ABSTRACT
To explore the association of LEP and leptin receptor (LEPR) gene single-nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. Four LEP SNPs (rs11761556, rs12706832, rs2071045 and rs2167270) and nine LEPR SNPs (rs10749754, rs1137100, rs1137101, rs13306519, rs8179183, rs1805096, rs3790434, rs3806318 and rs7518632) were genotyped in a cohort of 633 patients with SLE and 559 healthy controls. Genotyping of SNPs was performed with improved multiple ligase detection reaction (iMLDR). No significant differences were detected for the distribution of allele and genotype frequencies of all 13 SNPs between patients with SLE and controls. The genotype effects of recessive, dominant and additive models were also analysed, but no significant evidence for association was detected. However, further analysis in patients with SLE showed that the TT genotype and T allele frequencies of the LEP rs2071045 polymorphism were nominally significantly higher in patients with pericarditis (P = 0.012, P = 0.011, respectively). In LEPR, the GA/AA genotype and A allele frequencies of the rs1137100 polymorphism were both nominally associated with photosensitivity in patients with SLE (P = 0.043, P = 0.018, respectively). Moreover, the genotype and allele distribution of rs3806318 were also nominally associated with photosensitivity in patients with SLE (P = 0.013, P = 0.008, respectively). No significant differences in serum leptin levels were observed in patients with SLE with different genotypes. In summary, LEP and LEPR SNPs are not associated with genetic susceptibility to SLE, but may contribute to some specific clinical phenotype of this disease; further studies are necessary to elucidate the exact role of LEP and LEPR genes in the pathogenesis of SLE.
Subject(s)
Asian People/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Leptin/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Leptin/genetics , Adult , Case-Control Studies , Demography , Female , Gene Frequency/genetics , Haplotypes/genetics , Humans , Male , Risk FactorsABSTRACT
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.
Subject(s)
Asian People/genetics , Chromosomes, Human, X/genetics , Genes, X-Linked , Lupus Erythematosus, Systemic/genetics , Ribose-Phosphate Pyrophosphokinase/genetics , China , Female , Genome-Wide Association Study , Humans , Male , Polymorphism, Single NucleotideABSTRACT
OBJECTIVE: In the present study, DNA methylation level of CD4+ T cells exposed to ultraviolet B (UVB) was investigated and its potential mechanisms were also explored. METHODS: CD4+ T cells from 12 cases of healthy subjects and 33 cases of SLE patients were isolated and exposed to different dosages (0, 50, 100 mJ/cm2) of UVB. Further, SLE patients were divided into two groups: active SLE group (22 cases, SLEDAI scores >4) and inactive SLE group (11 cases, SLEDAI scores ≤4). DNA methylation was evaluated by the Methylamp™ Global DNA Methylation Quantification Ultra Kit. The mRNA and protein expression levels of DNA methyltransferases (DNMT1 and DNMT3A) were detected by real-time PCR and western blot, respectively. RESULTS: The levels of DNA methylation and DNMT3A mRNA in SLE patients were significantly decreased compared with those in healthy subjects at baseline. After different dosages of ultraviolet irradiation (0, 50 and 100 mJ/cm2), DNA methylation levels of CD4+ T cells were all reduced in a dose-dependent manner in three subgroups. Additionally, 100 mJ/cm2 ultraviolet irradiation in active SLE group contributed to a significant decrease of both DNA methylation and DNMT3A mRNA levels in CD4+ T cells. UVB exposure had no significant effects on expression levels of DNMT1 mRNA and protein and DNMT3A protein. CONCLUSION: UVB decreases DNA methylation level of CD4+ T cells in SLE patients probably via inhibiting DNMT3A mRNA expression level, which needs to be further explored.
Subject(s)
CD4-Positive T-Lymphocytes/radiation effects , DNA (Cytosine-5-)-Methyltransferases/radiation effects , DNA Methylation/radiation effects , Lupus Erythematosus, Systemic , Ultraviolet Rays , Adult , CD4-Positive T-Lymphocytes/metabolism , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/physiology , DNA Methyltransferase 3A , Dose-Response Relationship, Radiation , Female , Humans , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Male , Middle Aged , Ultraviolet Rays/adverse effectsABSTRACT
Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.
Subject(s)
Chromosomes, Human, Pair 11 , DEAD-box RNA Helicases/genetics , Intracellular Signaling Peptides and Proteins/genetics , Lupus Erythematosus, Systemic/genetics , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins/genetics , Receptors, CXCR5/genetics , Asian People/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genetic Variation , Genome-Wide Association Study , Humans , Logistic Models , Lupus Erythematosus, Systemic/diagnosisABSTRACT
OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1â 659 cases and 3â 398 controls in the discovery stage and 2â 612 cases and 3â 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.
Subject(s)
5-Lipoxygenase-Activating Proteins/genetics , Asian People/genetics , B7-1 Antigen/genetics , Epistasis, Genetic/genetics , Lupus Erythematosus, Systemic/genetics , Adult , Case-Control Studies , Female , Gene Expression Regulation/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Male , Oncogene Proteins, Fusion/genetics , Polymorphism, Single Nucleotide , Tetraspanins , fas Receptor/geneticsABSTRACT
OBJECTIVE: A recent genome-wide association study identified that genetic variants in DPP4 and CCR6 are connected with a risk of RA in the Han Chinese population. The aim of this study was to estimate the epistatic interaction between DPP4 and CCR6 in RA. METHODS: Two single-nucleotide polymorphisms identified in a Han Chinese genome-wide association study (rs12617656 in DPP4, rs1854853 in CCR6) were genotyped. Logistic regression was used to estimate the multiplicative interaction and the additive interaction was analysed by 2 × 2 factorial design. RESULTS: A total of 1224 subjects (377 RA patients, 847 healthy controls) were included in the initial analysis. Additionally, 600 patients with lupus arthritis were included for comparison. Significant multiplicative interaction between DPP4 and CCR6 was observed in RA [codominant model: odds ratio (OR) = 1.49, P = 0.003]. The epistatic effect seems to be stronger in ACPA-positive RA (codominant model: OR = 1.66, P = 0.001). However, no significant multiplicative interactions were observed in ACPA-negative RA or lupus arthritis. Additive interaction analysis showed a significant epistatic effect, but only in ACPA-positive RA [attributable proportion due to interaction = 0.48 (95% CI 0.10, 0.85)]. A further replication study of an independent cohort (476 subjects) found similar results. Pooled results confirmed that there was significant interaction between DPP4 and CCR6 on both the multiplicative and additive scales. CONCLUSION: The study suggests that a genetic interaction between DPP4 and CCR6 is involved in RA susceptibility. Furthermore, these findings highlight Th17 cell response as an important contributor in the pathogenesis of RA.
Subject(s)
Arthritis, Rheumatoid/genetics , Dipeptidyl Peptidase 4/genetics , Epistasis, Genetic/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, CCR6/genetics , Adult , Age of Onset , Asian People , Case-Control Studies , Female , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Male , Th17 Cells/immunologyABSTRACT
OBJECTIVE: To evaluate the plasma levels of six adipokines, including chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin, in patients with SLE. METHODS: Ninety SLE patients and ninety control subjects were recruited, plasma adipokines levels were measured by enzyme-linked immunosorbent assay, and their associations with major clinical and laboratory indexes were analyzed. RESULTS: There were no significant differences in plasma chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin levels between SLE patients and controls. Further subgroup analyses by major clinical and laboratory indexes showed that plasma omentin-1 level was significantly lower in SLE patients without nephritis when compared with those patients with nephritis (P=0.002). Plasma chemerin, cathepsin-S levels in SLE patients without nervous system disorder were significantly lower in comparison with SLE patients with nervous system disorder (P=0.035, P=0.029). No significant associations of other adipokines with any major clinical and laboratory indexes were observed. CONCLUSIONS: Plasma levels of chemerin, omentin-1, lipocalin-2, cathepsin-S, cathepsin-L and adipsin in SLE patients were not markedly different from the normal controls. The presence of nephritis was connected with higher plasma omentin-1 levels in SLE patients, and the presence of nervous system disorder was associated with higher plasma chemerin, cathepsin-S levels in SLE patients. However, functional studies are awaited to further explore the potential roles of these cytokines in SLE.
Subject(s)
Adipokines/blood , Lupus Erythematosus, Systemic/blood , Adult , Cathepsins/blood , Complement Factor D/analysis , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , GPI-Linked Proteins/blood , Humans , Lectins/blood , Lipocalin-2/blood , Lupus Nephritis/blood , Middle Aged , Nervous System Diseases/blood , Young AdultABSTRACT
Systemic lupus erythematosus (SLE) is a severe complex rheumatic disease, but good estimate of its prevalence and risk factors is lacking in China. The aim of the study was to explore the prevalence of SLE and risk factors in rural areas of Anhui Province of China. Eleven counties were randomly selected in Anhui Province, and then, 15% of the villages in selected counties were randomly sampled as study sites. Patients with SLE were identified through two phases. Based on the cases identified, a population-based case-control study was designed to examine risk factors associated with SLE. A total of 1,253,832 individuals and identified 471 SLE cases were surveyed. Crude and age-standardized prevalence were estimated at 37.56 and 36.03 per 100,000 persons, respectively. Gender difference in the prevalence of SLE was significant (P = 4.62 × 10(-76)), and the age-standardized prevalence was 6.17 for males and 67.78 for females per 100,000 persons. The distribution of SLE prevalence was significant by age group (P = 1.78 × 10(-53)), and the peak prevalence was observed at 40-50 years. Multiple environmental factors were associated with SLE, including birth conditions, sweet food, cooking oil, taste, fruit consumption, sunlight exposure, quality of sleep, physical activities, drinking water, residence, negative life events, hepatitis B vaccine, age of menarche, and age at birth of first child (P < 0.05). Our large population-based epidemiological survey estimated the prevalence of SLE at 37.56 per 100,000 persons. Multiple environmental factors were associated with the development of SLE.
Subject(s)
Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/epidemiology , Rural Population/statistics & numerical data , Adolescent , Adult , Age Factors , Case-Control Studies , Child , Child, Preschool , China/epidemiology , Cluster Analysis , Environment , Female , Health Surveys , Humans , Infant , Infant, Newborn , Male , Middle Aged , Prevalence , Risk Factors , Young AdultABSTRACT
Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.
Subject(s)
Ephrin-A2/genetics , Lupus Erythematosus, Systemic/genetics , Asian People/genetics , China , Databases, Genetic , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Haplotypes , Hong Kong , Humans , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , T-Lymphocytes/metabolism , Thailand , Transcription FactorsABSTRACT
The Fas gene polymorphisms -670A/G (rs1800682) and -1377G/A (rs2234767) have been shown to be associated with systemic lupus erythematosus (SLE), but findings are not consistent. To clarify this point, a meta-analysis was performed. We searched PubMed, CNKI, CBM and Wanfang database. Meta-odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to combine the data by fixed/random effects models based on heterogeneity test. The statistical analyses were conducted using Stata software. A total of seven studies involving 759 cases and 820 controls were considered in this study and ethnicity-specific meta-analysis was performed on Caucasian and Asian population. In overall population, meta-analysis revealed a trend toward to an association between SLE and Fas -670 A allele (OR = 1.310, 95 %CI = 1.028 ~ 1.670, P = 0.029). Similar results were detected in recessive model (OR = 1.626, 95 %CI = 1.104 ~ 2.395, P = 0.014) and in homozygous genotypic contrast (OR = 1.728, 95 %CI = 1.049 ~ 2.848, P = 0.032). Stratification by ethnicity indicated a significant association between SLE and the Fas -670A/G polymorphism in Asian population when allelic contrast (OR = 1.331, 95 %CI = 1.066 ~ 1.662, P = 0.011), homozygous genotypic contrast (OR = 1.848, 95 %CI = 1.164 ~ 2.932, P = 0.009) and dominant model were performed (OR = 1.542, 95 %CI = 1.045 ~ 2.275, P = 0.029). Meta-analysis of the Fas -1377G/A polymorphism indicated a significant association between SLE and the G allele in overall population (OR = 1.277, 95 %CI = 1.004 ~ 1.624, P = 0.046). The results from this meta-analysis provide evidence for the association between the Fas -670A/G and -1377G/A polymorphism and the risk of SLE. However, further studies are needed to draw a definitive conclusion.
Subject(s)
Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide , fas Receptor/genetics , Alleles , Case-Control Studies , Humans , Odds Ratio , Publication BiasABSTRACT
Recently, evidence is emerging that inappropriate regulation of type 17 T helper cells (Th17) plays a fundamental role in the development of many autoimmune diseases including systemic lupus erythematosus (SLE). However, the role of Th17-related cytokines in SLE remains elusive. To further investigate the role and imbalance of Th17-related cytokines in the pathogenesis of SLE. A Quantitative RT-PCR Array (Human Th17 for Autoimmunity & Inflammation PCR Array) analyses were performed to study Th17-related genes expression in peripheral white blood cells of 25 new-onset patients with SLE and 15 healthy subjects. When gene expression for SLE patients was compared to the mean of normal controls, among the 84 target genes related to Th17 pathway, 7 (CXCL1, ICAM1, IL10, IL5, IL8, ISG20, JAK2,) were upregulated and 6 (CD28, CD40LG, S1PR1, IL17RE, IL23R, RORC) downregulated. However, comparisons of mRNA expression of Th17 related cytokines between lupus nephritis (LN) patients and SLE patients without nephritis (SLE non LN) showed no significant difference. In conclusion, SLE patients and normal controls showed different expression of a few genes in Th17 pathway, indicating that the pathway may be involved in the pathogenesis of SLE.
Subject(s)
Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , Signal Transduction , Th17 Cells/immunology , Th17 Cells/metabolism , Adult , Autoimmunity/genetics , Autoimmunity/immunology , Case-Control Studies , Cytokines/genetics , Cytokines/immunology , Female , Gene Expression Profiling , Gene Expression Regulation , Humans , Male , Middle Aged , Young AdultABSTRACT
Transforming growth factor-ß1 (TGF-ß1) plays an important role in the pathogenesis of systemic sclerosis (SSc). To investigate whether TGF-ß1 gene promoter polymorphisms were associated with the susceptibility of SSc, we performed a meta-analysis based on all available studies through PubMed, Elsevier Science Direct, Embase, and Chinese Biomedical, China National Knowledge Infrastructure and Google Scholar with the last report up to March 15, 2013. Crude odds ratios with 95% confidence intervals were used to estimate the strength of the association. A fixed or random effects model was adopted according to heterogeneity test. Heterogeneity among studies was evaluated using I (2) . Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Begg's and Egger's test. Totally, seven papers with 663 SSc patients and 908 healthy controls were subjected to the final analysis. These studies encompass seven for TGF-ß1 codon 10, three for codon 25 and three for -509C/T. We failed to detect any association of these promoter polymorphism with SSc susceptibility. For TGF-ß1 codon 10 polymorphism, subgroup analyses by race, genotype testing method and classification of SSc were further performed. Similarly, no association was observed. Significant heterogeneity was detected among the studies in all genetic models of TGF-ß1 codon 10 polymorphism. Publication bias was absent. Taken together, our meta-analysis did not provided an evidence of confirming association between TGF-ß1 (codon 10, codon 25, -509C/T) gene polymorphism and SSc. Nevertheless, due to smaller sample sizes, larger sample studies including different ethnic groups should be considered in future to confirm our results.
Subject(s)
Scleroderma, Systemic/genetics , Transforming Growth Factor beta1/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Polymorphism, Single Nucleotide , Promoter Regions, GeneticABSTRACT
This study aims to investigate the serum IL-21 levels in systemic lupus erythematosus (SLE) and its relations with clinical and laboratory features. Fifty-seven patients with SLE and 30 healthy volunteers were recruited in the current study. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Statistical analyses were performed by SPSS 10.01. Results showed that IL-21 levels were significantly decreased in the serum of patients with SLE compared with controls (P = 0.026). There was no significant difference regarding serum IL-21 level between SLE patients with nephritis and those without nephritis (P = 0.066); no significant difference was found between less active SLE and more active SLE (P = 0.588). The presence of anemia was associated with low serum IL-21 levels (P = 0.030) in SLE patients. In summary, decreased serum level of IL-21 and its association with anemia indicate a possible role of IL-21 in human SLE. However, further studies are needed to confirm this preliminary results.
Subject(s)
Interleukins/physiology , Lupus Erythematosus, Systemic/etiology , Adolescent , Adult , Anemia/blood , Female , Genome-Wide Association Study , Humans , Interleukins/blood , Interleukins/genetics , Lupus Erythematosus, Systemic/blood , Male , Middle Aged , Polymorphism, Single NucleotideABSTRACT
Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
Subject(s)
Asian People/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Intracellular Signaling Peptides and Proteins/genetics , Lupus Erythematosus, Systemic/genetics , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Protein c-ets-1/genetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Alleles , Cohort Studies , DNA-Binding Proteins , Female , Haplotypes/genetics , Humans , Interferon Regulatory Factors/genetics , Leukocytes, Mononuclear/metabolism , Linkage Disequilibrium/genetics , Lupus Erythematosus, Systemic/enzymology , Male , Membrane Proteins/genetics , Nuclear Proteins/genetics , Principal Component Analysis , Reproducibility of Results , STAT4 Transcription Factor/genetics , Tumor Necrosis Factor alpha-Induced Protein 3 , src-Family Kinases/geneticsABSTRACT
OBJECTIVE: To explore the probable function of peptidyl arginine deiminase 4 (PAD4) in rheumatoid arthritis(RA). METHODS: Real-time quantitative polymerase chain reaction (PCR) was used to determine the expression of PAD4 mRNA in peripheral blood mononucleated cells (PBMCs) from 60 RA patients and 40 healthy individuals. Asymmetric di-methylation of histone H3R17, symmetric di-methylation and mono-methylation of H4R3 were semi-quantified by Western blotting in 12 patients with osteoarthritis (OA), 26 patients with RA and 10 healthy controls. RESULTS: PAD4 mRNA in RA was significantly higher than that in healthy controls[34.6(16.7, 70.8) vs 20.6(11.1, 51.8), P < 0.05]. The level of histone H3R17 asymmetric di-methylation in RA was significantly higher than that of OA or control groups (71.34 ± 25.65 vs 37.18 ± 18.62 vs 50.67 ± 13.99, P < 0.01) , which was positively related to Tender joint count and Swollen joint count in 28 joints (r = 0.418, P = 0.034;r = 0.402, P = 0.042). The level of histone H4R3 symmetric di-methylation was similar in RA,OA and control groups (75.02 ± 20.35 vs 57.92 ± 22.77 vs 68.37 ± 17.57, P > 0.05) . The level of histone H4R3 mono-methylation in RA patients was significantly lower than that of OA patients and healthy individuals (11.24 ± 7.81 vs 32.77 ± 30.77 vs 51.20 ± 47.14, P < 0.05). The level of histone H4R3 mono-methylation in RA patients was negatively correlated to PAD4 (r = -0.643, P < 0.01) . The level of histone H3R17 asymmetric di-methylation and H4R3 symmetric di-methylation was not associated with PAD4 level in RA group (r = -0.185, P = 0.377; r = 0.198, P = 0.344). CONCLUSIONS: The level of histone H3R17 asymmetric di-methylation is significantly higher and the level of histone H4R3 mono-methylation is significantly lower in RA patients comparing with OA and control groups. Abnormality of histone methylation may be one of the mechanisms for the development of RA. PAD4 probably plays an important role in rheumatoid arthritis by influencing histone methylation.
Subject(s)
Arthritis, Rheumatoid/blood , Histones/metabolism , Hydrolases/metabolism , Monocytes/metabolism , Adult , Case-Control Studies , Female , Humans , Male , Methylation , Middle Aged , Protein-Arginine Deiminase Type 4 , Protein-Arginine Deiminases , RNA, Messenger/genetics , Young AdultABSTRACT
OBJECTIVE: To explore the activation of hypomethylated DNA on plasmacytoid dendritic cells (pDC) in patients with systemic lupus erythematosus (SLE). METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of SLE patients and healthy controls. The methylation level of DNA and the expression of DNA methyltransferase 1 (DNMT1) mRNA were detected. Flow cytometry was used to detect the expression of CD32 on pDC and the serum concentration of interferon-alpha (IFN-α) measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The DNA methylation level from SLE patients (1.4 ± 0.6) % was lower than that of controls (1.8 ± 0.7) % (P < 0.01). The expression of DNMT1 mRNA significantly decreased in SLE patients (0.06 ± 0.03) versus the controls (0.09 ± 0.02) (P < 0.01). The CD32 expression on pDC from SLE patients (29 ± 19)% was higher than that from controls (18.02 ± 7.80)% (P < 0.01). The serum level of IFN-α in SLE patients (4.5 ± 6.7) ng/L was significantly higher than that of controls (2.1 ± 2.0) ng/L (P < 0.01). The methylation level of DNA in SLE patients was positively correlated with the expression of DNMT1 mRNA (r = 0.257, P < 0.05) and negatively with the expression of CD32 (r = -0.358, P < 0.01) and IFN-α (r = -0.280, P < 0.05). CONCLUSIONS: The methylation level of genomic DNA decreases in SLE patients due to the down-regulated expression of DNMT1 gene. Hypomethylated DNA may be translocated intracellularly via endocytic receptor (CD32) on pDC. And the activation of pDC is induced to produce IFN-α so as to participate in the onset of SLE.
Subject(s)
DNA Methylation , Dendritic Cells/metabolism , Lupus Erythematosus, Systemic/blood , Adolescent , Adult , Case-Control Studies , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/metabolism , Female , Flow Cytometry , Humans , Interferon-alpha/blood , Male , Middle Aged , RNA, Messenger/genetics , Receptors, IgG/metabolism , Young AdultABSTRACT
OBJECTIVE: To explore the effects of transcription factor ETS-1 mRNA and B lymphocyte-associated cytokines on the differentiation of B cells in systemic lupus erythematosus (SLE) patients and explore its pathogenic and clinical significance. METHODS: Thirty-one SLE patients (20 active and 11 inactive) and 15 healthy controls were enrolled. CD19+ B cells were isolated with magnetic beads. The levels of ETS-1 mRNA in B cells were determined by real-time polymerase chain reaction (PCR). Flow cytometry was used to detect the altered ratio of CD19-CD138 + plasma cells and CD19 + B cells. And enzyme-linked immunosorbent assay (ELISA) was performed to detect the serum levels of B cell differentiation-related cytokines interleukin-10 (IL-10) and APRIL. RESULTS: Compared to the healthy controls, SLE patients showed decreased mRNA expression level of ETS-1 in B cells (Z = -4.218, P < 0.01) . Moreover, the expression level of ETS-1 mRNA was significantly negatively correlated with the proportion of CD19-CD138+ plasma cells (r = -0.359, P < 0.05) and negatively correlated with the CD19-CD138 +B cells/CD19+ plasma cells ratio (r = -0.493, P < 0.01) . However, there was no correlation in normal controls. Significant negative correlation existed between the expression level of ETS-1 mRNA in B cells and the serum levels of IL-10 and APRIL in active SLE patients. But no correlation existed in inactive group. CONCLUSION: ETS-1 may participate in the pathogenesis of SLE through its effects on the differentiation of B cells and cooperation with IL-10 and APRIL.
Subject(s)
B-Lymphocytes/metabolism , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Proto-Oncogene Protein c-ets-1/metabolism , Adolescent , Adult , Case-Control Studies , Female , Humans , Interleukin-10/metabolism , Male , Middle Aged , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Young AdultABSTRACT
Our previous study has shown that ATP action on P2X7R could be the second signal to induce the onset of gouty arthritis. However, the functional changes of P2X7R single nucleotide polymorphisms (SNPs) on the effects of ATP-P2X7R-IL-1ß signaling pathway and uric acid remained unknown. We aimed to investigate the association between the functional change of P2X7R containing the Ala348 to Thr polymorphisms (rs1718119) and the pathogenesis of gout. First, 270 gout patients and 70 hyperuricemic patients (without gout attack history in recent 5 years) were recruited for genotyping. In addition, the changes of ATP-induced pore formation were assessed in HEK-293T cells overexpressing different mutants in P2RX7, and the effects on P2X7R-NLRP3-IL-1ß pathway activation were explored in P2RX7 overexpression THP-1 cells. The risk allele for gout was A at rs1718119, and the AA and AG genotypes exhibited a higher risk of gout. Furthermore, Ala348 to Thr mutants increased P2X7-dependent ethidium+ bromide uptake, upregulated IL-1ß and NLRP3 levels as compared to the wild-type. We suggest that genetic polymorphisms of P2X7R containing the Ala348 to Thr are associated with the increased risk of gout, showing an enhanced gain-of-function effect on the development of this disease.
Subject(s)
Gout , Hyperuricemia , Receptors, Purinergic P2X7 , Humans , Adenosine Triphosphate/metabolism , Gout/genetics , Hyperuricemia/genetics , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Polymorphism, Single Nucleotide , Receptors, Purinergic P2X7/geneticsABSTRACT
The aim of this study was to evaluate whether two single-nucleotide polymorphisms (SNPs), AF4/FMR2 family, member 1 (AFF1) rs340630 and AF4/FMR2 family, member 3 (AFF3) rs10865035, show significant evidence for association with systemic lupus erythematosus (SLE) in a Chinese population. A total of 868 Chinese patients with SLE and 975 geographically and ethnically matched healthy control subjects were enrolled in the current study. The genotypes of these two SNPs were determined by Sequenom MassArray technology. Significant evidence for association of AFF3 rs10865035 with SLE was detected (for A versus G, P = 4.81 × 10(-4), odds ratio (OR) 1.26, 95% confidence interval (95% CI) 1.11-1.44). However, no association between AFF1 rs340630 and SLE was found in the Chinese population (for A versus G, P = 0.79, OR 0.98, 95% CI 0.86-1.12). No significant evidence for association of AFF3 rs10865035 polymorphism with any clinical features was detected. By targeting a variant with convincing evidence for association with rheumatoid arthritis, significant association of AFF3 rs10865035 with SLE was detected in the Chinese population, indicating that AFF3 might be a common autoimmunity gene. Further case-control studies based on larger sample sizes in diverse ethnic populations are required to clarify the role of AFF1 rs340630 in SLE.
Subject(s)
Asian People/genetics , DNA-Binding Proteins/genetics , Lupus Erythematosus, Systemic/genetics , Nuclear Proteins/genetics , Polymorphism, Genetic , Adult , Arthritis, Rheumatoid/genetics , Base Sequence , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Molecular Sequence Data , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Transcriptional Elongation Factors , Young AdultABSTRACT
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. Because of double damages of body and mind, SLE patients are in a potential risk of suicide. Many factors may contribute to the occurrence of suicide in SLE: socioeconomic factors, medical factors, mental health, family support and coping style. This study aims to investigate the prevalence and correlates of suicidal ideation in SLE inpatients in China in order to determine whether they had risk of suicide, and if so, what factors should be paid more attention to prevent suicide in wards. A total of 285 SLE patients were interviewed with questionnaires on suicidal ideation and socio-demographic characteristics, Beck Depression Inventory (BDI), Family APGAR and Trait Coping Style Questionnaire (TCSQ). Disease activity was assessed with SLE Disease Activity Index. The other medical information was collected from the patients' medical records. In total, 34.4% of SLE patients had current suicidal ideation. Significant individual risk factors for current suicidal ideation in SLE patients included having religious belief, heavy self-reported financial burdens, long duration of SLE, low level of family functioning and negative coping style. And in the presence of these risk factors, being separated, divorced or widowed, having premorbid suicidal ideation and depression were independent predictors of suicidal ideation. In summary, the rate of suicidal ideation in SLE patients in China is higher than that in other countries. Factors that contribute to risk of suicidal ideation include social and cultural domains and physical and psychological health. Although the association of suicidal ideation to religions and medical factors is still to be investigated, these findings may give some references to suicide prevention efforts for SLE patients in China.