Systematic analyses of GWAS summary statistics from UK Biobank identified novel susceptibility loci and genes for upper gastrointestinal diseases.

In recent decades, upper gastrointestinal (GI) diseases have been highly prevalent worldwide. Although genome-wide association studies (GWASs) have identified thousands of susceptibility loci, only a few of them were conducted for chronic upper GI disorders, and most of them were underpowered and with small sample sizes. Additionally, for the known loci, only a tiny fraction of heritability can be explained and the underlying mechanisms and related genes remain unclear. In this study, we conducted a multi-trait analysis by the MTAG software and a two-stage transcriptome-wide association study (TWAS) with UTMOST and FUSION for seven upper GI diseases (oesophagitis, gastro-oesophageal reflux disease, other diseases of oesophagus, gastric ulcer, duodenal ulcer, gastritis and duodenitis and other diseases of stomach and duodenum) based on summary GWAS statistics from UK Biobank. In the MTAG analysis, we identified 7 loci associated with these upper GI diseases, including 3 novel ones at 4p12 (rs10029980), 12q13.13 (rs4759317) and 18p11.32 (rs4797954). In the TWAS analysis, we revealed 5 susceptibility genes in known loci and identified 12 novel potential susceptibility genes, including HOXC9 at 12q13.13. Further functional annotations and colocalization analysis indicated that rs4759317 (A>G) driven the association for GWAS signals and expression quantitative trait loci (eQTL) simultaneously at 12q13.13. The identified variant acted by decreasing the expression of HOXC9 to affect the risk of gastro-oesophageal reflux disease. This study provided insights into the genetic nature of upper GI diseases.

Urine caffeine metabolites are positively associated with cognitive performance in older adults: An analysis of US National Health and Nutrition Examination Survey (NHANES) 2011 to 2014.

The aim of this study was to explore urine caffeine metabolites in relation to cognitive performance among 2011-2014 National Health and Nutrition Examination Survey participants aged ≥60 years. We hypothesized that urine caffeine metabolites were positively associated with cognition in older adults. Caffeine and 14 of its metabolites were quantified in urine by use of high-performance liquid chromatography-electrospray ionization-tandem quadruple mass spectrometry with stable isotope labeled internal standards. Cognitive assessment was based on scores from the word learning and recall modules. Participants were categorized based on the quartiles of caffeine and its metabolites level. The association between caffeine metabolites and each cognitive dimension was analyzed using multiple logistic regression analysis in adjusted models. Stratification analyses by gender were also performed. For CERAD test, there was a significant association between 1-methyluric acid (OR=0.62, 95% CI: 0.42 to 0.92), 7-methylxanthine(OR=0.49, 95% CI: 0.27 to 0.89), theophylline (OR=0.52, 95% CI: 0.29 to 0.92), as well as paraxanthine (OR=0.49, 95% CI: 0.27 to 0.88) and cognitive function. For animal fluency test, there was a positive association between theophylline (TP) (OR=0.44, 95% CI: 0.22 to 0.89) and cognitive function. The trend that the risk of low cognitive function decreased with increasing concentration of 1-methylxanthine (P trend=0.0229) was also observed. Furthermore, the same trend existed for 3-methylxanthine (p trend = 0.0375) in men. In conclusion, there was a significant positive association between urine caffeine metabolites and cognitive performance in older adults, particularly for theophylline, paraxanthine and caffeine; and the association might be dependent on gender.

Associations between fucosyltransferase 3 gene polymorphisms and ankylosing spondylitis: A case-control study of an east Chinese population.

Many susceptibility genes of inflammatory bowel disease (IBD) are associated with ankylosing spondylitis (AS). Fucosyltransferase 2 (FUT2) and FUT3 genes are related to IBD. This study aimed to investigate whether these genes correlated with the susceptibility to AS. Questionnaires of 673 patients with AS, and peripheral blood specimens of the patients and 687 healthy controls were collected. FUT2 and FUT3 genes were genotyped using the SNPscan method. Frequency differences of the genes at different levels, haplotypes, and interactions were analyzed. No frequency differences were found between the cases and the controls in all the genotypes and the alleles of rs1047781, rs1800028, rs1800030, and rs812936. For rs28362459, a significant difference in allele frequencies was observed in the total participants between the groups [χ2 = 7.515, Pcorrected = 0.030; adjusted odds ratio (ORadjusted)G/T = 0.782; 95% confidence interval (CI), 0.650-0.941]. The frequencies of haplotypes TT (rs812936-rs28362459) (χ2 = 5.663, Ppermutation = 0.039) and TG (rs812936-rs28362459) (χ2 = 7.456, Ppermutation = 0.013) in the total participants, and TG (rs812936-rs28362459) in the female subgroup (χ2 = 5.624, Ppermutation = 0.047) showed significant differences between the cases and the controls. No frequency differences at the phenotypic level were found. Two-factor interactions were observed between rs28362459-TG and age, rs28362459-TG and sex, rs28362459 and rs1047781, and the Lewis and secretor status. Rs28362459-G was related to some aggravated symptoms of AS (all Pcorrected < 0.05). These findings indicated that FUT3 polymorphisms were associated with human predisposition to AS at the allele and haplotype level. Rs28362459-G might decrease the susceptibility to AS, but aggravate relevant symptoms.

H19 Increases IL-17A/IL-23 Releases via Regulating VDR by Interacting with miR675-5p/miR22-5p in Ankylosing Spondylitis.

Long non-coding RNA (lncRNA) H19 is associated with inflammatory diseases, but the molecular mechanism of H19 in the inflammatory process of ankylosing spondylitis (AS) is unclear. Here, we investigated the role of H19 and its downstream molecules in the inflammation of AS by microarray analysis, qRT-PCR, western blot, and dual-luciferase reporter assay. H19 small interfering RNA (siRNA) (Si-H19) and adenovirus (AD-H19) were used to decrease and increase H19 expression, respectively. 42 annotated lncRNAs were identified, and H19 was overexpressed. H19, vitamin D receptor (VDR), and transforming growth factor ß (TGF-ß) can bind to microRNA22-5p (miR22-5p) and miR675-5p. Si-H19 significantly downregulated miR22-5p and upregulated miR675-5p expression; Si-H19 decreased the protein and mRNA expression of VDR and decreased the cytokine and mRNA levels of interleukin-17A (IL-17A) and IL-23. These results were verified by AD-H19. In addition, miR22-5p and miR675-5p inhibitors increased the protein and mRNA expression of VDR and increased the cytokine and mRNA levels of IL-17A and IL-23. These results were also confirmed by miRNA mimics. Furthermore, H19 directly interfered with miR22-5p and miR675-5p expression, whereas the two miRNAs directly inhibited VDR expression. Overall, the H19-miR22-5p/miR675-5p-VDR-IL-17A/IL-23 signaling pathways have important roles in the pathogenesis of AS.

Gene-gene interaction and association of Wnt/Β-catenin signalling pathway gene polymorphisms with ankylosing spondylitis susceptibility in the Chinese Han population.

Objectives: To explore the genetic interaction between Wnt/ß-catenin signalling pathway genes and ankylosing spondylitis (AS) in the Chinese population.Methods: Six single-nucleotide polymorphisms (SNPs) in DKK1, LRP5, LRP6, and SOST genes were genotyped in 673 AS patients and 687 healthy controls by using SNPs can Technic. Single marker genetic association analysis was performed. Haplotypes were constructed after linkage disequilibrium analysis; additive, multiplicative, and higher-order interactions were analysed.Results: The DKK1 gene rs1569198 polymorphism was significantly associated with AS susceptibility in females (χ2 = 4.55, p = .03), but the association disappeared after Bonferroni correction. Moreover, a haplotype (T-G) in the DKK1 gene showed a protective role in AS susceptibility in females (p = .04). Significant additive interactions were observed between DKK1: rs1896368 and LRP5: rs3736228, relative excess risk due to interaction (RERI) = 0.40, 95% CI = 0.08 - 0.71; attributable proportion due to interaction (AP) = 51%, 95% CI = 0.07 - 0.94, DKK1: rs1569198 and LRP5: rs3736228 (RERI = 0.49, 95% CI = 0.12 - 0.86; AP = 49%, 95% CI = 0.17 - 0.82), LRP5: rs3736228 and SOST: rs4792909 (RERI = 0.33, 95% CI = 0.002 - 0.65; AP = 41%, 95% CI = 0.01 - 0.81) in the dominant model.Conclusions: Our research implies a potential gene-gene interaction, thus revealing the importance of the Wnt/ß-catenin signalling pathway for understanding the genetic architecture of AS.

Low serum levels of insulin-like growth factor-1 are associated with an increased risk of rheumatoid arthritis: a systematic review and meta-analysis.

Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are not only involved in individual growth and metabolism, but they are also associated with inflammation and homeostasis of articular cartilage and bone. Recent studies have identified the involvement of IGF-1 and IGFBP-3 in the development of rheumatoid arthritis (RA). Nevertheless, the results were inconsistent, and the relevant data were not synthetically assessed. Therefore, this review aimed to systematically evaluate the associations of serum IGF-1 and IGFBP-3 levels with the development of RA. Several databases were used to retrieve relevant publications (up to January 2018). Pooled standard mean difference (SMD) and 95% confidence interval (CI) were demonstrated using a forest plot. A total of 27 studies from 19 publications were included. Meta-analysis results showed that RA patients had lower serum IGF-1 levels when compared to controls (SMD = -0.650, 95% CI = -1.184 to -0.115, P = .017). However, there was no significant association between serum IGFBP-3 levels and RA (SMD = 0.590, 95% CI = -1.323 to 2.504, P = .545). Subgroup analyses further showed that serum IGF-1 levels in RA patients are discrepant in terms of race, age, and measurement type (all P < .05). In conclusion, the decreased levels of serum IGF-1 were closely associated with the development of RA. Future longitudinal studies are needed to validate the link between serum IGF-1 levels with RA pathogenesis as well as the effects of IGF-1 on RA treatment.

Fecal microbiota in patients with ankylosing spondylitis: Correlation with dietary factors and disease activity.

BACKGROUND: We investigated the characterization of the gut microbiome in Chinese patients with ankylosing spondylitis (AS) and healthy controls (HCs) and to explore the association ofbacteria communities with dietary factors and disease activity. METHODS: 16S ribosomal RNA gene sequencing was performed on fecal DNA isolated from stool samples in consecutive cross-sectional cohorts. Alpha and beta diversities were assessed using QIIME, and comparisons were performed using one-way ANOVA, Student's t-test, and SKN multiple range comparisons to examine differences between groups and a correlation network analysis was performed. RESULTS: We investigated 207 samples from 103 AS patients and 104 HCs. Alpha diversity was not significant difference in AS compared with HCs. For the community structure, Bacteroidetes was the most represented class. Megamonas, Dorea, and Blautia were significantly greater in AS than in HCs, whereas the abundance of Lachnospira, Ruminococcus, and Clostridium_XlVb was significantly lower in AS than in HCs. In addition, Specific gut microbiome was significantly correlated with disease activity and dietary factors. CONCLUSIONS: Our results suggest that the human gut microbiome of AS patients was clearly different from that of HCs and bacteria communities are associated with dietary factors and disease activity.

TNFAIP3 genetic polymorphisms reduce ankylosing spondylitis risk in Eastern Chinese Han population.

This study was conducted to clarify the associations of tumor necrosis factor-α induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1) genetic polymorphisms with ankylosing spondylitis (AS) susceptibility. Five single nucleotide polymorphisms (SNPs) in TNFAIP3 gene and four in TNIP1 gene were genotyped in 667 AS patients and 667 matched healthy controls. Genotypes and haplotype analysis were conducted by using SPSS 23.0 and Haploview 4.2 software. The T allele and CT genotype in TNFAIP3 rs10499194 were significantly associated with a reduced AS risk (T allele vs. C allele, OR = 0.619, 95% CI = 0.430-0.889, P = 0.009; CT vs. CC, OR = 0.603, 95% CI = 0.416-0.875, P = 0.007). However, no association remained significant after Bonferroni correction. The rs13207033A- rs10499194T haplotype of TNFAIP3 conferred a protective effect on AS susceptibility. Stratification analyses suggested that rs10499194 polymorphism decreased the risk of AS in the male subgroup, subgroup aged ≥ 29, HLA-B27 positive subgroup as well as the subgroups of BASFI < 4 and BASDAI < 4 (all P < 0.05). Furthermore, the functional annotation suggested a potential function of rs10499194 mutation. Our results demonstrated that TNFAIP3 rs10499194 polymorphism may be associated with a reduced risk of AS.

Elevated circulating IL-17 level is associated with inflammatory arthritis and disease activity: A meta-analysis.

OBJECTIVES: Previous studies found that the interleukin (IL)-17 level was elevated in inflammatory arthritis, but results were inconsistent. This meta-analysis aimed to investigate the association of IL-17 cytokine with osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: Relevant studies were searched using databases. Standardized mean difference (SMD) was calculated. Correlation coefficient was utilized to evaluate the relationship between IL-17 and disease activity of AS and RA. Subgroup analysis, sensitivity analysis and meta-regression were applied to explore the sources of heterogeneity. RESULTS: 83 records were enrolled. The IL-17 level was elevated in AS (SMD = 2.348, P < .001), RA (SMD = 1.502, P < .001), PsA (SMD = 1.710, P < .001) and OA (SMD = 1.192, P = .016), and similar results occurred in subgroup analysis. Furthermore, the IL-17 level was positively associated with disease activity of AS and RA. CONCLUSION: Circulating IL-17 level is significantly elevated in inflammatory arthritis and is related to the disease activity of AS and RA, suggesting that it plays an important role in the pathogenesis and progression of inflammatory arthritis (especially in AS and RA).

Chronic obstructive pulmonary disease in rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: The risk and prevalence of chronic obstructive pulmonary disease (COPD) in rheumatoid arthritis (RA) is still obscure. The current study was aimed to systematically review and meta-analyse the risk ratio (RR) and prevalence of COPD in RA. METHODS: A comprehensive systematic review was conducted based on PubMed, Web of Science and Cochrane Library from inception to April 30, 2018. The primary outcome of our study was the RR of COPD in RA patients compared with controls, and secondary was the prevalence of COPD in RA patients. Pooled effect sizes were calculated according to fixed effect model or random effects model depending on heterogeneity. RESULTS: Six and eight studies reported the RR and prevalence of COPD in RA respectively. Compared with controls, RA patients have significant increased risk of incident COPD with pooled RR 1.82 (95% CI = 1.55 to 2.10, P <  0.001). The pooled prevalence of COPD in RA patients was 6.2% (95% CI = 4.1 to 8.3%). Meta-regression identified that publication year was an independent covariate negatively associated with the RR of COPD, and smoker proportion of RA population was also positively associated with the prevalence of COPD significantly in RA patients. CONCLUSIONS: The present meta-analysis has demonstrated the significant increased risk and high prevalence of COPD in RA patients. Patients with RA had better cease tobacco use and rheumatologists should pay attention to the monitoring of COPD for the prevention and control of COPD.

Ankylosing spondylitis is associated with aberrant DNA methylation of IFN regulatory factor 8 gene promoter region.

OBJECTIVES: To investigate the role of methylation levels of the IFN regulatory factor 8 (IRF8) gene promoter in the development of ankylosing spondylitis (AS). METHODS: In this study, we compared the methylation levels of the IRF8 gene promoter between 99 AS patients and 99 healthy controls using MethylTarget approach. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was performed to compare the mRNA levels of the IRF8 gene in the other 19 AS patients and 19 healthy controls. RESULTS: Differential methylation was found in 91 CpG sites of the IRF8 gene promoter, and 4 CpG regions were highly methylated in AS patients compared to healthy controls (p < 0.05). In the verification stage, we found that the mRNA levels of the IRF8 gene in AS patients were significantly lower than that in controls (AS 0.77 (0.39-1.74), P = 0.038). Positive correlations between methylation of the IRF8 gene and the duration of disease, BASFI, and ESR were observed in AS patients. CONCLUSIONS: We found a significant hypermethylation of the IRF8 gene promoter and a downregulation of the mRNA levels of the IRF8 gene in AS patients. This suggests that aberrant methylation of the IRF8 gene promoter may probably contribute to the development and pathogenesis of AS through regulating the expression of mRNA.

Serum Sclerostin and Bone Morphogenetic Protein-2 Levels in Patients with Ankylosing Spondylitis: A Meta-Analysis.

Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI - 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.

Serum Levels of OPG, RANKL, and RANKL/OPG Ratio in Patients with Ankylosing Spondylitis: A Systematic Review and Meta-analysis.

Objectives: To investigate the role of osteoprotegerin (OPG), receptor activator of nuclear factor-kB ligand (RANKL), and RANKL/OPG ratio in the pathogenesis of ankylosing spondylitis (AS). Methods: Studies that compared serum levels of OPG, RANKL, and RANKL/OPG ratio between AS patients and healthy controls were gathered. Pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by the random-effects model. Results: Twenty studies containing 1592 AS patients and 1064 healthy controls were included in this meta-analysis. Serum levels of OPG, RANKL, and RANKL/OPG ratio in AS patients were significantly higher than that in normal controls (OPG: SMD = 0.401, 95%CI = 0.026-0.777, p = 0.036; RANKL: SMD = 1.116, 95%CI = 0.510-1.723, p < 0.001; RANKL/OPG ratio: SMD = 0.691, 95%CI = 0.084-1.299, p = 0.026, respectively). Subgroup analysis suggested that Asian AS patients and patients with elevated ESR (ESR >20 mm/h) had higher serum OPG levels compared to normal controls. Asian patients, CRP >10 mg/L, ESR >20 mm/h, duration of disease ≤8 years, and BASDAI score >4 points subgroups showed increased RANKL levels compared to controls. Conclusions: Serum levels of OPG, RANKL, and RANKL/OPG ratio may be used as potential susceptible biomarkers for AS, but they could be influenced by race, inflammatory factors, and disease activity of AS patients.

Carotid Intima-Media Thickness in Patients with Ankylosing Spondylitis: A Systematic Review and Updated Meta-Analysis.

AIM: Inflammatory arthritis (IA) diseases are relevant with subclinical atherosclerosis, but the data in ankylosing spondylitis (AS) were inconsistent. Therefore, we performed this meta-analysis to explore the relationship between the marker of subclinical atherosclerosis (carotid intima-media thickness (IMT)) and AS. METHODS: We performed a systematic literature review using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) databases up to March 2018. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to assess the association between carotid IMT and AS. Subgroup analysis, sensitivity analysis, and meta-regression were applied to explore the sources of heterogeneity, and publication bias was calculated to access the quality of pooled studies. RESULTS: A total of 24 articles were collected. The carotid IMT was significantly increased in AS compared with healthy controls (SMD=0.725, 95% CI=0.443-1.008, p＜0.001). Subgroup analyses showed the Bath Ankylosing Spondylitis Activity Index (BASDAI) was the source of heterogeneity. Notably, IMT was not significantly increased in those studies that included ＞50% patients treated with anti-TNF. Meta-regression revealed severe inflammation status (BASDAI and C-reactive protein (CRP)) could significantly impact carotid IMT in AS. CONCLUSIONS: Carotid IMT was significantly increased in patients with AS compared with healthy controls, which suggested subclinical atherosclerosis is related to AS.

Genetic polymorphisms of G protein-coupled receptor 65 gene are associated with ankylosing spondylitis in a Chinese Han population: A case-control study.

OBJECTIVE: This study aimed to assess the association between two tag single nucleotide polymorphisms (SNPs) (rs68177277 and rs11624293) of G protein-coupled receptor 65 (GPR65) gene and ankylosing spondylitis (AS) susceptibility in a Chinese Han population. METHODS: 673 patients with AS diagnosed according to the modified New York criteria and 679 age- and gender-matched healthy controls were recruited. SNP genotyping for rs68177277 and rs11624293 polymorphisms were performed using the SNPscan technique. Disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS: Genotype and allele distribution of rs11624293 but not rs68177277 were significantly different between AS and controls (p = 0.004 and p = 0.002). Compared to the wild-type T/T genotype and T allele at rs11624293, the frequencies of C/T genotype and C allele were significantly higher in AS than controls after adjusting for age and gender (OR = 1.527, 95%CIs: 1.190-1.958; OR = 1.515, 95%CIs: 1.183-1.942, respectively). Dominant and co-dominant model of rs11624293 were predictive of AS susceptibility. In AS patients, the genotype of rs11624293 was significantly associated with BASFI scores in those with low disease activity (BASDAI < 4, p = 0.007). CONCLUSIONS: The results of our study suggest that rs11624293 polymorphism of GPR65 gene is associated with the susceptibility and severity of AS in Chinese Han population.

The correlation between microRNA-221/222 cluster overexpression and malignancy: an updated meta-analysis including 2693 patients.

BACKGROUND: Although miR-221/222 cluster plays an important role in many human malignancies, the correlation between miR-221/222 cluster overexpression and tumor prognosis remains controversial. Therefore, an updated meta-analysis was conducted to clarify its prognostic value in malignancy. METHODS: We conducted a search of literature in English electronic databases of PubMed, Embase, and Cochrane Library, and Chinese electronic databases of China Biology Medicine disc and China National Knowledge Infrastructure to obtain appropriate studies. Besides, we extracted hazard ratios (HRs) and 95% CIs to evaluate the strength of the correlations. In addition, the results of different subgroups analyses and publication bias test were also shown in this article. RESULTS: 32 publications, including 15 tumor types and 2,693 patients were embraced in this meta-analysis. The results of univariate (HR =1.69, 95% CI: 1.18-2.44, P<0.01) and multivariate (HR =2.10, 95% CI: 1.63-2.69, P<0.01) analyses revealed that miR-221/222 cluster high expression in various tumors was significantly associated with adverse overall survival (OS). Correspondingly, we also found subgroups analyses consisted of country, miR-221/222 cluster component, sample size, and test method have similar results. CONCLUSION: miR-221/222 cluster overexpression was closely related to adverse OS in human carcinoma, while overexpression of miRNA-221/222 cluster could be viewed as a protection factor in prostate cancer. Blood-derived miR-221/222 cluster was not proper to assess OS.

Associations of Estrogen Receptor Alpha Gene Polymorphisms with Type 2 Diabetes Mellitus and Metabolic Syndrome: A Systematic Review and Meta-Analysis.

The associations between PvuII (T>C) and XbaI (A>G) polymorphisms of estrogen receptor alpha (ESR1) gene with type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS) are reported in many studies, but the results are inconsistent. This present work aims to assess the associations by performing a comprehensive meta-analysis. Relevant studies were searched through several databases. The pooled odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of PvuII and XbaI polymorphisms with the risk of T2DM and MetS by using the STATA 14.0 software. Eight studies for T2DM and three articles about MetS were included in this meta-analysis. The overall results indicated that PvuII, rather than XbaI polymorphism, was associated with T2DM (regressive model: OR=0.673, 95% CI=0.550 to 0.823, praw<0.001, pFDR<0.003). The subgroup analysis based on race revealed an association of PvuII polymorphism with the decreased T2DM risk in Chinese population and a relationship between XbaI polymorphism and the reduced T2DM susceptibility in Caucasians. The difference of country may be one source of the heterogeneity for PvuII polymorphism and T2DM. However, neither PvuII nor XbaI polymorphism was related to the risk of MetS. The C allele of PvuII polymorphism presents a protective role in T2DM risk, especially in Chinese people. The G allele of XbaI polymorphism is related to a reduced risk for T2DM in Caucasian population. Nevertheless, neither of PvuII nor XbaI polymorphism is associated with MetS risk.

The serum level of Dickkopf-1 in patients with rheumatoid arthritis: A systematic review and meta-analysis.

OBJECTIVE: Dickkopf-1 (DKK-1) is an endogenous inhibitor of canonical Wnt pathway that was implicated in the pathogenesis of rheumatoid arthritis (RA), but the serum levels of DKK-1 in RA were inconsistent among studies. Therefore, we conducted a meta-analysis to systematically evaluate the relationship between serum DKK-1 levels and RA. METHODS: PubMed, Web of Science and Cochrane Library were comprehensively retrieved till 1 January 2018 for pertinent studies. The pooled standard mean differences (SMDs) of serum DKK-1 levels were calculated according to the random effects model. RESULTS: Nine original studies containing 1305 RA patients and 504 healthy controls were included in the meta-analysis. The pooled SMD of serum DKK-1 between RA patients and healthy controls was 0.79 (95% CI = 0.11 to 1.48, Z = 2.28 and P = 0.023), indicating a significantly higher serum level of DKK-1 in RA patients. CONCLUSION: Serum level of DKK-1 is elevated in patients with RA compared to healthy controls, suggesting an important role of DKK-1 in the pathogenesis and treatment of RA.

Dickkopf-1 in ankylosing spondylitis: Review and meta-analysis.

BACKGROUND: Current findings regarding serum Dickkopf-1 (DKK-1) concentration in ankylosing spondylitis (AS) have proven inconsistent. This meta-analysis was performed to provide a better understanding of serum DKK-1 and AS. METHODS: Online electronic databases were used to retrieve all relevant articles published before November 2017. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. RESULTS: 23 studies, containing 1348 AS patients and 909 healthy controls, were included in this meta-analysis. No significant difference in serum DKK-1 concentration was found between AS patients and healthy controls (pooled SMD = 0.488, 95%CI = -0.176 to 1.152, p = 0.150). Subgroup analyses suggested that serum DKK-1 in patients with increased C-reactive protein (CRP) (CRP > 10 mg/L) and high modified Stroke AS Spine Score (mSASSS) (mSASSS > 30) were significantly lower than healthy controls. Serum DKK-1 was, however, increased in patients with normal CRP (CRP ≤ 10 mg/L). CONCLUSION: Although serum DKK-1 concentration was not significantly different in AS vs. healthy controls, it may be used as a biomarker of inflammation and radiographic damage in AS.

Association of TLR7 gene copy number variations with ankylosing spondylitis in a Chinese population: a case control study.

OBJECTIVES: To explore the association of TLR7 gene copy number variations (CNVs) with the susceptibility of ankylosing spondylitis (AS). METHODS: The case control study was performed in 649 Chinese Han patients with AS and 628 healthy controls. The copy numbers of TLR7 gene (2 fragments) were measured by AccuCopyTM methods. Chi-square and logistic regression models were performed to investigate the association of TLR7 gene CNVs with AS. Odds ratio (ORs) and 95% confidence intervals (CIs) was calculated to estimate AS risk and the Bonferroni correction was applied owing to multiple testing. RESULTS: The logistic regression analysis showed that one copy was significantly associated with AS susceptibility after Bonferroni correction (for the TLR7_1 fragment: OR=1.458, 95%CI(1.098,1.936), p=0.009; for the TLR7_2 fragment: OR=1.451, 95%CI (1.093,1.927), p=0.010), and this association still exists after adjustment of age and sex (for the TLR7_1 fragment: adjusted OR=2.066, 95%CI (1.318,3.238), p=0.002; for the TLR7_2 fragment: adjusted OR=2.061, 95%CI (1.315,3.230), p=0.002). However, logistic regression analysis stratified by gender showed a higher OR in males (for the TLR7_1 fragment: OR(95%CI)=7.987(3.756,16.983); for the TLR7_2 fragment: OR(95%CI)=7.947(3.738,16.897)) than in females (for the TLR7_1 fragment: OR(95%CI)=0.204(0.080,0.524); for the TLR7_2 fragment: OR(95%CI)=0.204(0.080,0.524)). CONCLUSIONS: We conclude that the lower copy number (=1) of TLR7 gene confers a risk factor for AS susceptibility in males but protective factor in females.