transforming-growth-factor-beta and Spondylitis--Ankylosing

Dickkopf-1 (Dkk-1) is a soluble inhibitor of the canonical Wnt pathway, which plays critical roles in embryonic development. Evidence suggests that this molecule regulates several aspects of both bone biology and fibrosis.. To provide an overview of our current knowledge of the role of Dkk-1 in joint remodeling and fibrosis.. We performed an electronic search (Medline) using the following key words: Dickkopf-1 (or Dkk-1), new bone formation, joint remodeling, ankylosing spondylitis, systemic sclerosis (or scleroderma), and fibrosis, supplemented by a manual search of references from retrieved articles.. Dkk-1 is a master regulator of joint remodeling in animal models of arthritis shifting the balance toward new bone formation when its expression is decreased and toward erosion/joint destruction when its expression is increased. In humans, evidence suggests that Dkk-1 may be dysfunctional in patients with ankylosing spondylitis, a prototype bone forming disease. Moreover, data from animal models indicate that Dkk-1 has a protective role against fibrosis in several organs. Recent data suggest that inhibiting the canonical Wnt pathway by overexpression of Dkk-1 could be a way to target TGF-β signaling in fibrotic diseases. Finally, B-cell depletion therapy in systemic sclerosis may exert its effects through TGF-β dependent upregulation of Dkk-1.. Dkk-1 appears to play a crucial role in both joint remodeling/ectopic ossification and fibrosis, and may be a prospective therapeutic modality for fibrotic diseases or diseases characterized by pathologic joint remodeling.

Topics: Animals; B-Lymphocytes; Bone Remodeling; Fibrosis; Humans; Intercellular Signaling Peptides and Proteins; Scleroderma, Systemic; Spondylarthropathies; Spondylitis, Ankylosing; Transforming Growth Factor beta; Wnt Signaling Pathway

There is strong evidence from twin and family studies indicating that a substantial proportion of the heritability of susceptibility to ankylosing spondylitis (AS) and its clinical manifestations is encoded by non-major-histocompatibility-complex genes. Efforts to identify these genes have included genomewide linkage studies and candidate gene association studies. One region, the interleukin (IL)-1 gene complex on chromosome 2, has been repeatedly associated with AS in both Caucasians and Asians. It is likely that more than one gene in this complex is involved in AS, with the strongest evidence to date implicating IL-1A. Identifying the genes underlying other linkage regions has been difficult due to the lack of obvious candidates and the low power of most studies to date to identify genes of the small to moderate magnitude that are likely to be involved. The field is moving towards genomewide association analysis, involving much larger datasets of unrelated cases and controls. Early successes using this approach in other diseases indicates that it is likely to identify genes in common diseases like AS, but there remains the risk that the common-variant, common-disease hypothesis will not hold true in AS. Nonetheless, it is appropriate for the field to be cautiously optimistic that the next few years will bring great advances in our understanding of the genetics of this condition.

Topics: Asian People; Cytochrome P-450 CYP2D6; Family Health; Genetic Linkage; Genetic Markers; Genetic Predisposition to Disease; HLA-B27 Antigen; Humans; Interleukin-1; Intracellular Signaling Peptides and Proteins; Major Histocompatibility Complex; Nod2 Signaling Adaptor Protein; Phosphate Transport Proteins; Proteins; Spondylitis, Ankylosing; Transforming Growth Factor beta; Twin Studies as Topic; White People

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antirheumatic Agents; Blood Sedimentation; Bone Density; Diagnosis, Differential; Etanercept; HLA-B27 Antigen; Humans; Immunoglobulin G; Infliximab; Interleukin-1; Magnetic Resonance Imaging; Methotrexate; Orthopedic Procedures; Receptors, Tumor Necrosis Factor; Spondylitis, Ankylosing; Transforming Growth Factor beta

Topics: CD8-Positive T-Lymphocytes; Humans; Immunoglobulin A; Psoriasis; Spondylitis, Ankylosing; Transforming Growth Factor beta

Ankylosing spondylitis (AS) is an inflammatory rheumatic disease with increased bone mass in the main sites of inflammation. Regulatory T (Treg) cells have been reported to involve in pathology of AS. This study designed at investigating the effects of nanocurcumin on Treg cell responses in peripheral blood (PB) of AS patients.. Test group including 12 AS patients received nanocurcumin daily for 4 months and control group including 12 patients received placebo. The frequency of Treg was measured by flow cytometry. The expression levels of FoxP3 and several associated microRNAs (miRNAs; miR-27, miR-17, and miR-146a) and cytokines including Interleukin-10 (IL-10), TGF-β, and IL-6 were assessed by real-time polymerase chain reaction. Furthermore, enzyme-linked immunosorbent assay was done to determine the secretion levels of cytokines.. After treatment with nanocurcumin the frequency of Treg cells in AS patients increased significantly. The RT-PCR data indicated that the expression of miR-17 and miR-27 were significantly decreased following nanocurcumin treatment while miR-146a and FoxP3 were significantly increased. Moreover, nanocurcumin-treated group had high levels of IL-10 and TGF-β and low levels of IL-6 production than control group.. The findings suggested that dysregulation of Treg cells in PB influences the AS development and nanocurcumin therapy could regulate the Treg cells, and so could be useful in the treatment of AS and may be other autoimmune diseases. This study is registered with IRCT.ir, number IRCT2017052927520N7.

Topics: Adult; Curcumin; Double-Blind Method; Female; Forkhead Transcription Factors; Humans; Inflammation; Interleukin-10; Interleukin-6; Leukocytes, Mononuclear; Male; MicroRNAs; Middle Aged; Nanoparticles; Spondylitis, Ankylosing; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Young Adult

Tumor necrosis factor-alpha has a prominent role in the inflammatory process and bone resorption in patients with ankylosing spondylitis (AS). We evaluated the markers of clinical efficacy and bone biochemical changes in Korean patients with AS treated with etanercept therapy.. Serum samples from 26 patients receiving etanercept for refractory AS were obtained at baseline and 12 weeks after treatment. Clinical measures and serum levels of transforming growth factor-Beta (TGF-Beta), matrix metalloproteinase-3 (MMP-3), macrophage-colony stimulating factor (M-CSF), bone-specific alkaline phosphatase (BALP), osteocalcin, C-telopeptide (CTX), receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) were measured at each timepoint.. Significant improvement of the Bath AS Disease Activity Index (BASDAI) and Functional Index (BASFI) was achieved after 12 weeks (p < 0.001). ASsessments in Ankylosing Spondylitis Working Group (ASAS) 20 criteria were achieved by 22 patients (84.6%) after 12 weeks' treatment. ASAS 50 and 70 were achieved by 10 (38.5%) and 7 patients (26.9%). Serum levels of BALP and osteocalcin were significantly increased after 12 weeks of treatment (p < 0.05). Serum levels of CTX were not changed after treatment. Serum levels of TGF-Beta, MMP-3, and M-CSF were significantly decreased after 12 weeks of treatment (p < 0.05). Serum levels of OPG and RANKL were not changed. Change of MMP-3 had a high correlation coefficient with changes of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) upon etanercept treatment (CRP, r = 0.446, p = 0.022; ESR, r = 0.449, p = 0.021).. In patients with AS, etanercept therapy may be effective for reducing disease activity and improving bone biochemical markers. MMP-3 may be a useful biomarker for monitoring etanercept therapy.

Topics: Adult; Alkaline Phosphatase; Antirheumatic Agents; Biomarkers; Collagen Type I; Dose-Response Relationship, Drug; Etanercept; Female; Humans; Immunoglobulin G; Korea; Macrophage Colony-Stimulating Factor; Male; Matrix Metalloproteinase 3; Middle Aged; Osteocalcin; Osteoprotegerin; Peptides; RANK Ligand; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Spondylitis, Ankylosing; Transforming Growth Factor beta

This study aimed to investigate whether Forkhead box O3a (FOXO3a) modulates inflammation and oxidative stress in ankylosing spondylitis (AS). We applied bioinformatics analysis, quantitative real-time polymerase chain reaction, immunoblotting, enzyme linked immunosorbent assay, chromatin immunoprecipitation, and dual-luciferase reporter assay. Gene overexpression and knockdown of FOXO3a were conducted

Topics: Antioxidants; Forkhead Box Protein O3; Heme Oxygenase-1; Humans; Inflammation; Oxidative Stress; Spondylitis, Ankylosing; Transforming Growth Factor beta

Ankylosing spondylitis (AS) is a prototype of chronic inflammatory arthritis termed seronegative spondyloarthropathies that typically affects the joints. Among the non-Human leukocyte antigen (HLA) loci, the strongest association has been observed with Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene single nucleotide polymorphisms (SNPs). Moreover, the effect of ERAP1 gene SNPs on the pro-inflammatory and anti-inflammatory cytokines in AS disease has still been poorly elucidated. In this study, we aimed to determine the association of ERAP1 gene SNPs (rs30187 and rs2287987) with AS risk as well as their effect on the mRNA expression of pro-inflammatory and anti-inflammatory cytokines, with emphasis on the immunoregulation of the IL-17/IL-23 pathway, in an Iranian population.. We performed Single specific primer (SSP)-PCR for genotyping of 160 AS patients and 160 healthy controls. After isolation of peripheral blood mononuclear cells (PBMCs), total RNA of PBMCs was isolated, complementary DNA (cDNA) was synthesized, and quantitative analyses of mRNA expression of cytokines were performed by Real-time PCR for 40 HLA-B27 positive AS patients and 40 healthy individuals as controls.. It was seen that T allele of rs30187 (OR = 1.54, 95% CI = 1.07-2.22, P =  0.017) and C allele of rs2287987 (OR 1.50, 95% CI 1.05-2.14, P = 0.024) were associated with the risk of AS. Both of these alleles were associated more strongly in the HLA-B27 positive AS patients. There was a significant overexpression of mRNAs of pro-inflammatory (IL-17A, IL-17F, IL-23, TNF-α and IFN-γ), while downregulation of anti-inflammatory cytokines (IL-10 and TGF-β) in PBMCs from 40 HLA-B27 positive AS patients in comparison to controls. AS patients with rs30187 SNP TT genotype expressed mRNA of IL-17A, IL-17F, and IL-23 significantly higher than patents with CT and CC genotypes for this SNP.. This study represented the association of ERAP1 gene rs30187 and rs2287987 polymorphism with the risk of AS. Additionally, it appears that rs30187 polymorphism may be involved in the immunomodulation of the IL-17/IL-23 pathway in the AS disease.

Topics: Adult; Alleles; Aminopeptidases; Case-Control Studies; Cytokines; Female; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; HLA-B27 Antigen; Humans; Interferon-gamma; Interleukin-10; Interleukin-17; Interleukin-23; Iran; Leukocytes, Mononuclear; Male; Middle Aged; Minor Histocompatibility Antigens; Polymorphism, Single Nucleotide; Spondylitis, Ankylosing; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

To evaluate the T helper 17 (Th17) axis and its relation to tumor necrosis factor (TNF) alpha blockage and disease activity in ankylosing spondylitis (AS). The study included 127 AS patients (100M/27F) and 38 (27M/11F) controls. Spinal mobility was assessed by the bath ankylosing spondylitis metrology index (BASMI). Patients were also evaluated with the bath ankylosing spondylitis functional (BASFI) and bath ankylosing spondylitis disease activity index. Cytokines including IL-6, IL-12, TGF-β, IL-17A, and IL-23 were measured in serum sample using commercially available ELISA kits. Cytokines including IL-6, IL-12, TGF-β, IL-17, and IL-23 were significantly higher in the AS patients than the controls (P < 0.05). The Th-17-related cytokines were not different between patients treated with anti-TNF and conventional therapies (P > 0.05). Cytokines were also similar between patients with active and inactive disease (P > 0.05). On correlation analysis, IL-17 was correlated with IL-23 and IL-12 (P < 0.05) and IL-23 showed correlations with IL-12 and BASMI (P < 0.05). We found serum levels of Th-17-related cytokines to be significantly increased in the sera of AS patients. Disease activity and treatment type did not affect the level of these cytokines.

Topics: Adolescent; Adult; Biomarkers; Biomechanical Phenomena; Case-Control Studies; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunosuppressive Agents; Interleukin-12; Interleukin-17; Interleukin-23; Interleukin-6; Male; Middle Aged; Physical Examination; Predictive Value of Tests; Range of Motion, Articular; Severity of Illness Index; Spine; Spondylitis, Ankylosing; Th17 Cells; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha; Turkey; Up-Regulation; Young Adult

To investigate p38 mitogen activated protein kinase (MAPK) signalling in an in vitro model of bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ)-induced chondrogenesis and in vivo, with specific attention to its potential role in ankylosing enthesitis.. Human periosteum-derived cells (hPDCs) were cultured in pellets and stimulated with BMP2 or TGFβ1 in the presence or absence of a p38 inhibitor SB203580 or proinflammatory cytokines. Chondrogenic differentiation was evaluated using quantitative PCR. Male DBA/1 mice from different litters were caged together at the age of 8 weeks and treated with SB203580 in both a preventive and therapeutic strategy. The mice were evaluated for prospective signs of arthritis and the toe joints were analysed histologically to assess disease severity.. p38 inhibition by SB203580 and proinflammatory cytokines downregulated chondrogenic markers in pellet cultures stimulated by BMP2 or TGFβ1. In contrast, the in vivo experiments resulted in an increased clinical incidence of arthritis and pathology severity score, reflecting progression towards ankylosis in mice given SB203580.. Inhibition of p38 inhibited chondrogenic differentiation of progenitor cells, showing that not only the SMAD signalling pathways and also alternative activation of MAPKs including p38 contribute to chondrogenesis. Such an inhibitory effect is not found in an in vivo model of joint ankylosis and spondyloarthritis. Increased incidence and severity of disease in preventive experiments and shifts in disease stages in a therapeutic experimental set-up suggest that specific inhibition of p38 may have deleterious rather than beneficial effects.

Topics: Animals; Ankylosis; Bone Morphogenetic Proteins; Cell Proliferation; Cells, Cultured; Chondrocytes; Chondrogenesis; Disease Models, Animal; Enzyme Activation; Enzyme Inhibitors; Gene Expression; Imidazoles; Male; Mice; Mice, Inbred DBA; p38 Mitogen-Activated Protein Kinases; Periosteum; Pyridines; Signal Transduction; Smad Proteins; Spondylitis, Ankylosing; Transforming Growth Factor beta

Subclinical gut inflammation has been demonstrated in patients with ankylosing spondylitis (AS). This study was undertaken to determine the frequency of regulatory CD4+CD25(high) T cells (Treg cells) and to evaluate Treg cell-related cytokines (interleukin-2 [IL-2], transforming growth factor β [TGFβ], and IL-10) and transcription factors (FoxP3 and STAT-5) in the ileum of patients with AS.. Quantitative gene expression analysis, by reverse transcriptase-polymerase chain reaction, of Treg-related cytokines (IL-2, TGFβ, and IL-10) and transcription factors (STAT-5 and FoxP3) was performed on ileal biopsy specimens from 18 patients with AS, 15 patients with active Crohn's disease (CD), and 15 healthy subjects. Tissue and circulating Treg cells were also analyzed by flow cytometry.. A significant up-regulation of IL-2, TGFβ, FoxP3, STAT-5, and IL-10 transcripts in the terminal ileum of AS patients displaying chronic ileal inflammation was observed. Flow cytometric analysis of Treg cells showed significant peripheral expansion in both patients with AS and chronic inflammation and patients with CD (mean ± SD 1.08 ± 0.4% and 1.05 ± 0.3%, respectively) as compared with healthy subjects (0.25 ± 0.12%) (P < 0.05). Interestingly, a 5-fold increase in the proportion of Treg cells was observed in the gut of patients with AS (5 ± 3%) as compared with healthy subjects (1.2 ± 0.4%) (P < 0.001), with 70-80% of these cells also producing IL-10. In vitro studies showed that blocking IL-10 was sufficient to induce Th17 polarization on lamina propria mononuclear cells isolated from AS patients.. Our findings provide the first evidence that an active Treg cell response, mainly dominated by IL-10 production, occurs in the gut of AS patients and is probably responsible for the absence of a clear Th17 polarization in the ileum of AS patients.

Topics: Adult; Biopsy; Case-Control Studies; Cells, Cultured; Female; Forkhead Transcription Factors; Humans; Ileum; Interleukin-10; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Interleukin-23; Intestinal Mucosa; Male; Middle Aged; RNA, Messenger; Spondylitis, Ankylosing; STAT5 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Topics: Adult; Biomarkers; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Female; Humans; Interleukin-17; Male; Spondylitis, Ankylosing; Transforming Growth Factor beta

Topics: Antirheumatic Agents; Biomarkers; Bone Matrix; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bone Remodeling; Etanercept; Humans; Immunoglobulin G; Macrophage Colony-Stimulating Factor; Matrix Metalloproteinase 3; Osteoprotegerin; Receptors, Tumor Necrosis Factor; Spondylitis, Ankylosing; Transforming Growth Factor beta; Treatment Outcome

To characterise the immunohistological features of sacroiliitis in ankylosing spondylitis (AS) at different disease stages.. Biopsy samples from sacroiliac joints (SIJs) of five patients with AS, two with early, three with advanced changes and samples from age matched controls from one necropsy SIJ and two iliac bone marrow (BM) biopsies were studied. Paraffin sections were immunostained in triplicate for T cells (CD3, CD8), macrophages (CD68), and the cytokines tumour necrosis factor alpha (TNFalpha), interferon gamma, interleukin (IL) 1beta, IL6, IL10, and transforming growth factor beta1 (TGFbeta1). Stained cells were counted over one entire high power field (x400) per section in BM, cartilage, and other connective tissue (CT). Results are the mean of three sections.. CD3+ T cells were numerous in the BM of early AS, and in the CT of one patient with early and one with late AS, with variable proportions of CD8+ T cells. All patients with AS had more CD68+ macrophages than controls in BM and CT; in cartilage, one patient with early and one with late AS had increased CD68+ cells, some being osteoclasts. The patient with very early AS had large numbers of TNFalpha cells in the three tissular areas; for the other patient with early disease they were found only in CT and cartilage. IL6 was seen in 4/4 patients with AS in most areas. Patients with early disease had more T cells, TNFalpha, and IL6, and patients with advanced AS more TGFbeta1.. The immunohistological findings of a limited sample suggest a role for BM in sacroiliitis, for TNFalpha and IL6 in early, active lesions, and for TGFbeta1 at the time of secondary cartilage and bone proliferation.

Topics: Adolescent; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Biopsy; Bone Marrow Cells; Cartilage, Articular; Case-Control Studies; CD8-Positive T-Lymphocytes; Connective Tissue; Disease Progression; Female; Humans; Immunohistochemistry; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-6; Macrophages; Male; Sacroiliac Joint; Spondylitis, Ankylosing; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial joints with no satisfactory therapy. Reduction of joint pain has been reported after a course of therapy at a spa, Gasteiner Heilstollen, in Badgastein in Austria. The mechanism underlying this beneficial effect is not clearly understood and objective evidence for the biological response to therapy is lacking. The aim of this study was to find evidence for a biological response to speleotherapy in patients with AS and to study the involvement of the antiinflammatory cytokine TGF-beta1 in this response.. 83 patients with AS were treated in Badgastein for 3-4 weeks. Therapy included active exercises, hyperthermia and exposure to low doses of radon in a former mine. Response to therapy was assessed from measurement of morning pain and immunoassay of serum levels of TGF-beta1 before and after therapy. Ten AS patients who received conventional therapy and 10 patients with low back pain (LBP) served as controls.. A significant increase in TGF-beta1 (total and active) was found in AS patients after spa therapy. Mean concentration of total TGF-beta1 increased from 28,715 pg/ml to 43,136 pg/ml, (P<0.01) and active TGF-beta1 increased from 77 pg/ml to 1096 pg/ml (P<0.001). When the AS patients were divided into two groups according to pain reduction, group 1 (decrease in morning pain, responders: n=46) exhibited a 17-fold increase of active TGF-beta1 levels (96 pg/ml to 1654 pg/ml, P<0.0001) whereas group 2 (no change or an increase in morning pain: nonresponders: n=37), showed only 7-fold increase (53 pg/ml to 402 pg/ml, P<0.01). There was a moderate increase in active TGF-beta1 from 31 pg/ml to 42 pg/ml (P<0.05) in patients with LBP and no significant change was observed in the patients treated with conventional therapy.. These results demonstrate a significant increase in circulating TGF-beta1 in patients with AS after the combined spa-exercise therapy in Badgastein. The results also provide evidence for a biological response to speleotherapy and suggest that TGF-beta, through its antiinflammatory function, may play a role in this response.

Topics: Adult; Aged; Balneology; Biomarkers; Combined Modality Therapy; Exercise Therapy; Female; Humans; Immunologic Factors; Male; Middle Aged; Retrospective Studies; Spondylitis, Ankylosing; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

To study serum levels of transforming growth factor beta-1 (TGFbeta1) and the expression of TGFbeta1 in in vitro peripheral blood mononuclear cell (PBMC) cultures in oriental ankylosing spondylitis (AS) patients, and to determine their association with codon 10 and 25 TGFB1 gene polymorphisms.. Serum levels of TGFbeta1 were measured by enzyme-linked immunosorbent assay (ELISA). The ability of PBMCs to synthesize TGFbeta1 and other cytokines was assessed by in vitro cultures stimulated with mitogen. Genomic DNA was extracted from PBMCs of AS patients (n=72) or unrelated healthy controls (n=96). The codon 10 and 25 polymorphisms in the TGFB1 gene were analysed using standard polymerase chain reaction-based methods.. AS patients had significantly higher serum TGFbeta1 levels than controls (P<0.001). There was no difference in the distribution of codon 10 and 25 TGFB1 genotypes between AS patients and controls. Incubation of AS and control PBMC with phytohaemagglutinin (PHA) led to upregulation of TGFbeta1, interleukin-10, tumour necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) assessed by ELISA. Importantly, PHA-induced TGFbeta1 production was significantly enhanced in AS patients compared with normal controls whereas the production of the pro-inflammatory cytokines TNFalpha and IFNgamma was reduced.. Our results show that AS patients express significantly higher levels of serum TGFbeta1 independent of the codon 10 and 25 genotype. Activation of AS PBMCs led to enhanced TGFbeta1 production accompanied by reduction of TNFalpha and IFNgamma while the converse was observed in normal controls.

Topics: Cells, Cultured; Cytokines; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Lymphocyte Activation; Phytohemagglutinins; Polymorphism, Genetic; Spondylitis, Ankylosing; Transforming Growth Factor beta; Transforming Growth Factor beta1

Genetic factors are thought to be crucial in the pathogenesis of ankylosing spondylitis. Transforming growth factor beta 1 (TGF beta 1) is a multifunctional cytokine that plays a key role in inflammation. Two functional single nucleotide polymorphisms (SNPs) in the TGFB1 gene have been described: TGFB1 T869C and TGFB1 G915C.. To determine whether these SNPs contribute to ankylosing spondylitis susceptibility or its disease characteristics.. Genomic DNA was isolated from the peripheral blood of 134 patients with ankylosing spondylitis and 194 healthy blood donors. All subjects were unrelated and of white Dutch ethnicity. The diagnosis of ankylosing spondylitis was made according to the modified New York criteria. The TGFB1 T869C and TGFB1 G915C SNPs were genotyped by a polymerase chain reaction-single strand conformation polymorphism haplotyping method.. No significant differences were found between patients and controls in genotype, allele, and haplotype frequencies or in the carrier rate of the rare alleles of the TGFB1 T869C and TGFB1 G915C SNPs.. TGFB1 T869C and TGFB1 G915C SNPs are not major factors in the susceptibility to ankylosing spondylitis or its disease characteristics.

Topics: Adult; Aged; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Heterozygote; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Spondylitis, Ankylosing; Transforming Growth Factor beta; Transforming Growth Factor beta1

To determine whether genetic polymorphisms in or near the transforming growth factor beta1 (TGFB1) locus were associated with susceptibility to or severity of ankylosing spondylitis (AS).. Five intragenic single-nucleotide polymorphisms (SNP) and three microsatellite markers flanking the TGFB1 locus were genotyped. Seven hundred and sixty-two individuals from 184 multiplex families were genotyped for the microsatellite markers and two of the promoter SNPs. One thousand and two individuals from 212 English and 170 Finnish families with AS were genotyped for all five intragenic SNPs. A structured questionnaire was used to assess the age of symptom onset, disease duration and disease severity scores, including the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index).. A weak association was noted between the rare TGFB1 +1632 T allele and AS in the Finnish population (P = 0.04) and in the combined data set (P = 0.03). No association was noted between any other SNPs or SNP haplotype and AS, even among those families with positive non-parametric linkage scores. The TGFB1 +1632 polymorphism was also associated with a younger age of symptom onset (English population, allele 2 associated with age of onset greater by 4.2 yr, P = 0.05; combined data set, allele 2 associated with age of onset greater by 3.2 yr, P = 0.02). A haplotype of coding region SNPs (TGFB1 +869/+915+1632 alleles 2/1/2) was associated with age of symptom onset in both the English parent-case trios and the combined data set (English data set, haplotype 2/1/2 associated with age of onset greater by 4.9 yr, P = 0.03; combined data set, haplotype 2/1/2 associated with greater age of onset by 4.2 yr, P = 0.006). Weak linkage with AS susceptibility was noted and the peak LOD score was 1.3 at distance 2 cM centromeric to the TGFB1 gene. No other linkage or association was found between quantitative traits and the markers.. This study suggests that the polymorphisms within the TGFB1 gene play at most a small role in AS and that other genes encoded on chromosome 19 are involved in susceptibility to the disease.

Topics: Adult; Chi-Square Distribution; England; Female; Finland; Genetic Predisposition to Disease; Haplotypes; HLA-B27 Antigen; Humans; Linkage Disequilibrium; Male; Microsatellite Repeats; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Spondylitis, Ankylosing; Transforming Growth Factor beta

Topics: Animals; Animals, Genetically Modified; Antigen Presentation; Arthritis, Psoriatic; Arthritis, Reactive; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Crohn Disease; Cystine; Dimerization; Fibrillins; Genetic Predisposition to Disease; Histocompatibility Antigens Class I; HLA-B27 Antigen; Humans; Lung; Lymphocyte Activation; Marfan Syndrome; Mice; Microfilament Proteins; Models, Immunological; Organ Specificity; Protein Conformation; Rats; Sacroiliac Joint; Spondylitis, Ankylosing; Stress, Mechanical; Transforming Growth Factor beta; Uveitis, Anterior