Qing Lv

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10−10) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10−8). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10−324) and at 2p15 (rs10865331; P = 1.98 × 10−8). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.

MiR-27a Targets sFRP1 in hFOB Cells to Regulate Proliferation, Apoptosis and Differentiation

MicroRNAs (miRNAs) play a key role in the regulation of almost all the physiological and pathological processes, including bone metabolism. Recent studies have suggested that miR-27 might play a key role in osteoblast differentiation and bone formation. Increasing evidence indicates that the canonical Wnt signaling pathway contributes to different stages of bone formation. In this study, we identify miR-27a can promote osteoblast differentiation by repressing a new target, secreted frizzled-related proteins 1 (sFRP1) expression at the transcriptional level. Here, 21 candidate targets of miR-27a involved in canonical Wnt/β-catenin signaling were predicted, and a significant decrease in sFRP1 luciferase activity was observed both in 293T and MG63 cells co-transfected with the matched luciferase reporter constructs and miR-27a mimic. Furthermore, the presence of exogenous miR-27a significantly decreased sFRP1 mRNA and protein expression in hFOB1.19 cells during both proliferation and osteogenic differentiation. The over-expression of miR-27a or knockdown sFRP1 significantly increased the percentage of apoptotic hFOBs, the percentage of cells in the G2-M phase of the cell cycle and the expression of key osteoblastic markers, including ALP, SPP1, RUNX2 and ALP activity. Over-expression of miR-27a or knockdown of endogenous sFRP1 led to an accumulation of β-catenin in hFOBs. In the present study, we demonstrate that miR-27a induced gene silencing effect is a vital mechanism contributing to bone metabolism in hFOB cells in vitro, which is partly affected by the post-transcriptional regulation of sFRP1, during osteoblast proliferation, apoptosis and differentiation.

Higher risk of uveitis and dactylitis and older age of onset among ankylosing spondylitis patients with HLA-B*2705 than patients with HLA-B*2704 in the Chinese population.

Human leukocyte antigen (HLA)-B27 is closely associated with ankylosing spondylitis (AS). However, the exact correlation between HLA-B27 subtypes and AS manifestations remains unknown. This study aimed to investigate the correlation between HLA-B27 polymorphism and the clinical features of AS. This study included 846 patients with AS and 959 healthy controls. Direct sequencing was used to identify the HLA-B27 genotype. Clinical parameters, including age, age of onset, family history, low back pain, peripheral arthritis, hip joint involvement, dactylitis, uveitis, and sex ratio, were compared among patients with various HLA-B27 subtypes. In total, 741 AS patients (87.6%) and 39 healthy controls (4%) were HLA-B27-positive. The most prevalent subtypes were HLA-B*2704 (88%) and HLA-B*2705 (10.1%) in patients with AS. Compared with HLA-B*2704-positive patients, HLA-B*2705-positive patients demonstrated a significant increase in the incidence of uveitis (16% vs 6.13%, P = 0.002) and dactylitis (9.3% vs 3.8%, P = 0.028) and they had an older age of onset (22.9 ± 8.0 vs 20.7 ± 6.7 years, P = 0.028). Binary logistic regression analysis revealed that presence of uveitis was significantly associated with HLA-B*2705 (P = 0.008; odds ratio, 2.63; 95% confidence interval, 1.283-5.393). There were no significant differences in family history, low back pain, peripheral arthritis, or hip joint involvement among HLA-B27 subtypes. Specific HLA-B27 subtypes were positively associated with particular clinical features of AS. AS patients with HLA-B*2705 demonstrated an older age of onset and had a higher risk of uveitis and dactylitis than did AS patients with HLA-B*2704.

Disorders of MicroRNAs in Peripheral Blood Mononuclear Cells: As Novel Biomarkers of Ankylosing Spondylitis and Provocative Therapeutic Targets

Background. MicroRNAs can potentially regulate every aspect of cellular activity. In this study, we investigated whether AS pathogenesis involves microRNAs disorders. Result. The expression of 2 microRNAs, hsa-miR-126-3p and hsa-miR-29a, was significantly lower in active AS group before etanercept therapy than in control group. Marched fold changes of them were 3.76 and 16.22. Moreover, expressions of hsa-miR-126-3p and hsa-miR-29a were dramatically upregulated after 12-weeks etanercept treatment. Fold changes were 2.20 and 3.18. All regulations of microRNAs expression mentioned before were statistically significant (fold change >2 and P < 0.05). The expression disorders of the 2 microRNAs did not statistically significantly correlated with BASDAI, CRP, and ESR. Conclusion. AS pathogenesis involved dysregulation of microRNAs. Hsa-miR-126-3p and hsa-miR-29a will probably become the potential biomarkers and provocative therapeutic targets of AS.

Epidemiological comparison of clinical manifestations according to HLA-B*27 carrier status of Chinese Ankylosing Spondylitis patients

The aim of the study was to investigate and compare the clinical manifestations between HLA-B27(+) and HLA-B27(-) ankylosing spondylitis (AS) patients in order to obtain knowledge of the impact of HLA-B27 status on AS, and to inform clinical treatment. A nationwide epidemiological investigation was performed from November 2008 to October 2010. The demographic data and clinical characteristics, and the status of HLA-B27 were collected using questionnaires and laboratory assay, respectively. A total of 2144 patients (78.5% males and 78.4% HLA-B27(+) AS patients) participated in this study. The percentages of males, patients with family history, and involvement of lumbar spine, thoracic spine and hip joints, were observed to be significantly higher in the HLA-B27(+) AS patients than in their HLA-B27(-) AS peers.

A Rare Co-Segregation-Mutation in the Insulin Receptor Substrate 1 Gene in One Chinese Family with Ankylosing Spondylitis

Ankylosing spondylitis (AS; MIM 106300) is a common rheumatic disease with strong genetic components affecting approximately 0.3% of the population. The exact genetic mechanism of AS remains elusive. Our previous study showed that AS could be transmitted in an autosomal dominant inheritance mode and a 6-cM candidate region located on the chromosome 2q36.1-36.3 was mapped in a Chinese family. Mutation screening was conducted within the candidate region in the family and other AS by sequencing, and the novel mutation will be further validated in other AS families, sporadic cases and healthy controls by mass spectrometry. We identified a rare non-synonymous mutation (Arg580Gly) in insulin receptor substrate 1 (IRS1) co-segregated with disease phenotype in patients of the family, which was not found in other AS families, sporadic patients and healthy controls. In the study, we found a rare non-synonymous mutation in IRS1 co-segregation in one Chinese family with AS, which indicated a new candidate disease causative gene for AS.

Association between vitamin D receptor gene polymorphism and ankylosing spondylitis in Han Chinese.

To investigate whether vitamin D receptor (VDR) gene polymorphisms confer susceptibility to aankylosing spondylitis (AS) and study its polymorphisms in Han Chinese.

Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells

OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/β-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS : Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway.

AB0772 Color Doppler Ultrasonography Can be Used to Detect the Changes of Sacroiliitis and Peripheral Enthesitis in Patients with Ankylosing Spondylitis During the Treatment of Adalimumab

Background Adalimumab is a TNF-α blocking agent that it is effective in patients with ankylosing spondylitis (AS). Ultrasonography can be used to detect sacroiliitis and peripheral enthesitis. Objectives To investigate whether color Doppler ultrasonography (CDUS) can be used to detect the effect of adalimumab on sacroiliitis and peripheral enthesitis in patients with AS. Methods AS patients (n=41) received 40 mg adalimumab every other week for 24 weeks. BASDAI, BASFI, CRP, MRI examinations of the sacroiliac joints (SIJs) and CDUS examinations of both SIJs and 10 peripheral entheseal sites were taken at baseline, week 12, and week 24. We scored the MR images by SPARCC method. We recorded the resistive index (RI) value of SIJs and graded the blood signal on a semi quantitative 0-3 scale. We also scored lesions of peripheral entheses seen by CDUS. We analyzed the associations between the results of CDUS and clinical indices and MRI data. Results Significant reduction in mean CDUS score of SIJs and peripheral enthesitis and increase in mean RI value were observed in AS patients treated with adalimumab for 12 weeks and 24 weeks as compared with baseline (all p<0.05). The CDUS scores of SIJs and peripheral enthesitis positively related with clinical assessments (including BASDAI, BASFI, and CRP), while the RI value negatively related with them at all visits (all p<0.05). The results of CDUS also correlated well with the MRI data (all p<0.05) during the treatment of adalimumab in AS patients. Conclusions Our study found that CDUS could be used to detect the changes of sacroiliitis and peripheral enthesitis in AS patients under the therapy of adalimumab. References Schueller-Weidekamm C, Mascarenhas VV, Sudol-Szopinska I, et al. Imaging and interpretation of axial spondylarthritis: the radiologists perspective–consensus of the Arthritis Subcommittee of the ESSR. Semin Musculoskelet Radiol. 2014;18:265-79. Mohammadi A, Ghasemi-rad M, Aghdashi M, et al. Evaluation of disease activity in ankylosing spondylitis; diagnostic value of color Doppler ultrasonography. Skeletal Radiol. 2013;42:219-24. Kelly S, Taylor P, Pitzalis C. Ultrasound imaging in spondyloathropathies: from imaging to diagnostic intervention. Curr Opin Rheumatol. 2008;20:408-15. Disclosure of Interest None declared

Prevalence of comorbidities and evaluation of screening in Chinese patients with spondyloarthritis

The aim of the study was to determine whether the presence of spondyloarthritis (SpA) is associated with particular comorbidities and evaluate the prevalence of comorbidities, risk factors, and monitoring status in China. Three hundred forty-six patients fulfilling ASAS criteria for SpA were recruited from the Third Affiliated Hospital of Sun Yat-sen University. The prevalence of comorbidities and percentage of patients optimally monitored for comorbidities were calculated. The most frequent comorbidities were osteoporosis (31.0%) and hepatitis B virus infection (18.5%). Only 1 patient was found to have active tuberculosis. Several cancer screenings were performed in very few patients. Among 45 patients ever exposed to a biological DMARDs, 35 (77%) and 36 (80%) underwent a screening test for viral hepatitis and tuberculosis. Among patients without a history of hypertension, elevated blood pressure was detected in 5.8% of the patients. Hyperglycemia and hyperlipidemia were also found in patients during the study. One hundred twenty-two (35.3%) of the 346 patients never had either calcium or vitamin D for prevention of osteoporosis. Patients with SpA have high risks of comorbidities but have not monitored properly. More attention should be paid for systematic screening and an early detection of comorbidities in patients with SpA.