Identification of the Genetic Association Between Type-2-Diabetes and Pancreatic Cancer.

Type-2-diabetes (T2D) and pancreatic cancer (PC) are both common diseases globally. Although T2D is reported as the adverse factor for predicting PC prognosis, its pathophysiology and relation with PC remain unknown. This study focused on exploring differentially expressed genes (DEGs) as well as their functional roles in T2D and PC, aiming to reveal the underlying association between the T2D and PC. To identify DEGs in T2D and PC, this study analyzed four microarray datasets obtained from Gene Expression Omnibus (GEO) database. Then, this work carried out enrichment as well as protein-protein interaction (PPI) network analysis for exploring DEGs-enriched functions and pathway. Besides, expression of hub genes was explored. TISIDB database was adopted to analyze the correlations among key gene and immune characteristics. Finally, the key gene expression was confirmed in vitro. DEGs were first screened from gene expression profiles of T2D and PC datasets, respectively. Then 135 common genes were identified in these four datasets. Based on functional analysis, common DEGs were mostly related to hormone secretion and metabolism pathways. Four hub genes were up-regulated, among which, MAFB was the most significant potential biomarker for PC. MAFB expression was strongly correlated with chemokines, chemokine receptors and immunomodulators. Finally, RT-qPCR was conducted to demonstrate the MAFB expression in T2D and PC. This study identified 15 hub genes with significant effects on the association of T2D with PC, and MAFB gene might be a biomarker for PC and had potential treatment value for PC.

CYLD Deubiquitinase Negatively Regulates High Glucose-Induced NF-κB Inflammatory Signaling in Mesangial Cells.

Nuclear factor-kappa B (NF-κB) is the key part of multiple signal transduction of inflammation in the pathogenesis of diabetic nephropathy (DN). The ubiquitin-proteasome system is extensively involved in the regulation of the NF-κB pathway. Cylindromatosis (CYLD) has deubiquitinase activity and acts as a negative regulator of the NF-κB signaling pathway. However, the association between CYLD and NF-κB inflammatory signaling in DN is unclear. In the present study, mouse glomerular mesangial cells (GMCs) and rat GMCs were stimulated by elevated concentrations of glucose (10, 20, and 30 mmol/L high glucose) or mannitol as the osmotic pressure control. CYLD was overexpressed or suppressed by transfection with a CYLD expressing vector or CYLD-specific siRNA, respectively. Our data showed that high glucose significantly inhibited the protein and mRNA expression of CYLD in a dose- and time-dependent manner (both p < 0.05). siRNA-mediated knockdown CYLD facilitated the high glucose-induced activation of NF-κB signaling and triggered the release of MCP-1, IL-6, and IL-8 (all p < 0.05). However, these high glucose-mediated effects were blunted by overexpression of CYLD (p < 0.05). The present results support the involvement of CYLD in the regulation of NF-κB inflammatory signaling induced by elevated glucose, implicating CYLD as a potential therapeutic target of DN.

SUMO E3 Ligase PIASy Mediates High Glucose-Induced Activation of NF-κB Inflammatory Signaling in Rat Mesangial Cells.

BACKGROUND: Sumoylation is extensively involved in the regulation of NF-κB signaling. PIASy, as a SUMO E3 ligase, has been proved to mediate sumoylation of IκB kinase γ (IKKγ) and contribute to the activation of NF-κB under genotoxic agent stimulation. However, the association of PIASy and NF-κB signaling in the pathogenesis of diabetic nephropathy (DN) has not been defined. METHODS: Rat glomerular mesangial cells (GMCs) were stimulated by high glucose; siRNA was constructed to silence the expression of PIASy; the expression of PIASy, SUMO isoforms (SUMO1, SUMO2/3), and NF-κB signaling components was analyzed by Western blot; the interaction between IKKγ and SUMO proteins was detected by coimmunoprecipitation; and the release of inflammatory cytokines MCP-1 and IL-6 was assayed by ELISA. RESULTS: High glucose significantly upregulated the expression of PIASy, SUMO1, and SUMO2/3 in a dose- and time-dependent manner (P < 0.05), induced the phosphorylation and sumoylation of IKKγ (P < 0.05), and then triggered NF-κB signaling whereas MCP-1 and IL-6 were released from GMCs (P < 0.05). Moreover, these high glucose-induced effects were observably reversed by siRNA-mediated knockdown of PIASy (P < 0.05). CONCLUSION: The SUMO E3 ligase PIASy mediates high glucose-induced activation of NF-κB inflammatory signaling, suggesting that PIASy may be a potential therapeutic target of DN.

Association between HLA-â ¡gene polymorphism and Helicobacter pylori infection in Asian and European population: A meta-analysis.

BACKGROUND: It is generally considered that HLA-Ⅱ genes contribute to the Helicobacter pylori (Hp) infection and disease development process. AIMS: To perform a meta-analysis to explore the relationship between HLA-Ⅱgene polymorphism and host susceptibility to Hp infection. METHODS: Relevant cohort studies, case-control studies and cross-sectional studies were identified by searching Cochrane Library, PubMed, EMBASE, Web of Science and CBM up to July 2014. The data were extracted and methodological quality of the studies were evaluated. RevMan5.0 software was used to perform statistical analysis. RESULTS: In Asian population, HLA-DQB1*0303 acted as the protective gene in Hp infection (statistically significant pooled OR = 0.54) and the susceptible genes in Hp infection involved HLA-DQB1*0401, HLA-DQA1*0103 and HLA-DQA1*0301 (statistically significant pooled OR and 95%CI were 3.34(1.93,5.77), 1.64(1.16,2.33) and 2.03(1.20,3.44) respectively). No statistically significant difference between DQB1*0303, HLA-DQA1*0103 and DQA1*0301 and Hp infection in European population (P>0.05). And no statistically significant difference (P>0.05) in the overall effect of the association between the rest of HLA-Ⅱalleles and Hp infection. CONCLUSIONS: In Asian population, the protective gene HLA-DQB1*0303 and the susceptible genes HLA-DQB1*0401, HLA-DQA1*0103 and HLA-DQA1*0301 in Hp infection were established by meta-analysis. And there was no HLA-Ⅱallele was found to associate with Hp infection among European population.

Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis.

The association between the signal transducer and activator of transcription 4 (STAT4) gene rs7574865 single nucleotide polymorphism and different autoimmune diseases remains controversial and ambiguous. We conducted this study to investigate whether combined evidence shows the association between STAT4 rs7574865 polymorphism and autoimmune diseases. Comprehensive Medline search and review of the references were used to get the relevant reports published before September 2011. Meta-analysis was conducted for genotype T/T (recessive effect), T/T + G/T (dominant effect) and T allele in random effects models. 40 studies with 90 comparisons including 32 systemic lupus erythematosus (SLE), 19 rheumatoid arthritis (RA), 3 type 1 diabetes (T1D), 11 Systemeric Sclerosis (SSc), 4 inflammatory bowed diseases (IBD), 3 Primary Sjogren's syndrome (pSS), 4 juvenile idiopathic arthritis (JIA), 2 Primary antiphospholipid syndrome (APS), 1 Autoimmune thyroid diseases, 1 multiple sclerosis, 1 Psoriasis, 1 Wegener's granulomatosis, 1 Type 2 diabetes, and 1 giant cell arteritis disease were available for this meta-analysis. The overall odds ratios for rs7574865 T-allele significantly increased in SLE, RA, T1D, SSc, JIA, and APS (OR = 1.56, 1.25, 1.13, 1.34, 1.25, and 2.15, respectively, P < 0.00001) and in IBD-UC and pSS (OR = 1.11 and 1.33, respectively, P < 0.05). This meta-analysis demonstrates that the STAT4 rs7574865 T allele confers susceptibility to SLE, RA, T1D, SSc, JIA, APS, IBD-UC, and pSS patients, supporting the hypothesis of association between STAT4 gene polymorphism and subgroup of autoimmune diseases.

The CRISPLD2 gene is involved in cleft lip and/or cleft palate in a Chinese population.

BACKGROUND: Nonsyndromic cleft lip and/or cleft palate (NSCLP) are common congenital anomalies in humans, the etiologies of which are complex and associated with both genetic and environmental factors. Previous data suggested single nucleotide polymorphisms (SNPs) of rs1546124, rs4783099, and rs16974880 of the CRISPLD2 gene were associated with an increased risk of NSCLP; however, subsequent studies have yielded conflicting results. This study aims to evaluate the associations of the aforementioned polymorphisms with NSCLP in a Northwestern Chinese population. METHODS: Three CRISPLD2 SNPs were genotyped in a case-control study (n = 907), including 444 NSCLP patients and 463 healthy individuals, using polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC). RESULTS: The genotype and allele frequencies of rs1546124 (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.58-3.34; p = 1 × 10(-5) ) and rs4783099 (OR, 0.73; 95% CI, 0.54-1.00; p = 0.05) were different in NSCLP patients compared with controls. Furthermore, the CC genotype at rs1546124 was associated with increased risk for cleft lip with or without cleft palate (CL/P; OR, 2.11; 95% CI, 1.41-3.15; p(correct) = 1.5 × 10(-4) ) and for cleft palate only (CPO; OR, 2.93; 95% CI, 1.69-5.07; p(correct) = 5.4 × 10(-4) ), whereas the T allele of rs4783099 was associated with decreased risk for CPO. Further gender stratification showed that the statistical association of these two loci is mainly in the male patients, and not in female patients. CONCLUSION: Our results suggest that the CRISPLD2 gene contributes to the etiology of NSCLP in the Northwestern Chinese population. SNP rs1546124 is significantly related to NSCLP, associated with both CL/P and CPO groups, and SNP rs4783099 is significantly associated with CPO.

Signal transducer and activator of transcription 4 gene polymorphisms associated with rheumatoid arthritis in Northwestern Chinese Han population.

AIMS: Signal transducer and activator of transcription 4 (STAT4) gene encode a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. Recently, several single nucleotide polymorphisms (SNPs) in STAT4 gene have been reported to be significantly associated with Rheumatoid arthritis (RA) in different ethnic populations. We undertook this study to investigate whether the association of STAT4 genetic polymorphisms with RA is present in Northwestern Chinese Han population. MAIN METHODS: A case-control association study in individuals with RA (n=208) and healthy controls (n=312) was conducted. Four SNPs (rs7574865, rs8179673, rs10181656, rs11889341) in STAT4 gene were genotyped by using polymerase chain reaction followed by denaturing high-performance liquid chromatography (PCR-DHPLC) and DNA sequencing. KEY FINDINGS: The genotype and allele distributions of four polymorphisms were significantly different in individuals with RA compared to controls, with SNP rs7574865 T allele and T/T genotype showing the most significant association with susceptibility to RA (uncorrected P=1×10(-4), OR=1.645, 95% CI=1.272-2.129; uncorrected P=4.8×10(-5), OR=3.111, 95% CI=1.777-5.447, respectively). Stratification studies showed that STAT4 gene polymorphisms were significantly associated with anti-cyclic citrullinated peptide (anti-CCP) positive subgroup in Northwestern Chinese Han population. SIGNIFICANCE: These findings strongly suggest that STAT4 genetic polymorphisms are associated with RA in Northwestern Chinese Han population, and support the hypothesis of STAT4 gene polymorphisms increasing the risk for RA across major populations.

Fc receptor-like 3 gene polymorphisms confer susceptibility to rheumatoid arthritis in a Chinese population.

Polymorphisms in the Fc receptor-like 3 (FCRL3) gene have been reported to be associated with rheumatoid arthritis (RA) in Japanese populations. However subsequent studies have yielded conflicting results. Hence the aim of present study was to clarify whether these genetic variants in FCRL3 gene are associated with RA in a Chinese population. We conducted a case-control study of 234 RA patients and 260 controls by genotyping four polymorphisms in FCRL3. The genotype and allele distributions of four polymorphisms were significantly different in RA patients compared with controls (uncorrected p = 0.021 and p = 0.031; 0.027 and 0.008; 0.028 and 0.042; and 0.019 and 0.029, respectively). The FCRL3-169 C allele was significantly associated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)-positive RA, but no association was detected for RF and anti-CCP-negative RA. Furthermore, the frequency of the -169C allele was increased disproportionately in female patients, and the resulting odds ratio for female homozygote was increased to 2.375 (uncorrected p = 0.006). Haplotype analysis showed that the most common haplotype TGGG was associated with decreased risk of RA (uncorrected p = 0.001, odds ratio = 0.656). However CACA appeared to be a risk haplotype for RA cases (uncorrected p = 0.031, odds ratio = 1.398). Taken together, these results suggest that FCRL3 polymorphisms and haplotypes may contribute to genetic susceptibility to RA in Chinese population.