1,25-Dihydroxyvitamin D3 induces human myeloid cell differentiation via the mTOR signaling pathway.

1,25-Dihydroxyvitamin D3 or 1,25(OH)2D3 is known to play an important role in the differentiation of human myeloid cells. However, the molecular mechanism underlying the 1,25(OH)2D3-mediated differentiation of human myeloid cells is incompletely understood. Here, we report that 1,25(OH)2D3 induces differentiation of human myeloid cell lines such as U937 and THP-1 cells via the mammalian target of rapamycin (mTOR) signaling pathway. Both the expression of the differentiation marker CD14 and activation of the mTOR signaling pathway were induced by 1,25(OH)2D3 in phorbol 12-myristate 13-acetate (PMA)-differentiated U937 and THP-1 cells. The 1,25(OH)2D3-induced expression of CD14 in PMA-differentiated U937 and THP-1 cells was prevented by mTOR inhibitors, PP242 and Torin1. The 1,25(OH)2D3-induced morphological changes as characteristics of differentiated myeloid cells were also reversed after PP242 and Torin1 treatment. Silencing of either regulatory-associated protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) in PMA-differentiated THP-1 cells with small-interfering RNA resulted in the inhibition of CD14 expression and morphological changes induced by 1,25(OH)2D3, indicating that both mTORC1 and mTORC2 were important for the differentiation of myeloid THP-1 cells. Previous studies have shown that phosphatidic acid (PA) maintains the stability of the mTOR complex. Here we found that the attenuation of PA production with 1-butanol or a PLD inhibitor prevented the 1,25(OH)2D3-induced upregulation of CD14. Taken together, our results show that 1,25(OH)2D3 enhances the differentiation of human myeloid cells through the mTOR signaling pathway.

Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways.

Toll-like receptor (TLR) responses are regulated to avoid toxicity and achieve coordinated responses appropriate for the cell environment. We found that Notch and TLR pathways cooperated to activate canonical Notch target genes, including transcriptional repressors Hes1 and Hey1, and to increase production of canonical TLR-induced cytokines TNF, IL-6, and IL-12. Cooperation by these pathways to increase target gene expression was mediated by the Notch-pathway component and transcription factor RBP-J, which also contributed to lethality after endotoxin injection. TLR- and Notch-induced Hes1 and Hey1 attenuated IL-6 and IL-12 production. This Hes1- and Hey1-mediated feedback inhibitory loop was abrogated by interferon-gamma (IFN-gamma), which blocked TLR-induced activation of canonical Notch target genes by inhibiting Notch2 signaling and downstream transcription. These findings identify new immune functions for RBP-J, Hes, and Hey proteins and provide insights into mechanisms by which Notch, TLR, and IFN-gamma signals are integrated to modulate specific effector functions in macrophages.

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach.

Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1ß (IL-1ß)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1ß. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1ß. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

Calcium channels: the potential therapeutic targets for inflammatory bone destruction of rheumatoid arthritis.

INTRODUCTION: Inflammatory bone resorption causes progressive joint destruction which ultimately leads to functional disability in rheumatoid arthritis (RA). The primary cell responsible for bone resorption is the osteoclast, which means it is a potential therapeutic target against bone destruction. In fact, experimental and clinical findings suggest that blockade of osteoclast differentiation and function is highly effective in inhibiting bone destruction in RA. DISCUSSION AND CONCLUSION: In this report, we show several lines of experimental evidence which suggest that a variety of Ca(2+) channels are essential in osteoclast differentiation and function, and present a hypothesis that modulation of Ca(2+) channels is a highly effective therapeutic strategy in preventing osteoclast-induced structural damage in RA.

Unique gene expression profile in osteoarthritis synovium compared with cartilage: analysis of publicly accessible microarray datasets.

The purpose of this study was to identify a gene expression signature in osteoarthritis (OA) synovium and genomic pathways likely to be involved in the pathogenesis of OA. Four publicly accessible microarray studies from synovium of OA patients were integrated, and a transcriptomic and network-based meta-analysis was performed. Based on pathways according to the Kyoto Encyclopedia of Genes and Genomes, functional enrichment analysis was performed. Meta-analysis results of OA synovium were compared to two previously published studies of OA cartilage to determine the relative number of common and specific DEGs of the cartilage and synovium. According to our meta-analysis, a total of 1350 genes were found to be differentially expressed in the synovium of OA patients as compared to that of healthy controls. Pathway analysis found 41 significant pathways in the total DEGs, and 22 and 16 pathways in the upregulated and downregulated DEGs, respectively. Cell adhesion molecules and cytokine-cytokine receptor interaction were the most significant pathway in the upregulated and downregulated DEGs, respectively. Comparison of meta-analysis results of OA synovium with results of two previous studies of OA cartilage identified 85 common genes and 1632 cartilage-specific DEGs and 1265 synovium-specific DEGs in the first study; and 142 common genes, and 856 cartilage-specific DEGs and 1208 synovium-specific DEGs in the second study. Our results show a small overlap between the DEGs of the synovium compared to DEGs of the cartilage, suggesting different pathogenic mechanisms that are specific to the synovium.

Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis : A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.

AIMS: This study aimed to assess the relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen at recommended dosages in patients with osteoarthritis (OA). METHODS: Randomized controlled trials (RCTs) examining the efficacy and tolerability of etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg, based on the number of patient withdrawals among those with OA, were included in this network meta-analysis. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. RESULTS: Eight RCTs, including 5,942 patients, met the inclusion criteria. The proportion of patient withdrawals due to lack of efficacy was significantly lower in the etoricoxib 30-60 mg (OR 0.21, 95 % CrI 0.12-0.38), celecoxib 200-400 mg (OR 0.29, 95 % CrI 0.18-0.47), and naproxen 1000 mg (OR 0.31, 95 % CrI 0.18-0.51) groups than in the placebo group. The number of patient withdrawals due to lack of efficacy tended to be lower in the etoricoxib 30-60 mg group than in the naproxen 1000 mg and celecoxib 200-400 mg groups, although they did not reach statistical significance (OR 0.68, 95 % CrI 0.36-1.33 and OR 0.70, 95 % CrI 0.38-1.37, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that etoricoxib 30-60 mg had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy (SUCRA = 0.9168) followed by celecoxib 200-400 mg (SUCRA = 0.5659), naproxen 1000 mg (SUCRA = 0.5171), and placebo (SUCRA = 0.000189). With respect to tolerability, the number of withdrawals due to adverse events was not significantly different among etoricoxib, celecoxib, naproxen, and placebo, although it tended to be lower with etoricoxib and placebo. CONCLUSIONS: Etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg were more efficacious than placebo. However, there was no significant difference in efficacy and tolerability between the medications.

Association between FCGR3B copy number variations and susceptibility to autoimmune diseases: a meta-analysis.

OBJECTIVE: This study determined whether FCGR3B copy number variations (CNVs) were associated with susceptibility to autoimmune diseases. METHODS: A meta-analysis was conducted to determine the association between FCGR3B CNVs and susceptibility to autoimmune diseases by comparing low FCGR3B CN (<2 to ≥2) and high FCGR3B CN (>2 to ≤2). RESULTS: In all, 28 comparative studies from 15 reports involving 12,160 patients and 11,103 controls were included in this meta-analysis. The meta-analysis showed a significant association between low FCGR3B CN and autoimmune diseases (OR=1.496, 95% CI=1.301-1.716, p=1.0×10(-9)). Subgroup analysis according to ethnicity indicated an association between low FCGR3B CN and autoimmune diseases in Caucasians (OR=1.482, 95% CI=1.219-1.801, p=7.7×10(-6)) and Asians (OR=1.498, 95% CI=1.306-1.717, p=1.0×10(-9)). Meta-analysis according to the type of autoimmune disease indicated a significant association of low FCGR3B CN with systemic lupus erythematosus (SLE; OR=1.797, 95% CI=1.562-2.068, p<1.0×10(-9)), primary Sjogren's syndrome (pSS; OR=2.263, 95% CI=1.316-3.892, p=0.003), and Wegener's granulomatosis (WG; OR=1.973, 95% CI=1.178-3.302, p=0.010), but not with rheumatoid arthritis (RA; OR=1.333, 95% CI=0.947-1.877, p=0.099). However, the meta-analysis showed no association between high FCGR3B CN and SLE, RA, pSS, and WG. CONCLUSIONS: Thus, the results of this meta-analysis indicated that low FCGR3B CN increased susceptibility to autoimmune diseases, especially SLE, pSS, and WG.

Association between TNF-α promoter -308 A/G polymorphism and Alzheimer's disease: a meta-analysis.

The aim of this study was to determine whether the tumor necrosis factor-α (TNF-α) promoter -308 A/G polymorphism is associated with susceptibility to Alzheimer's disease (AD) in multi-ethnic populations. MEDLINE and EMBASE databases and manual literature search were used to identify published articles in which TNF-α polymorphism was determined in AD patients and control subjects. Meta-analysis was conducted on the association between the TNF-α -308 A/G polymorphism and AD using allele contrast and the recessive, dominant, and additive models. A total of 16 studies involving 3,826 AD patients and 4,327 control subjects were examined. The meta-analysis showed no association between the TNF-α -308 A allele and AD when all the subjects were considered [odds ratio (OR) = 1.275, 95 % CI 0.966-1.685, p = 0.087]. After stratification by ethnicity, the meta-analysis indicated that the A allele is significantly associated with AD in East Asian (OR = 1.743, 95 % CI 1.256-2.418, p = 0.001), but not in the European (OR = 0.963, 95 % CI 0.822-1.128, p = 0.637) or Middle Eastern populations (OR = 3.921, 95 % CI 0.411-37.42, p = 0.235). Meta-analysis under dominant, recessive, and additive models also showed a similar pattern of results as with the A allele. This meta-analysis shows that the TNF-α -308 A/G polymorphism may represent a significant risk factor for AD in East Asians but not in the European or Middle Eastern populations.

Paraoxonase 1 Q192R and L55M polymorphisms and susceptibility to amyotrophic lateral sclerosis: a meta-analysis.

This study aimed to investigate whether paraoxonase 1 (PON1) Q192R and L55M polymorphisms are associated with susceptibility to amyotrophic lateral sclerosis (ALS). We conducted a meta-analysis of the associations between the PON1 Q192R and L55M polymorphisms and ALS. A total of 2,831 patients and 3,123 controls from eight studies of the PON1 Q192R polymorphism and seven studies of the PON1 L55M T polymorphism were considered for this study. Meta-analysis showed no association between ALS and the PON1 192R allele (OR = 1.052, 95 % CI = 0.923-1.207, p = 0.447), and the PON1 55M allele (OR = 1.015, 95 % CI = 0.884-1.164, p = 0.837) in all study subjects. Similarly, no association was found between ALS and the PON1 Q192R and L55M polymorphisms using recessive, dominant or homozygote contrast models. Stratification by ethnicity indicated no association between ALS and the PON1 192R allele (OR = 1.058, 95 % CI = 0.910-1.231, p = 0.464) and the PON1 55M allele (OR = 1.027, 95 % CI = 0.889-1.185, p = 0.721) in the European population. This meta-analysis showed lack of associations between PON1 Q192R and L55M polymorphisms and susceptibility to ALS in the European population.

Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis.

We examined whether methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) polymorphisms are associated with susceptibility to multiple sclerosis (MS). We performed a meta-analysis on the association between MS and the following genotypes: MTHFR C677T, A1298C, and GSTP1 A313G polymorphisms, and GSTM1 and GSTT1 null alleles. Fifteen comparisons involving 2,486 patients and 2,861 controls were considered. Meta-analysis of all study subjects considered together showed no association between MS and the MTHFR 677 T allele (OR = 1.014, 95 % CI 0.803-1.280, p = 0.909). Stratification by ethnicity showed no similar association in Caucasian and Arab populations. Likewise, no link was found between MS and the MTHFR 1298 C allele in the total data (OR = 2.477, 95 % CI 0.507-12.10, p = 0.263), nor when it was stratified by ethnicity. No association with MS was observed in relation to the GSTM1 null genotype in Caucasian populations (OR = 1.229, 95 % CI 0.693-2.181, p = 0.481), nor with the GSTP1 A313G polymorphism (OR for G allele = 1.133, 95 % CI 0.903-1.421, p = 0.281). However, there was an association between MS and the GSTT1 null genotype in data obtained from Caucasian populations (OR = 1.945, 95 % CI 1.452-2.605, p = 8.6 × 10(-7)). GSTT1 null genotype is associated with MS in Caucasian populations; however, no association was found between MS and polymorphisms of MTHFR, GSTM1, and GSTP1.

Association between IL-6 -174 G/C, IL-6 -634 G/C, and IFN-γ +874 A/T polymorphisms and susceptibility to recurrent pregnancy loss: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether interleukin-6 (IL-6) -174 G/C, IL-6 -634 G/C, and interferon-γ (IFN-γ) +874 A/T polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL). METHODS: We conducted a literature search using PubMed and EMBASE databases and performed a meta-analysis using fixed- or random-effects models. RESULTS: A total of 15 articles met the study inclusion criteria. When all study subjects were considered together, meta-analysis showed no association between RPL and the IL-6 -174 GG + GC genotype (odds ratio [OR] = 0.794, 95 % confidence interval [CI] = 0.542-1.163, p = 0.236). However, stratification of the data by ethnicity indicated an association between this genotype and RPL in non-Caucasians (OR = 0.528, 95 % CI = 0.302-0.925, p = 0.028), but not in Caucasian populations. Moreover, meta-analysis revealed an association between RPL and the IL-6 -634 GG + GC genotype in all study subjects (OR = 0.556, 95 % CI = 0.383-0.806, p = 0.002), while stratification by ethnicity revealed a negative association between this genotype and RPL in Asian (OR = 0.545, 95 % CI = 0.371-0.800, p = 0.002) but not Middle Eastern populations. Furthermore, a relationship between the IFN-γ +874 A allele and RPL was identified in non-Caucasians (OR = 1.403, 95 % CI = 1.133-1.734, p = 0.002), but not in Caucasians. CONCLUSIONS: This meta-analysis demonstrates that IL-6 -174 G/C, IL-6 -634 G/C, and IFN-γ +874 A/T polymorphisms are associated with susceptibility to RPL, particularly in non-Caucasians.

The immune regulatory function of B7-H3 in malignancy: spotlight on the IFN-STAT1 axis and regulation of tumor-associated macrophages.

B7-H3 is a member of the B7 superfamily and a putative inhibitory immune checkpoint molecule. Several early-phase clinical trials have reported promising anti-tumor activity and safety of anti-cancer drugs targeting B7-H3, suggesting that it may be a promising target for a potential next-generation immune checkpoint inhibitor. Despite ongoing clinical studies, most B7-H3-targeted drugs being currently investigated rely on direct cytotoxicity as their mechanisms of action rather than modulating its function as an immune checkpoint, at least in part due to its incompletely understood immune regulatory function. Recent studies have begun to elucidate the role of B7-H3 in regulating the tumor microenvironment (TME). Emerging evidence suggests that B7-H3 may regulate the interferon-STAT1 axis in the TME and promote immune suppression. Similarly, increasing evidence shows B7-H3 may be implicated in promoting M1 to M2 polarization of tumor-associated macrophages (TAMs). There is also accumulating evidence suggesting that B7-H3 may play a role in the heterotypic fusion of cancer stem cells and macrophages, thereby promoting tumor invasion and metastasis. Here, we review the recent advances in the understanding of B7-H3 cancer immunobiology with a focus on highlighting its potential role in the interferon priming of TAMs and the heterotypic fusion of TAMs with cancer stem cells and suggest future direction in elucidating its immune checkpoint function.

Toll-like receptor polymorphisms and vasculitis susceptibility: meta-analysis and systematic review.

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confers susceptibility to vasculitis. A literature search was conducted using the PubMed and Embase. A meta-analysis on the associations between the TLR4 Asp299Gly polymorphisms and vasculitis was carried out using allele contrast, dominant, and codominant models and a systematic review of other TLR polymorphisms. Fourteen studies involving 2,064 patients and 2,481 controls were included in this systematic review, which comprised nine on Behcet's disease (BD), three on giant cell arteritis (GCA), and one on Henoch-Schenlein purpura (HSP). Meta-analysis of six studies showed a significant association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis and GCA (Odds ratio [OR] = 1.368, 95 % confidence interval [CI] = 1.300-1.815, p = 0.030; OR = 1.523, 95 % CI = 1.099-2.112, p = 0.012). Under a random effects model, the adjusted ORs calculated using the trim and fill technique revealed an association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis (OR = 1.544, 95 % CI = 1.091-2.185, p < 0.05). Stratification by vasculitis type using the codominant model showed the trend for the association with GCA (OR = 1.569, 95 % CI = 0.970-2.538, p = 0.066). There were three studies on the TLR2 Arg753Gln polymorphism and two on the TLR4 Thr399Ile polymorphism; no association with vasculitis was evident. Among the TLR2, TLR7, and TLR9 polymorphisms included in this review, one Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 with BD (p = 0.002, 0.036) and one Asian study showed an association of TLR9 rs352140 with BD (p = 0.009). This meta-analysis demonstrates that the TLR4 Asp299Gly polymorphism may confer susceptibility to GCA. The review of published data suggests that other TLR polymorphisms such as TLR7 and TLR9 may play a role in vasculitis.

Association between tumor necrosis factor-α promoter -308 A/G, -238 A/G, interleukin-6 -174 G/C and -572 G/C polymorphisms and periodontal disease: a meta-analysis.

The aim of this study was to determine whether tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) promoter polymorphisms confer susceptibility to periodontitis in ethnically different populations. A literature search was performed using PubMed and Embase and a meta-analysis of the identified studies was conducted to explore the associations between TNF-α -308 A/G, -238 A/G, IL-6 promoter -174 G/C and -572 G/C polymorphisms and periodontitis. Seventeen comparison studies for the TNF-α -308 A/G polymorphism and three studies for the TNF-α -238 A/G polymorphism were included in the meta-analysis. And 16 separate studies for the IL-6 -174 G/C polymorphism and 10 studies for the IL-6 -572 G/C polymorphism were considered in our meta-analysis. Analysis after stratification by ethnicity indicated that the TNF-α -308 A allele was associated with periodontitis in Brazilian, Asian, and Turkish populations (OR=0.637, 95% CI=0.447-0.907, p=0.013; OR=0.403, 95% CI=0.204-0.707, p=0.009; OR=1.818, 95; % CI=1.036-3.189, p=0.037). The meta-analysis showed no association between the TNF-α -238 A/G polymorphism and periodontitis. The meta-analysis indicated an association of the IL-6 -174 G/C polymorphisms with periodontitis in Brazilian populations (OR for GG+GC=2.394, 95% CI=1.081-5.302, p=0.031). Stratification by ethnicity and disease type indicated an association between the IL-6 -572 G allele and chronic periodontitis (OR=1.585, 95 % CI=1.030-2.439, p=0.036), and periodontitis in Europeans (OR=2.118, 95% CI=1.254-3.577, p=0.005). This meta-analysis demonstrates that the TNF-α -308 A/G polymorphism confers susceptibility to periodontitis in Brazilian, Asian and Turkish populations. The IL-6 -174 G/C polymorphism may confer susceptibility to periodontitis in Brazilians, and the IL-6 -572 G/C polymorphism may be associated with susceptibility to periodontitis in Europeans, and chronic periodontitis.

PTGDR polymorphisms and susceptibility to asthma: a meta-analysis.

The aim of this study was to explore whether prostaglandin D2 receptor (PTGDR) polymorphisms confer susceptibility to asthma. A meta-analysis was conducted on the associations between the PTGDR -549 C/T, -441 C/T, and -197 C/T polymorphisms and asthma using: (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. Three polymorphism haplotypes were constructed in the order -549/-441/-179. Meta-analysis was performed on the haplotype CCC (high transcriptional activity) and of TCT (low transcriptional activity). A total of 13 separate comparative studies in 9 articles involving 7,155 patients with asthma and 7,285 control subjects were included in this meta-analysis. An association between asthma and the PTGDR -549 C/T polymorphism was found by allele contrast (OR = 1.133, 95 % CI = 1.004-1.279, P = 0.043). Ethnicity-specific meta-analysis showed an association between asthma and the PTGDR -549 C allele in Europeans (OR = 1.192, 95 % CI = 1.032-1.377, P = 0.017). Furthermore, stratifying subjects by age indicated an association between the PTGDR -549 C allele and asthma in adults (OR = 1.248, 95 % CI = 1.076-1.447, P = 0.003), but no association in children (OR = 0.933, 95 % CI = 0.756-1.154, P = 0.324). Analyses using the dominant and additive models showed the similar pattern as that observed for the PTGDR -549 C allele, that is, a significant association in Europeans and adults, but not in children. No association was found between asthma and the PTGDR -441 C/T or -197 C/T polymorphisms, and meta-analysis stratified by ethnicity and age also revealed no association between asthma and these polymorphisms. Furthermore, no association was found between asthma and the CCC and TCT haplotypes of PTGDR, and meta-analysis stratified by ethnicity and age revealed no association between asthma and the CCC and TCT PTGDR haplotypes. This meta-analysis demonstrates that the PTGDR -549 C/T polymorphism confers susceptibility to asthma in Europeans and adults. However, no association was found between the PTGDR 441 C/T and -197 C/T polymorphisms or the CCC and TCT haplotypes and asthma susceptibility.

Genome-wide pathway analysis of a genome-wide association study on multiple sclerosis.

The aims of this study were to identify candidate single nucleotide polymorphisms (SNPs) and mechanisms of multiple sclerosis (MS) and to generate SNP to gene to pathway hypotheses. A MS genome-wide association study (GWAS) dataset that included 505,763 SNPs in 500 cases and 500 controls of European descent was used in this study. Identify candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 9 candidate SNPs and 5 pathways, which provided 5 hypothetical biological mechanisms. The candidate SNPs, namely, rs1802127 (MSH5), rs9277471 (human leukocyte antigen [HLA]-DPB1), rs8084 (HLA-DRA), rs7192 (HLA-DRA), rs2072895 (HLA-F), rs2735059 (HLA-F), rs915669 (HLA-G), rs915668 (HLA-G), and rs1063320 (HLA-G) were all at HLA loci (-log10(P) = 3.301-4.000). The most strongly associated pathway was rs1802127 to MSH5 to meiotic recombination and meiotic cell cycle (nominal P < 0.001, false discovery rate [FDR] < 0.001). When HLA loci were excluded, ICSNPathway analysis identified seven candidate non-HLA SNPs (rs5896 [F2], rs8181979 [SHC1], rs9297605 [TAF2], rs669 [A2 M], rs2228043 [IL6ST], rs1061622 [TNFRSF1B], rs1801516 [ATM]) and ten candidate causal pathways, which provided seven hypothetical biological mechanisms (nominal P ≤ 0.001, FDR ≤ 0.047). The most strongly associated pathway was SNP rs5896 to F2 to the transcriptional activation DNA-binding protein B from mRNA (nominal P < 0.001, FDR = 0.006). The application of ICSNPathway analysis to the MS GWAS dataset resulted in the identification of candidate SNPs, pathways, and biological mechanisms that might contribute to MS susceptibility.

Association between interleukin-18 polymorphisms and systemic lupus erythematosus: a meta-analysis.

The aim of this study was to determine whether the three functional interleukin-18 (IL-18) promoter -607 C/A (rs1946518), -137 G/C (rs187238), and -1297 C/T (rs360719) polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between these IL-18 polymorphisms and SLE using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 11 comparisons (nine studies) involving 8,453 subjects (2,928 SLE patients and 5,525 controls) were included in the meta-analysis. In all study subjects, meta-analysis showed no association between SLE and the IL-18 -607 C allele (odds ratio [OR] = 1.065, 95 % confidence interval [CI] = 0.870-1.303, p = 0.541). However, stratification by ethnicity indicated a significant association between this allele and SLE in Europeans (OR = 0.864, 95 % CI = 0.757-0.986, p = 0.031), but not in Asians (OR = 1.230, 95 % CI = 0.902-1.676, p = 0.190). Meta-analyses showed the same pattern for the IL-18 -607 C allele using the dominant and additive models. Meta-analysis of the IL-18 -137 G/C polymorphism showed no association between SLE and the IL-18 -137 G allele in all study subjects (OR = 0.916, 95 % CI = 0.836-1.003, p = 0.057), but stratification by ethnicity indicated a significant association between this allele and SLE in Asians (OR = 0.792, 95 % CI = 0.629-0.997, p = 0.047), but not in Europeans (OR = 0.930, 95 % CI = 0.839-1.032, p = 0.171). Furthermore, meta-analysis showed that the IL-18 -1297 C allele was significantly associated with SLE in all study subjects and in Europeans (OR = 1.240, 95 % CI = 1.052-1.482, p = 0.010 and OR = 1.303, 95 % CI = 1.050-1.617, p = 0.016). This meta-analysis shows that the IL-18 -607 C/A and -1297 C/T polymorphism are associated with the development of SLE in Europeans, and the IL-18 -137 G/C polymorphism is associated with SLE in Asians.

Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis: a meta-analysis.

The aim of this study was to determine whether interferon regulatory factor 5 (IRF5) polymorphisms confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. We searched the literature using the Pubmed and Embase databases and conducted meta-analyses on associations between the four IRF5 polymorphisms (rs2004640, rs729302, rs752637, and rs2280714) and RA susceptibility, using fixed and random effects models. A total of 12 comparison studies were considered in this meta-analysis, which in total involved 7,916 RA patients and 6,452 controls, and eight European, three Asian, and one Argentinean population. Meta-analysis showed an association between the minor allele of rs2004640 and RA in all subjects (odds ratio [OR] = 0.928, 95 % confidence interval [CI] = 0.865-0.996, P = 0.037). After stratification by ethnicity, analysis indicated that the minor allele was significantly associated with RA in Europeans (OR = 0.889, 95 % CI = 0.839-0.941, P = 5.03 × 10(-6)), but not in Asians (OR = 1.057, 95 % CI = 0.978-1.144, P = 0.164). A direct comparison between anti-citrullinated peptide antibody-positive and -negative patients revealed no difference of the frequency of the rs2004640 minor allele (OR = 1.047, 95 % CI = 0.813-1.348, P = 0.724). Meta-analysis identified a significant association between RA and the minor allele of the rs729302 polymorphism in the overall population (OR = 0.896, 95 % CI = 0.826-0.972, P = 0.009) and in Asians (OR = 0.862, 95 % CI = 0.795-0.935, P = 3.50 × 10(-5)), but not in Europeans (OR = 0.951, 95 % CI = 0.877-1.031, P = 0.225). Meta-analysis showed an association between the minor allele of rs752637 and RA in Europeans (OR = 0.858, 95 % CI = 0.789-0.932, P = 3.03 × 10(-5)), but not in Asians (OR = 1.035, 95 % CI = 0.918-1.168, P = 0.572). No association was found between the rs2280714 polymorphism and RA susceptibility. This meta-analysis confirms that the IRF5 rs2004640, rs729302 and rs752637 polymorphisms are associated with RA susceptibility in different ethnic groups, especially in Europeans and Asians, but further study of this association is required in other ethnic groups.

Fc receptor-like 3 (FCRL3) -169 C/T polymorphism and systemic lupus erythematosus: a meta-analysis.

Our aim was to determine whether the Fc receptor-like 3 (FCRL3) -169 C/T (rs7528684) polymorphism confers susceptibility to systemic lupus erythematosus (SLE). A meta-analysis was conducted on the associations between the FCRL3 -169 C/T polymorphism and the SLE. A total of nine sets of comparisons containing 3,628 patients and 6,490 controls were considered. The meta-analysis showed no association between the SLE and the FCRL3 -169 C allele in all study patients (odds ratio [OR] = 0.999, 95 % confidence interval [CI] = 0.925-1.080, p = 0.986). Stratification by ethnicity indicated no association between the C allele and the SLE in neither Europeans nor Asians (OR = 1.058, 95 % CI = 0.925-1.250, p = 0.414; OR = 0.981, 95 % CI = 0.884-1.088, p = 0.715). Furthermore, analysis using the recessive model, the dominant model, and the homozygote contrast showed the same pattern for the C allele in European and Asian groups, showing no association between the FCRL3 -169 C/T polymorphism and the SLE. Even after excluding studies whose controls were not in Hardy-Weinberg equilibrium, we found that this did not materially affect the meta-analysis results. However, the single Latin American study did show an association between the FCRL3 polymorphism and the SLE under homozygote contrast (OR for CC vs. TT = 2.689, 95 % CI = 1.152-1.277, p = 0.022). This meta-analysis of published studies including 2,544 patients and 3,913 controls demonstrates that the FCRL3 -169 C/T polymorphism does not confer susceptibility to SLE in Europeans or Asians.

Associations between interleukin-10 polymorphisms and susceptibility to psoriasis: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether three specific interleukin-10 (IL-10) polymorphisms confer susceptibility to psoriasis. METHODS: A meta-analysis was conducted on the associations between the IL-10-1082 G/A, -592 C/A polymorphisms and haplotypes of the IL-10-1082 G/A, -592 C/A, -819 C/T polymorphisms and psoriasis. RESULTS: A total of eight studies involving 1,018 psoriasis patients and 1,186 controls were considered in the meta-analysis. No association was found between psoriasis and the IL-10-1082 G allele in all study subjects [odds ratio (OR) = 1.098, 95 % confidence interval (CI) = 0.923-1.306, p = 0.291] or between this allele and psoriasis in Europeans (OR = 0.990, 95 % CI = 0.809-1.214, p = 0.925), but a significant association was found in Asians (OR = 1.785, 95 % CI = 1.144-2.76, p = 0.011). Three polymorphisms at the promoter region of IL-10 (-1082 G/A, -819 C/T, -592 C/A) are known to be in complete linkage disequilibrium, but no association was found between the haplotype and psoriasis. CONCLUSIONS: This meta-analysis shows that the IL-10-1082 G/A polymorphism confers susceptibility to psoriasis in Asians, and suggests that the IL-10 promoter -1082 polymorphism has an ethnicity-specific effect.