Xiao-Ke Yang

Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus.

Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene–gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48–3.44 [P = 1.21×104]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene–gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE.

IL-32 with potential insights into rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic inflammation in synovial joints. Effective treatment for RA is lacking because the clear etiology and pathogenesis of RA have not been fully elucidated. Cytokine-mediated immunity has been found to play an important role in the pathogenesis of various autoimmune diseases such as RA. Recently, IL-32 is identified with high expression in RA patients and mice models of experimental inflammatory arthritis. IL-32 is recognized to play a crucial role in RA with pro-inflammatory effects. Furthermore, interventions for blocking IL-32 in RA seem possible and applicable. Therefore, targeting IL-32 may give therapeutic potential. In this article, we discuss the biological features of IL-32 and summarize recent advances in understanding the role of IL-32 in disease onset of and treatment for RA. Hopefully the information obtained will benefit for developing novel therapeutic strategies.

Genetic interaction between genes involved in NF-κB signaling pathway in systemic lupus erythematosus.

Recently, multiple genetic associations have been found between genes involved in nuclear factor-kappaB (NF-κB) signaling pathway and systemic lupus erythematosus (SLE) or other autoimmune diseases. This study was undertaken to replicate some of these associations and further test for genetic interactions among these genes in SLE in a Chinese population. Ten single-nucleotide polymorphisms (SNPs) in NFKB1, REL, inhibitor of κB-like (IκBL), IκB kinase β (IKBKB), tumor necrosis factor receptor associated factor 6 (TRAF6), tumor necrosis factor a-induced protein 3 (TNFAIP3), TNFAIP3 interacting protein 1 (TNIP1) were genotyped in 898 Chinese patients with SLE and 988 healthy controls by Sequenom MassArray technology. Single-marker genetic association analysis was performed, and additive and multiplicative interactions were analyzed. Associations of TNFAIP3 rs2230926 (p=1.43 × 10(-3)) and TNIP1 rs10036748 (p=4.33 × 10(-3)) with SLE were replicated in our study. Two other SNPs, NFKB1 rs28362491 and IκBL rs2071592, showed nominal evidence for association (p=4.70 × 10(-2) and p=5.90 × 10(-3), respectively) but these were not significant after applying Bonferroni correction. Additive interaction analysis revealed significant interaction between NFKB1 rs28362491 and TNFAIP3 rs2230926 (RERI=0.98, 95%CI=0.02-1.93; AP=43.2%, 95%CI=0.12-0.74). Significant multiplicative interaction was observed between NFKB1 rs28362491 and TNIP1 rs3792783 (p=0.03). Our results provide evidence for gene-gene interactions, which further support the important role of NF-κB signaling pathway in the genetic basis of SLE and the notion of genetic interactions accounting for missing heritability.

Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis

BACKGROUND AND AIMS Studies investigating the association between the peptidylarginine deiminase 4 (PADI4) gene polymorphisms and rheumatoid arthritis (RA) reported conflicting results. The aim of this meta-analysis was to assess the association between PADI4 gene polymorphisms and RA. METHODS A systematic literature search was conducted to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. RESULTS A total of 34 studies from 28 articles involving 19859 patients with RA and 25771 healthy controls were included. Significant association of PADI4-94G/A polymorphism and RA was observed (OR = 0.891, 95% CI = 0.833-0.954, p = 0.001) in the overall study population and in the Asian populations (OR = 0.824, 95% CI = 0.759-0.894, p = 0.000) respectively. For the -92C/G polymorphism, a significant association was observed (OR = 1.481, 95% CI = 1.166-1.882, p = 0.001) in Africans. For the -90C/T polymorphism, a significant association was observed (OR = 0.576, 95% CI = 0.381-0.872, p = 0.009) in the Latin American population. The pooled estimates for the other polymorphisms were not statistically significantly associated with RA (PADI4-104C/T, -89A/G, -96T/C). CONCLUSIONS This meta-analysis demonstrates that PADI4-94G/A polymorphism is associated with susceptibility to RA in the overall population and in the Asian population. The PADI4 -92C/G polymorphism confers susceptibility to RA in Africans and the PADI4-90C/T polymorphism was associated with RA in the Latin American population.

Association of signaling transducers and activators of transcription 1 and systemic lupus erythematosus

Abstract Systemic lupus erythematosus (SLE) is complex autoimmune disease which involves various facets of the immune system. Signaling transducers and activators of transcription 1 (STAT1) belongs to the family of STAT transcription factors that mediate various biological responses. Recently, studies in both experimental animal models of lupus and patients with SLE have revealed expression and activation of STAT1 is closely associated with the pathogenesis of SLE. Moreover, increased production of interferons (IFNs) and aberrant activation of IFNs signaling, which is mechanistically linked to increased level of STAT1, are crucial for the development of SLE. Therefore, we will focus on the association of STAT1 and SLE based on recent understandings to render more information about the mechanisms of STAT1 might perform in. Hopefully, the information obtained will lead to a better understanding of the development and pathogenesis of systemic autoimmune diseases, as well as its clinical implications and therapeutic potential.

Therapeutic potential of tyrosine kinase 2 in autoimmunity

Introduction: Tyrosine kinase 2 (Tyk2) is a Janus kinase family member that is crucial for signaling transduction in response to a wide variety of cytokines, including type I IFNs, IL-6, IL-10, IL-12 and IL-23. An appropriate expression of Tyk2-mediated signaling might be essential for maintaining normal immune responses. Areas covered: This review summarizes that Tyk2 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, B cells, as well as T helper cells. In addition, Tyk2-mediated signaling promoted the production of autoimmune-associated components, which is implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis. Aberrant expression of Tyk2 was observed in many autoimmune conditions. Expert opinion: Until recently, no patent filings had claimed selective inhibitors of Tyk2. Both CP-690,500 and CMP6 failed to be used in clinical treatment due to the difficulties of finding suitable selective leads or due to detrimental toxicities. Although the result of Cmpd1 is promising, it remains to be seen how specific the Tyk2 inhibitor is and how they are working. Currently, structure-based drug design (SBDD) technology has provided us with a quite useful window for SBDD of Tyk2 inhibitors.

Therapeutic potential of IL-15 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, destructive inflammatory autoimmune disease. Cytokine-mediated immunity has been found to play an important role in the pathogenesis of autoimmune diseases including RA. Recently, much attention has been paid on the role of IL-15, which is a member of the 4 α-helix bundle cytokine family. IL-15 was detected in serum and synovial fluid from RA patients and arthritis mice models. Moreover, administration of IL-15 leads to the development of severe inflammatory arthritis, suggesting that IL-15 may be therapeutically relevant in RA. Therefore, targeting IL-15 may be significantly important and valuable. In this article, we discuss the biological features and effects of IL-15 and summarize recent advances on the pathological roles of IL-15 in RA and treatment for RA.

5,10-Methylenetetrahydrofolate reductase polymorphisms and colon cancer risk: a meta-analysis.

Previous studies investigating the association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and colon cancer risk have generated conflicting results. The aim of our meta-analysis was to clarify the precise association. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CI) were used to estimate the strength of the association. In this meta-analysis, a total of 13 articles, involving 5,386 cases and 8,017 controls met the inclusion criteria. Overall, a significant association was found between colon cancer risk and the MTHFR C667 polymorphism (TT vs CC+CT: OR=0.79; 95%CI=0.65-0.96; p=0.017). Stratification by ethnicity revealed that MTHFRC667 was associated with colon cancer risk in the non-Asian group (TT vs CC+CT:OR=0.77, 95%CI=0.68-0.89, p=0.000; TT vs CC: OR=0.84, 95%CI=0.73-0.97, p=0.016). Stratification by source of control indicated that MTHFR C667 also correlated with colon cancer risk in the population-based subgroup (TT vs CC: OR=0.85, 95%CI=0.74-0.97, p=0.017; TT vs CC+CT: OR=0.78, 95%CI=0.68-0.89, p=0.000) and hospital-based subgroup (TT vs CC+CT: OR=0.65, 95%CI=0.49-0.86, p=0.003). However, risk was significantly increased for MTHFR A1298C polymorphisms and colon cancer risk in hospital-based studies (C vs A: OR=1.52, 95%CI=1.26-1.83, p=0.000; CC+AC vs AA: OR=1.93, 95%CI=1.47-2.49, p=0.000) but reduced in population-based studies (CC vs AA: OR=0.83, 95%CI=0.70-0.99, p=0.042). In conclusion, the results of our meta-analysis suggest that the MTHFR C667 polymorphism is associated with reduced colon cancer risk, especially for non-Asian populations.

Evidence for genetic association of TBX21 and IFNG with systemic lupus erythematosus in a Chinese Han population

TBX21 recode T-bet which is an important transcription factor that drives the Th1 immune response primarily by promoting expression of the interferon-gamma (IFNG) gene. Recent studies have shown that genetic variants in TBX21 and IFNG are connected with risk of systemic lupus erythematosus (SLE). The aim of the present study was to replicate these genetic associations with SLE in Anhui Chinese population. Genotyping of 3 variants (rs4794067 in TBX21, rs2069705 and rs2069718 in IFNG) was performed. A total of 3732 subjects were included in the final analysis. The study only identified the association of rs2069705 with SLE susceptibility (T vs. C: odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.00–1.26, P = 0.046). Combined analysis with Hong Kong GWAS showed that the OR for rs2069705 was 1.10 (95% CI: 1.01–1.21, P = 0.027). Further pooled analysis with Korean populations involving 10498 subjects showed a more significant association between rs2069705 and SLE (T vs. C: OR = 1.11, 95%CI = 1.04–1.19, P = 0.002; TT + TC vs. CC: OR = 1.11, 95%CI = 1.02–1.21, P = 0.012; TT vs. TC + CC: OR = 1.28, 95%CI = 1.07–1.54, P = 0.008; TT vs. CC: OR = 1.33, 95%CI = 1.10–1.60, P = 0.003). In addition, we also identified a significant genetic interaction between rs2069705 and rs4794067 in Anhui Chinese population. Our study suggests that IFNG and IFNG-TBX21 interaction are involved in SLE susceptibility.

Association of IL-21 polymorphisms (rs907715, rs2221903) with susceptibility to multiple autoimmune diseases: A meta-analysis

Abstract Objectives: Previous published data indicated that interleukin-21 (IL-21) gene polymorphisms were shown to associate with multiple autoimmune diseases (ADs), but the results remain inconclusive. The aim of this study was to perform a meta-analysis to assess the overall association between IL-21 gene polymorphisms (rs907715, rs2221903) and multiple ADs. Methods: All eligible case–control studies were searched in the PubMed and Embase database. A meta-analysis was conducted on the association between the IL-21 gene variants and ADs using: (1) allelic contrast, (2) homozygote contrast, (3) the recessive model, and (4) the dominant model. Results: A total of 12 relevant studies including 10 535 cases and 19 356 controls were enrolled in this meta-analysis. A significant association between IL-21 rs907715 gene polymorphism and AD was found under the allelic (OR: 1.102, 95% CI: 1.057–1.149, p = 0.000), homozygous (OR: 1.220, 95% CI: 1.089–1.368, p = 0.001), dominant (OR: 1.160, 95% CI: 1.027–1.309, p = 0.017), and recessive genetic model (OR: 1.119, 95% CI: 1.055–1.187, p = 0.000) among Caucasian populations. However, there was no significant association between IL-21 rs2221903 polymorphism and AD in different genetic models. Conclusions: Data from the present study suggest that the IL-21 rs907715 polymorphism might be associated with multiple ADs susceptibility in Caucasians. Especially, the allele G of intronic rs907715 in IL-21 confers increased risk of ADs.