Risk Of Ankylosing Spondylitis Research Articles

Increased LncRNA TUG1 expression level impacted ankylosing spondylitis risk, association with disability, and patients’ quality of life

Increased LncRNA TUG1 expression level impacted ankylosing spondylitis risk, association with disability, and patients’ quality of life

Ankylosing spondylitis risk factors: a systematic literature review.

Radiographic axial spondyloarthritis (also known as ankylosing spondylitis [AS]) is a chronic immune-mediated arthritis characterized by inflammation of the axial skeleton, peripheral joints, and entheses. It is estimated that 1 in every 200 people are affected by AS, making it an important healthcare and socioeconomic issue. In this review, we aim to explore the current understanding of AS risk factors and provide a comprehensive update. Multiple search strings were used to identify articles of interest published in PubMed between January 1, 2013, and February 1, 2021. On the basis of the literature review and analysis, we present up-to-date information on the risk factors of developing AS and our viewpoints on disease onset and progression. Multiple genetic and nongenetic risk factors have been suggested in the onset of AS. HLA-B27 is known to have a strong association with the disease, but other genes have been implicated in disease development. Aside from genetics, other factors are thought to be involved; up to 70% of patients with AS have subclinical intestinal inflammation, suggesting that the origin of the disease may be in the gut. The exact mechanism by which AS onset begins is most likely complex and multifactorial. Key Points • It remains unclear how interactions between genes, microbes, mechanical stress, gender, and other environmental and lifestyle factors predispose patients to the development of ankylosing spondylitis (AS). • The exact mechanisms of AS are complex and multifactorial which will require much future research • Recognizing the risk factors, as well as understanding gene-environment interactions, may offer valuable insights into the etiology of AS and have important implications for diagnosis and treatment strategies.

The rs6427384 and rs6692977 Single Nucleotide Polymorphisms of the Fc Receptor-Like 5 (FCRL5) Gene and the Risk of Ankylosing Spondylitis: A Case Control Study in a Single Center in China.

BackgroundThe study aimed to explore the genetic association of Fc receptor-like 5 (FCRL5) gene variants (rs6427384 and rs6692977) with ankylosing spondylitis risk in Chinese Han population.Material/MethodsGenotyping for FCRL5 gene variations rs6427384 and rs6692977 was implemented among 130 ankylosing spondylitis cases and 135 healthy persons, through polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Frequency dissimilarity for 2 polymorphisms was compared between 2 groups using chi-square test. The association strength of FCRL5 gene polymorphism with ankylosing spondylitis risk was estimated by odds ratios with 95% confidence intervals.ResultsThe frequencies of rs6427384 CC genotype and C allele were significantly lower in the case group than that in the control group (P<0.05), which suggested that C allele of rs6427384 polymorphism might offer protection against ankylosing spondylitis onset. Whereas only 2 genotypes of rs6692977 were detected in the control group, and no significant association was found with ankylosing spondylitis susceptibility.ConclusionsFCRL5 gene polymorphism rs6427384 was correlated to ankylosing spondylitis occurrence among Chinese Han population, while rs6692977 was not.

Association of IFN-γ polymorphisms with ankylosing spondylitis risk.

The case‐control study was designed to investigate the genetic effects of interferon‐gamma (IFN‐γ) rs2069727 and rs1861494 polymorphisms on ankylosing spondylitis (AS) susceptibility in a Chinese Han population. Blood samples were collected from 108 AS patients and 110 healthy controls. IFN‐γ polymorphisms were genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). Hardy‐Weinberg equilibrium (HWE) test was performed in control group. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using chi‐square test to evaluate the association between AS susceptibility and IFN‐γ polymorphisms, and the results were adjusted by logistic regressive analysis. The frequency of rs2069727 CC genotype was much higher in cases than that in controls, suggested its significant association with increased AS risk (adjusted OR = 5.899, 95% CI = 1.563‐22.261; P = .009). In addition, C allele also showed close association with increased risk of AS (adjusted OR = 2.052, 95% CI = 1.286‐1.704, P = 0 .003). While the genotype and allele frequencies of IFN‐γ rs1861494 polymorphism were not significantly different between patients and controls (P > 0.05 for all), IFN‐γ rs2069727 polymorphism is significantly associated with increased AS risk in a Chinese Han Population.

Copy number variation of IL17RA gene and its association with the ankylosing spondylitis risk in Iranian patients: a case-control study

BackgroundAnkylosing spondylitis (AS) is considered as a subtype of spondyloarthritis (SpA) that mainly leads to fatigue, stiffness, spinal ankylosis, and impaired physical functions with reduced quality of life. Interleukin (IL)-17A provokes additional inflammatory mediators and recruits immune cells to the inflamed site. IL17 expression increased in various inflammatory disorders including psoriasis, rheumatoid arthritis, multiple sclerosis, crohn’s disease, and ankylosing spondylitis. The current study aimed to evaluate the association of IL17RA copy number changes with the susceptibility to AS and their correlation to IL17RA expression in Iranian population.MethodsIL17RA copy number genotyping assessments were carried out in 455 AS patients and 450 healthy controls, using custom TaqMan CNV assays. TaqMan primers and probe were located in Chr.22:17109553 based on pre-designed IL17RA Copy Number Assay ID, Hs02339506_cn. mRNA expression of IL17RA was also measured by SYBR Green real-time polymerase chain reaction (PCR).ResultsA IL17RA copy number loss (< 2) was associated with AS compared to 2 copies as reference (OR:2.18, 95% CI: (1.38–3.44), P-value < 0.001) and increased the risk of AS. IL17RA mRNA expression showed a significant increase in peripheral blood mononuclear cells (PBMCs) of all AS individuals than controls. The mRNA expression level of 2 copies was significantly higher in AS patients.ConclusionsOur findings revealed that a low copy number of IL17RA might confer a susceptibility risk to AS. However, it is probably not directly involved in the regulation of IL17RA mRNA expression. Epigenetic mechanisms like DNA methylation, post-transcriptional, and -translational modifications that regulate the expression of the genes may contribute in upregulation of IL17RA mRNA expression in the loss of gene copy number condition.

Associations of the IL-1B level, IL-1A and IL-1B gene polymorphisms and ankylosing spondylitis risk in a Chinese Han population

IntroductionThe aim of this study was to investigate the effect of interleukin (IL)-1A and IL-1B gene polymorphisms on ankylosing spondylitis (AS) susceptibility in a Chinese population. Additionally, we examined the association of IL-1B level with different genotype of rs2853550 polymorphism and clinicopathological features of AS patients. Materials and methodsThe IL-1B concentration in plasma was determined by an enzyme-linked immunosorbent assay. The IL-1A rs3783546, IL-1A rs3783550 and IL-1B rs2853550 gene polymorphisms were determined by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. ResultsOur data indicated that the average plasma IL-1B concentration in the AS patients was markedly higher than in the control samples. Subgroup analyses suggested that there was no significant association between plasma IL-1B concentration and sex, age, HLA-B27, C-reactive protein (CRP), or grade of the sacroiliac joint in AS patients. We also found that the IL-1B rs2853550 AG genotype showed significantly correlation with an increased risk of AS. In comparing AS patients to control participants, elevated plasma concentrations were observed in AS patients while significant differences were found between the IL-1B rs2853550 AA genotypes. There is a negative correlation between the IL-1A rs3783550 and IL-1A rs3783546 polymorphisms in the AS patients in relation to controls. ConclusionsThe IL-1B concentration in plasma was markedly higher in cases and AA genotype carriers. Furthermore, IL-1B rs2853550 AG was a genetic contributor to AS risk in a Chinese population.

TNFR1 -383 A˃C polymorphism and ankylosing spondylitis in a Russian Caucasian population: a preliminary study.

The aim of this study was to assess the association between the TNFR1 rs2234649 polymorphism and ankylosing spondylitis susceptibility in a Russian Caucasian population. A total of 41 ankylosing spondylitis patients and 43 healthy controls, matched according to age and sex, were enrolled, and polymerase chain reaction-restriction fragment length polymorphism analysis was used to genotype the rs2234649 variant. We evaluated genotype distributions in the patient and control groups with the chi-square test, and assessed the relationship between genotypes and ankylosing spondylitis using the odds ratio. Our analysis showed that the rs2234649 polymorphism does not increase ankylosing spondylitis risk. In conclusion, the TNFR1 gene polymorphism tested does not appear to be useful for assessing predisposition to this disease or for its diagnosis or prognosis.

Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors

Axial spondyloarthritis (axSpA), which encompasses ankylosing spondylitis, is a complex genetic disease. Aberrant bone formation is a key feature of pathogenesis that can lead to ankylosis of the spine. Our objective is to determine, whether genes whose variants confer susceptibility to AS are expressed in bone progenitors like mesenchymal stem cells (MSCs). Since MSCs from bone marrow is difficult to obtain, we first examined, whether MSCs can be derived from induced pluripotent stem cells (iPSCs). Dermal fibroblasts of two axSpA patients and one healthy control were reprogrammed into iPSCs using a Sendai virus vector encoding pluripotency genes. Pluripotency of iPSCs was examined by embryoid body formation and by testing for stem cell specific gene and protein expression using RT-PCR and immuno fluorescence. iPSCs were differentiated into MSCs by a TGFß inhibitor. MSCs were characterized by flow cytometry using lineage specific antibodies and by their capacity to develop into chondrocytes, adipocytes, and osteoblasts in lineage-specific medium. RNA-seq was applied to determine genome-wide gene expression patterns in MSCs, iPSCs, and blood. We show for the first time, that expression levels of several AS susceptibility genes (EDIL3, ANO6, HAPLN1, ANTXR2) involved in bone formation are significantly elevated in MSCs (2–15-fold; p ≤ 0.05) compared to blood or iPSCs and demonstrate that iPSC-derived MSCs can be differentiated into osteoblasts, chondrocytes, and adipocytes. We conclude, MSCs generated from patient fibroblast-derived iPSC lines are useful tools for studying functional genomics of risk genes associated with bone formation in AS pathogenesis.

Associations of the VEGF level, VEGF rs2010963 G/C gene polymorphism and ankylosing spondylitis risk in a Chinese Han population

To investigate the roles of the plasma vascular endothelial growth factor (VEGF) level and VEGF gene polymorphisms in ankylosing spondylitis (AS) susceptibility. The plasma VEGF level was measured using an enzyme-linked immunosorbent assay. The VEGF rs2010963 G/C gene polymorphism was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Our data indicated that the average plasma VEGF concentration in the AS patients was markedly higher than in the controls. Stratification analysis indicated a significant correlation between an elevated plasma VEGF level in AS patients and sex, but not age, HLA-B27, C-reactive protein (CRP), or grade of the sacroiliac joint. We also found that VEGF rs2010963 G/C was associated with a decreased risk of AS. Significant differences were found between the VEGF rs2010963 G/C genotypes and elevated plasma level in AS patients when compared with the controls. However, we did not find a significant association between the plasma VEGF level and different rs2010963 G/C genotypes in the AS patients or controls. To sum up, serum VEGF levels are significantly associated with the inflammatory process of AS. This study suggests that VEGF is involved in the immunological or inflammatory process of AS.

The programmed cell death 1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T and PD 1.9 C/T) and susceptibility to ankylosing spondylitis: a meta-analysis.

The objective is to integrate all the eligible studies and investigate whether the programmed cell death 1 (PDCD-1) gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T, and PD 1.9 C/T polymorphism) are correlated with ankylosing spondylitis risk (AS). Ankylosing spondylitis is a chronic inflammatory disease, and several genetic and environmental factors play an important role in the development and progression of AS. Significant associations between PDCD-1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T or PD 1.9 C/T) and AS risk have been reported; however, some of these results are controversial. A systematic online search was performed using PubMed, EMBASE, Web of Science, and the Cochrane Library to identify case-control studies investigating the relationship between PD 1.3 G/A, PD 1.5 C/T, and PD 1.9 C/T polymorphisms and the susceptibility of AS. The pooled odds ratio (OR) with 95 % confidence interval (CI; 95 %) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study populations. Five studies involving 909 cases and 982 controls met the inclusion criteria after assessment by two reviewers. Overall, there were no significant associations between PD 1.3 G/A and PD 1.5 C/T polymorphisms and AS risk. With regard to PD 1.9 C/T polymorphism, a significant association was found under the allele contrast model (T vs. C: OR 1.74, 95 % CI 1.48-2.06, P < 0.001), heterozygote model (CT vs. CC: OR 2.43, 95 % CI 1.65-3.59, P < 0.001), homozygote model (TT vs. CC: OR 1.87, 95 % CI 1.30-2.71, P = 0.001), and dominant model (CT/TT vs. CC: OR 2.29, 95 % CI 1.65-3.18, P < 0.001). In the subgroup analysis of ethnicity, no significant associations were found between PD 1.3 G/A, PD 1.5 C/T polymorphisms, and AS risk in either Asian or Caucasian populations. However, our study suggested that PD 1.9 C/T polymorphism was significantly associated with AS in Asian populations (T vs. C: OR 1.72, 95 % CI 1.46-2.04, P < 0.001; CT vs. CC: OR 2.44, 95 % CI 1.56-3.82, P < 0.001; TT vs. CC: OR 1.88, 95 % CI 1.30-2.73, P = 0.001; and CT/TT vs. CC: OR 2.29, 95 % CI 1.58-3.32, P < 0.001) but not in Caucasian populations. The PD 1.9 C/T polymorphism may be involved in susceptibility to AS, particular in Asian populations; however, no significant associations were found between PD 1.3 G/A, PD 1.5 C/T polymorphisms, and AS risk in either Asians or Caucasians.

Polymorphism of HLA-B27: 105 Subtypes Currently Known

HLA-B27 has a high degree of genetic polymorphism, with 105 known subtypes, named HLA-B*27:01 to HLA-B*27:106, encoded by 132 alleles. The most common subtypes associated with ankylosing spondylitis are HLA-B*27:05 (Caucasians), HLA-B*27:04 (Chinese), and HLA-B*27:02 (Mediterranean populations). For Chinese populations, HLA-B*27:04 is associated with a greater ankylosing spondylitis risk than HLA-B*27:05. Two subtypes, HLA-B27*06 and HLA-B27*09, seem to have no disease association. These differential disease associations of HLA-B27 subtypes, and the recent discovery that ERAP1 is associated with ankylosing spondylitis for patients with HLA-B27, have increased attempts to determine the function of HLA-B27 in disease pathogenesis by studying hemodynamic features of its protein structure, alterations of its peptidome, aberrant peptide handling, and associated molecular events. However, after 40 years we still do not fully know how HLA-B27 predisposes to ankylosing spondylitis and related spondyloarthritis.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.