotyped in 212 rheumatoid arthritis (RA) patients and 371 healthy control subjects using an allelic-specific polymerase chain reaction (PCR). No significant skewing in the distribution of FcgammaRIIa H/R131, FcgammaRIIIa F/V158 and FcgammaRIIIb NA1/NA2 was found between RA patients and healthy control subjects. However, a significant skewing distribution of the FcgammaRIIIa F/V158 polymorphism was observed between rheumatoid factor (RF)-positive versus RF-negative RA patients (P = 0.01). The low-affinity FcgammaRIIIa F158 allele seems to have a protective role in RF production, in comparison with the FcgammaRIIIa V158 allele (P = 0.004; OR = 0.485; 95% CI: 0.293-0.803). A high frequency of FcgammaRIIIa F/F158 was identified in RA patients with negative RF compared with RF-positive patients (for FF158 versus FV158 + VV158; P = 0.002; OR = 0.372; 95% CI: 0.194-0.713). In addition, no association was found between FcgammaRIIa H/R131, FcgammaRhoIIIa F/V158 and FcgammaRIIIb NA1/NA2 polymorphisms and other clinical parameters. The results of this study suggest that three activating FcgammaRs polymorphisms lack association with RA but FcgammaIIIa F/V158 polymorphism may influence RF production and IgG RF immune complex handling in Taiwanese RA patients.     

A transmembrane polymorphism in FcgammaRIIb (FCGR2B) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA

The aim of the current study was to determine whether the FcgammaRIIb 187-Ile/Thr polymorphism is a predisposition factor for subtypes of RA defined by disease severity and production of autoantibodies against cyclic citrullinated peptides (anti-CCPs) in Taiwanese RA patients. Genotype distributions and allele frequencies of FcgammaRIIb 187-Ile/Thr were compared between 562 normal healthy controls and 640 RA patients as stratified by clinical parameters and autoantibodies. Significant enrichment of 187-Ile allele was observed in RA patients positive for anti-CCP antibodies as compared with the anti-CCP negative RA patients (P=0.001, OR 1.652 (95% CI 1.210-2.257)) or as compared with the normal controls (P=0.005, OR 1.348 (95% CI 1.092-1.664)). In addition, 187-Ile allele was found to be enriched in RA patients positive for rheumatoid factor (RF) compared to the RF negative RA patients (P=0.024, OR 1.562 (95% CI 1.059-2.303)). Furthermore, the homozygotes were enriched in destructive male RA patients (P=0.035; OR 2.038 (95% CI 1.046-3.973)) and the 187-Ile allele was associated with early-onset of RA in Taiwanese patients (P=0.045, OR 1.548 (95% CI 1.007-2.379)). Thus, FcgammaRIIb SNP 187-Ile/Thr may influence the RA phenotypes in Taiwanese RA.     

Anti-citrullinated peptides as autoantigens in rheumatoid arthritis—relevance to treatment

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide autoantibodies (ACPAs). Citrulline derives from arginine by peptidyl arginine deiminases, and ACPAs are directed against different citrullinated antigens, including fibrinogen, fibronectin, α-enolase, collagen type II, histones. ACPAs are present in two thirds of RA patients have higher specificity than RF for RA, and are associated with joint radiographic damage and extra-articular manifestations and they are detected years before the onset clinical arthritis. Recent studies suggest that citrullinated antigens are most likely arthritogenic autoantigens in RA. ACPA production is associated with the HLA-DRB1 shared epitope (HLA-DRB1 SE) and accounts for the well-known RA-HLA-DRB1 SE association, as T cells recognize citrullinated peptides. Smoking and periodontitis, known environmental risk factors for RA promote protein citrullination and ACPA production. Cirullinated proteins are capable of inducing arthritis in transgenic mice carrying HLA-DRB1 SE genes, and ACPAs induce macrophage TNF-α production, osteoclastogenesis and complement activation. They also induce the formation of neutrophil extracellular traps (NETs). NETs, increased in RA, are a source of citrullinated autoantigens in RA and induce fibroblast interleukin-8 production. This knowledge is likely to have therapeutic implications, as there is a need of matching therapy with patient profile. Abatacept, a T cell activation modulator, is the best therapy for ACPA(+) RA patients, although clinical data are sparse at present. Rituximab, a monoclonal antibody that depletes B cells, is also the best therapy for ACPA(+) RA patients, and clinical data support this view.     

Association of PTPN22 single nucleotide polymorphism with rheumatoid arthritis but not with allergic asthma

PTPN22 gene encodes a lymphoid tyrosine phosphatase (LYP), an important negative regulator of T-cell responses. The 1858C>T (Arg620Trp) single nucleotide polymorphism (rs2476601) was found associated with autoimmune diseases, including rheumatoid arthritis (RA). Allergic diseases are similar to autoimmune diseases, by an exaggerated immune response to an antigen (allergen in this case) normally not invoking such response in healthy individuals. We investigated whether polymorphism 1858C>T in PTPN22 gene is associated with susceptibility to allergic asthma and RA in a Polish population. PTPN22 was genotyped in 173 patients with RA, in 198 patients with allergic asthma, and in 543 controls using PCR-RFLP. The patients with RA differed from healthy controls in frequencies of PTPN22 1858C>T alleles (P=0.0004; odds ratio (OR), 1.8; 95% CI, 1.33-2.55) and genotypes (P=0.0009). Strong associations of 1858T allele with RA limited to joints (0.21 vs 0.12, P=0.0002; OR, 2.1; 95% CI, 1.44-3.00), with erosive disease (0.20 vs 0.12, P=0.0003; OR, 1.92; 95% CI, 1.34-2.71), with a lack of rheumatoid factor (RF; 0.23 vs 0.12, P=0.0008; OR, 2.29; 95% CI, 1.44-3.63), and weak association with the presence of RF (0.17 vs 0.12, P=0.02; OR, 1.6; 95% CI, 1.10-2.40) in comparison with healthy controls were observed. Very strong association of 1858T allele (P<0.0001; OR, 2.72; 95% CI, 1.9-3.9) and T phenotype (P<0001; OR, 3.2; 95% CI, 2.1-4.9) with antibodies to cyclic citrullinated peptide (CCP) was found. When patients with allergic asthma were typed for PTPN22 1858C>T polymorphism, no difference with control was found. Subdivision of patients into those with mild, moderate, or severe asthma did not reveal any associations. In conclusion, we confirmed associations between several clinical manifestations of RA and PTPN22 1858T allele. However, no association with 1858C>T polymorphism was found for susceptibility to allergic asthma or for severity of the disease.     

Influence of Intron II microsatellite polymorphism in human toll-like receptor 2 gene in leprosy

Leprosy is a chronic granulomatous infection caused by the obligate intracellular organism Mycobacterium leprae. TLR2 plays a key role when activated by M. leprae lipoproteins initiating protective responses which induce bacterial killing and therefore control of disease spread. Microsatellite polymorphisms in intron2 of TLR2 gene have been reported to be associated with development of clinical features of several infectious diseases. The study aims to evaluate the influence of GT microsatellite on the expression of TLR2 which could make humans prone to M. leprae infections. A total of 279 individuals were enrolled in the study, 88 were leprosy patients, 95 were house hold contacts (HHC) and 96 were healthy controls (HC). Genotyping was done using PCR-Sequencing method. TLR2 mRNA expression was analyzed by RT-PCR. IL-10 and IFN-γ levels were measured using ELISA in MLSA stimulated cell culture supernatants. Statistical analysis was performed using Chi-Square (χ²) test and t-tests. Allele/genotype of TLR2 microsatellite which includes longer GT repeats was associated with low TLR2 mRNA expression and high IL-10 production while that including shorter GT repeats was associated with high TLR2 mRNA expression and low IL-10 production. High IL10 producing allele of TLR2 microsatellite might predispose house hold contacts to leprosy.     

Association of tumour necrosis factor-alpha -308 G/A promoter polymorphism with susceptibility and disease profile of rheumatoid arthritis

The objective was to analyze the possible involvement of tumour necrosis factor-alpha (TNF-α) -308 G/A promoter polymorphism in the susceptibility and/or the disease profile of rheumatoid arthritis (RA) in Egyptian patients. TNF-α-308 G/promoter polymorphism detection by amplification refractory mutation system (ARMS) technique was carried out for 122 RA patients and 120 healthy controls. TNF-α-308 G allele/GG homozygous genotype were higher in patients with rheumatoid arthritis than those in control group (P < 0.001, respectively). A statistically significant association was found between the frequency of the A allele and presence of erosion (OR = 3.42, P = 0.015). No associations were found between the distribution of TNF-α-308 G/A alleles/genotypes and age of patients, disease duration, absence of remission, presence of deformity, clinical manifestations of the disease and presence or absence of rheumatoid factor. The positivity of rheumatoid factor was associated with occurrence of erosion (OR = 25.0, P < 0.001). The results of this study demonstrate the association of the TNF-α-308 G allele and GG homozygous genotype with susceptibility to RA and the A allele with the presence of erosion in the Egyptian patients.     

Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.     

HLA-DRB1 ALLELES IN GREEK RHEUMATOID ARTHRITIS PATIENTS AND THEIR ASSOCIATION WITH CLINICAL CHARACTERISTICS

The association of certain HLA-DRB1 alleles in Greek rheumatoid arthritis (RA) patients with several features of the disease, the gender of the patient and the age at onset was investigated. This case control study includes 86 Greek RA patients and 130 healthy controls unrelated to the patients. HLA typing was performed by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide (SSO) probes. HLA-DR4 was significantly increased in RA patients. The alleles *0101, *0401, *0405 and *1001 were associated with a higher risk of RA. The *0408 allele was absent from our patients. Sixty-five per cent of RA patients carried the ‘shared epitope’ (SE) compared with 31.5% of controls. The risk for RA in individuals carrying a single allele positive for SE was 2.85 times higher, and for those carrying two alleles positive for SE 8.57 times higher, than in SE-negative individuals. The risk was higher in those carrying the *0401 allele, followed by *0405 and *0101, while the genotype *0401/*0404 was absent. Alleles positive for SE comprise a predisposing factor for RA at an early age, particularly in men, and are associated with positive rheumatoid factor, nodules and erosions.     

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5′ promoter (GT)_n (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3′UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS‐PCR and PCR‐RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24–3.41), but no significant differences between 5′ promoter, D543N, 3′UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.     

Analysis of two T-cell receptor BV gene segment polymorphisms in caucasoid Brazilian patients with rheumatoid arthritis

Considering the role of T-lymphocytes in rheumatoid arthritis (RA) and a possible involvement of the TCR in the pathology of this disease we analyzed allelic and genotypic frequencies of variants of two TCRBV gene segments (TCRBV3S1 and TCRBV18) in RA. A total of 95 caucasoid South Brazilian RA patients were genotyped for both TCRBV gene segment variants by restriction fragment length polymorphism preceded by PCR (PCR-RFLP) and the obtained frequencies were compared to those from healthy individuals. Allelic frequencies for the TCRBV3S1 gene segment were, respectively, for RA patients and controls, 0.447 and 0.545 (allele 1) and 0.553 and 0.455 (allele 2). Allelic frequencies for the TCRBV18 gene segment were, respectively, for RA patients and controls, 0.824 and 0.806 (allele 1) and 0.176 and 0.194 (allele 2). Neither allelic frequencies nor genotypic frequencies differ among RA and healthy individuals, suggesting that there is not a direct association among the TCRBV allelic variants studied and the development of RA and thus excluding the possibility of use of these gene segment polymorphisms as RA susceptibility markers.