UHRF1P contributes to IL-17A-mediated systemic lupus erythematosus via UHRF1-MAP4K3 axis.

Inflammatory T cells contribute to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Analysis of the T-cell transcriptomics data of two independent SLE patient cohorts by three machine learning models revealed the pseudogene UHRF1P as a novel SLE biomarker. The pseudogene-encoded UHRF1P protein was overexpressed in peripheral blood T cells of SLE patients. The UHRF1P protein lacks the amino-terminus of its parental UHRF1 protein, resulting in missing the proteasome-binding ubiquitin-like (Ubl) domain of UHRF1. T-cell-specific UHRF1P transgenic mice manifested the induction of IL-17A and autoimmune inflammation. Mechanistically, UHFR1P prevented UHRF1-induced Lys48-linked ubiquitination and degradation of MAP4K3 (GLK), which is a kinase known to induce IL-17A. Consistently, IL-17A induction and autoimmune phenotypes of UHRF1P transgenic mice were obliterated by MAP4K3 knockout. Collectively, UHRF1P overexpression in T cells inhibits the E3 ligase function of its parental UHRF1 and induces autoimmune diseases.

The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.

Genomic sequencing and functional analyses identify MAP4K3/GLK germline and somatic variants associated with systemic lupus erythematosus.

OBJECTIVES: MAP4K3 (GLK) overexpression in T cells induces interleukin (IL)-17A production and autoimmune responses. GLK overexpressing T-cell population is correlated with severity of human systemic lupus erythematosus (SLE); however, it is unclear how GLK is upregulated in patients with SLE. METHODS: We enrolled 181 patients with SLE and 250 individuals without SLE (93 healthy controls and 157 family members of patients with SLE) in two independent cohorts from different hospitals/cities. Genomic DNAs of peripheral blood mononuclear cells were subjected to next-generation sequencing to identify GLK gene variants. The functional consequences of the identified GLK germline or somatic variants were investigated using site-directed mutagenesis and cell transfection, followed by reporter assays, mass spectrometry, immunoblotting, coimmunoprecipitation, and in situ proximity ligation assays. RESULTS: We identified 58 patients with SLE from Cohort #1 and #2 with higher frequencies of a somatic variant (chr2:39 477 124 A>G) in GLK 3'-untranslated region (UTR); these patients with SLE showed increased serum anti-double-stranded DNA levels and decreased serum C3/C4 levels. This somatic variant in 3'-UTR enhanced GLK mRNA levels in T cells. In addition, we identified five patients with SLE with GLK (A410T) germline variant in Cohort #1 and #2, as well as two other patients with SLE with GLK (K650R) germline variant in Cohort #1. Another GLK germline variant, A579T, was also detected in one patient with SLE from Cohort #2. Both GLK (A410T) and GLK (K650R) mutants inhibited GLK ubiquitination induced by the novel E3 ligase makorin ring-finger protein 4 (MKRN4), leading to GLK protein stabilisation. CONCLUSIONS: Multiple GLK germline and somatic variants cause GLK induction by increasing mRNA or protein stability in patients with SLE.

Genetic and epigenetic alterations of cyclic AMP response element modulator in rheumatoid arthritis.

BACKGROUND: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune-mediated inflammatory processes, although it remains unknown whether CREM is involved in RA. METHODS: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real-time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t-tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression. RESULTS: Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001). CONCLUSIONS: Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology.

Lower HDAC6 mRNA expression and promoter hypomethylation are associated with RA susceptibility.

BACKGROUND/PURPOSE: Recent studies showed that Histone deacetylases 6 (HDAC6) inhibitors could improve arthritis in rheumatoid arthritis (RA) rodent models, whereas lower HDAC6 expression was observed in RA patients' synovial fibroblasts, raising the concerns to use HDAC6 inhibitors to treat RA patients. In the present study, we investigated the involvement of HDAC6 mRNA expression and promoter methylation in RA. METHODS: The DNA and RNAs were extracted from the peripheral blood mononuclear cells (PBMCs) from 138 RA patients and 102 healthy controls. The pyrosequencing technique was used for promoter methylation analysis. The quantitative real-time polymerase chain reaction was used to determine the HDAC6 mRNA expression. The patients' clinical characteristics and disease biomarkers were recorded when blood sampling. RESULTS: The HDAC6 mRNA expression was lower in the RA patients than controls (p = 0.001). The RA patients had significant hypomethylation of the HDAC6 promoter (p < 0.001). The HDAC6 promoter was hypo-methylated in the -229, -225, -144, and -142 CpG sites in RA patients (p < 0.05). Unexpectedly, promoter methylation and mRNA expression of the HDAC6 gene were positively associated (p < 0.001). The HDAC6 mRNA expression and promoter methylation status were associated with the risk of RA (p = 0.006 and 0.002, respectively). The inflammatory cytokines, TNF-α and IL-6, were significantly increased after HDAC6 knockdown in PMA-stimulated THP1 cells and SW982 cells (p < 0.05). CONCLUSION: The HDAC6 mRNA expression and promoter methylation were lower in RA patients. Both HDAC6 mRNA expression level and promoter hypomethylation were associated the susceptibility of RA. HDAC6 inhibitors seem not proper for RA patients' treatment.

Subgingival Microbiome in Rheumatoid Arthritis Patients with Periodontitis.

Rheumatoid arthritis (RA) and periodontitis are suggested to be closely linked based on microbial dysbiosis, but limited subgingival bacteria have been proven in the pathogenesis of RA. We enrolled 30 RA patients and 25 controls and divided them into three groups with matched age, gender, and diabetes statuses: group AM (all of the matched participants), group PD (periodontally diseased), and group PH (periodontally healthy). Their subgingival microbial composition was determined by V3-V4 16S rRNA gene sequencing. Significant differences in subgingival microbial clustering between the RA patients and controls were observed in groups AM and PD. Among the taxa enriched in RA, Aminipila butyrica and Peptococcus simiae were the only two species displaying positive correlation to the level of anti-citrullinated protein antibodies (ACPAs) in both of the groups. Surprisingly, the median of relative abundances of A. butyrica and P. simiae were 0% in the controls of group PD. Furthermore, a gene encoding arginine deiminase with the capability to produce citrulline was addressed in the complete genome sequence of A. butyrica. This is the first study to elucidate the important roles of A. butyrica and P. simiae as periodontal bacteria leading to RA possibly through the induction of ACPA production.

A novel CD209 polymorphism is associated with rheumatoid arthritis patients in Taiwan.

Single nucleotide polymorphisms (SNPs) in the promoter region of CD209 (cluster of differentiation 209) may influence expression levels, and higher expression of CD209 on immune cells correlate with severity of cartilage destruction in patients with rheumatoid arthritis (RA). Due to the lack of a comprehensive study, this study aimed to investigate the CD209 promoter variants and haplotypes in a Taiwanese population and the association with RA development. Deoxyribonucleic acid (DNA) of peripheral blood mononuclear cells from 126 RA patients and 124 healthy controls was purified, and the CD209 gene promoter was amplified by polymerase chain reaction and analyzed by Sanger sequencing. Results showed that a novel variant -96C>A polymorphism in CD209 promoter was identified in the Taiwanese population, and the frequency was significantly higher in RA patients than in controls (11.51% vs. 2.42%, P < .0001). The odds ratio (OR) for the development of RA was 5.88 (95% CI 2.35-14.74, P < .0001). Other known variants were also evaluated; for instance, -1180 T/T (rs7359874) was increased in RA patients, and the OR for the development of RA was 3.26, 95% CI 0.85-12.52, P = .07). Besides, the haplotype frequencies were calculated; -1180A-939C-871 T-336 T-139 T-96A and -1180 T-939 T-871C-336 T-139C-96A were increased in RA patients (P = .004 and 0.05, respectively). In summary, CD209-96A variant could be an important factor for the development of RA in the Taiwanese population.

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases.

Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.

Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout.

Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1ß production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (PGGT1B, INSIG1, ANGPTL2, JNK1, UBAP1, and RAPTOR) were novel genes in the field of gout. One (CNTN5) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1ß production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.

Dual Role of Chondrocytes in Rheumatoid Arthritis: The Chicken and the Egg.

Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.

Genetic and epigenetic alteration of the programmed cell death 1 in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease where both genetics and epigenetics are contributing factors. In order to discover genetic and epigenetic associations with RA and its phenotypes, we analysed RNA expression, DNA variations and DNA methylation of programmed cell death 1 (PDCD1) in a cohort of RA patients and healthy controls. METHODS: RA patients (n = 206) and healthy controls (n = 234) were included for analysis of PDCD1 expression, PDCD1 polymorphisms and PDCD1 methylation. Differences in continuous variables between groups were compared by applying t tests. Associations between phenotypes and genotypes were evaluated with contingency tables. Sensitivity analyses were conducted to confirm the robustness of results, considering potential confounding factors and different treatment response definitions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated. RESULTS: Higher expression of PDCD1 was found in RA compared to controls (P < 0.001), with similar PDCD1 polymorphisms in RA and controls. rs36084323 decreased inadequate response to conventional synthetic disease-modifying antirheumatic drugs (OR = 0.37, 95% CI = 0.19-0.72, P = 0.003), and rs41386349 increased rheumatoid factor seropositivity (OR = 11.89, 95% CI = 1.57-89.87, P = 0.003). Sensitivity analysis adjusting for further potential confounders and using different treatment response definition indicated similar results. Additionally, DNA methylation change at regulatory region of PDCD1 was detected in RA (P = 0.036). CONCLUSION: Altogether, this was the first study to suggest genetic and epigenetic changes of PDCD1 in RA subsets and RA. Independent prospective cohorts are awaited to address the implications of these genetic and epigenetic changes in disease pathogenesis and phenotypes of RA.

Sex differential association of dermatomyositis with Sjögren syndrome.

BACKGROUND: Although dermatomyositis and Sjögren syndrome share serologic autoantibodies and genetic polymorphisms, population data about the incidence of Sjögren syndrome in patients with dermatomyositis is unavailable. We performed a nationwide cohort study to explore the potential relation between dermatomyositis and Sjögren syndrome and, if an association exists, to elucidate whether it varies by sex. METHODS: We identified all patients with newly diagnosed dermatomyositis from the Registry of Catastrophic Illness Database in Taiwan between Jan. 1, 1998, and Dec. 31, 2011. Each patient was matched to, at most, 5 control patients from the National Health Insurance Research Database by age, sex and entry date. Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of Sjögren syndrome after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. RESULTS: A total of 1602 patients with dermatomyositis and 7981 control patients were enrolled in the study. There was a positive association of having Sjögren syndrome among patients with dermatomyositis after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis (HR 2.67, 95% CI 2.01-3.54). The association was more pronounced in the male cohort (HR 2.69, 95% CI 1.19-6.09). INTERPRETATION: We found a sex differential association of Sjögren syndrome among patients with dermatomyositis independent of age and concomitant autoimmune disease. Further studies are required to determine the clinical importance of this association for both outcomes and therapeutic options.

Increased incidence of multiple sclerosis in systemic sclerosis: A nationwide cohort study.

OBJECTIVE: Previous studies showed inconsistent results on the association of systemic sclerosis (SSc) with multiple sclerosis (MS), and are limited by a lack of adjustment for sex and age. The goals of this retrospective cohort study were to evaluate whether SSc is associated with increased incident MS independent of sex and age. METHODS: We enrolled patients with SSc from Taiwan's Registry of Catastrophic Illness Database and referent subjects from the National Health Insurance Research Database. Each SSc patient was matched to at most three referent subjects by sex, age, month and year of initial diagnosis of SSc. Incidence of MS in SSc patients and corresponding 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR) of MS. RESULTS: The study enrolled 1171 patients with SSc and 3409 referent subjects. Patients with SSc had higher incidence of MS than referent subjects (9.35 per 1000 person-years, 95% CI=6.86-11.85; 0.13 per 1000 person-years, 95% CI=0.03-0.37, respectively). Similar results also occurred in both men and women. SSc was associated with increased incidence of MS after adjusting for sex and age (HR: 69.48, 95% CI=21.69-222.54). CONCLUSION: SSc is associated with increased incidence of MS, independent of sex and age of the patients. Multidisciplinary teams should guide the assessment, treatment, and holistic care of SSc patients to reduce its morbidity.

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation.

Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n = 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP)IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n = 6, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43% (n = 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through platelet-activating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-α. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI.

Reduced incidence of Crohn's disease in systemic sclerosis: a nationwide population study.

BACKGROUND: To date, there has been no studies to evaluate the incidence of Crohn's disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn's disease and its relationship with sex and age in patients with systemic sclerosis. METHODS: We enrolled patients with systemic sclerosis and controls from Taiwan's Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn's disease in systemic sclerosis patients, and 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). RESULTS: The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn's disease (SIR: 0.18, 95% CI = 0.05-0.62; SIR: 0.10, 95% CI = 0.05-0.21, respectively). The risk of incident Crohn's disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn's disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95% CI = 0.06-0.21, p < 0.001). CONCLUSIONS: Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.

A polymorphism of ORAI1 rs7135617, is associated with susceptibility to rheumatoid arthritis.

Rheumatoid arthritis (RA), a chronic inflammatory disease usually occurring in synovial tissues and joints, is highly associated with genetic and environmental factors. ORAI1, a gene related to cellular immune system, has been shown to be involved in the pathogenesis of chronic inflammatory diseases and immune diseases. To identify whether ORAI1 gene contributes to RA susceptibility, we enrolled 400 patients with RA and 621 healthy individuals for a case-control genetic association study. Five tagging single nucleotides polymorphisms (tSPNs) within ORAI1 gene were selected for genotyping. An SNP, rs7135617, showed a significant correlation with the risk of RA. Our results indicated that genetic polymorphism of ORAI1 gene is involved in the susceptibility of RA in a Taiwanese population.

Increased serum adipokines are associated with sarcopenia in non-obese women with rheumatoid arthritis.

Large cohort studies have disclosed the association between obesity and rheumatoid arthritis (RA) risk. The sarcopenia prevalence in RA patients can be up to 31%. However, there is little information linking adipokines to sarcopenia in RA, so this study aimed to investigate whether adipokines were indeed involved in secondary sarcopenia in RA with a focus on non-obese females. Sixty-four female patients and 36 controls were included in this study. The serum adipokine levels (leptin and adiponectin) were determined by ELISA kits. The impacts of adipokines on muscle atrophy and potential autophagy were examined in mouse myoblasts, C2C12, upon treatment with recombinant leptin and adiponectin agonist (AdipoRan). Interestingly, serum adiponectin was significantly increased but the ratio of leptin/adiponectin was dramatically decreased in the RA patients with sarcopenia. After normalization by body mass, serum leptin was positively associated but adiponectin was negatively associated with muscle mass respectively, even after adjustment for fat mass. Treating C2C12 cells with leptin and AdipoRan inhibited proliferation of mature myotube respectively, as did treatment with the serum from RA patients. A combination of low leptin and high AdipoRan greatly decreased myogenin, but instead increased MAFbx and MuRF-1 as well as increased Beclin 1, Atg5, and LC3ß. Taken together, our study reveals that secondary sarcopenia of RA females may be an imbalance of RA-related, but not obesity-related, increase in adipokine production; additionally, the reduced leptin/adiponectin ratio could be a better indicator in monitoring sarcopenia in non-obese RA females. Moreover, adipokine imbalance may promote muscle atrophy through inducing autophagy.

HLA-DR genotypes in patients with systemic lupus erythematosus in Taiwan.

BACKGROUND: Different human leukocyte antigen (HLA)-DR genotypes have been known to be associated with the risk of development of systemic lupus erythematosus (SLE) in different populations, although Lu et al. have reported previously that no correlation exists between the HLA-DR genotype and disease manifestation in SLE patients in Taiwan. We investigated the effects different HLA-DR genotypes had on SLE incidence in Taiwanese patients as to whether risk alleles were associated with different clinical manifestations, and the effects risk alleles had on the age of disease onset. METHODS: Two hundred thirty-four SLE patients and 346 healthy controls were enrolled. HLA-DR genotyping was performed with the HLA FluoGene DRDQ kit for each subject. Chi-square tests and t tests were performed for statistical analysis. RESULTS: HLA-DR2 was significantly more frequently found in SLE patients than in controls (odds ratio [OR] = 2.05, 95% CI, 1.44-2.92, p < 0.001). Notably, HLA-DR6 appeared to trend toward negative correlation with SLE, whereas HLA-DR8 appeared to trend toward positive correlation. HLA-DR2 patients had an earlier onset of disease as well as a higher prevalence of oral ulcer, avascular necrosis of bone, and renal involvement (lupus nephritis). CONCLUSION: HLA-DR2 was associated with SLE susceptibility in this Taiwanese population as well as lower age of disease onset and more severe clinical manifestations.

NLRP3 Gene Polymorphisms in Rheumatoid Arthritis and Primary Sjogren's Syndrome Patients.

Aim: The activation of NLRP3 inflammasome leads to the stimulation of cytokines and is significantly involved in the pathogenesis and progression of autoimmune diseases. The purpose of this study is to examine the associations of NLRP3 gene polymorphisms with rheumatoid arthritis (RA) and primary Sjogren's syndrome (SS) patients. Methods: A total of 239 patients with RA, 285 patients with primary SS, and 170 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood mononuclear cells, and gene polymorphisms were genotyped through the TaqMan assay. Antinuclear antibody (ANA), anti-Ro, and anti-CCP antibodies were detected using immunofluorescence immunoassay. Results: The T allele of rs4612666 CT elevated the susceptibility to RA disease. The RF titer during diagnosis of RA was significantly high in RA patients with the A allele of rs12079994 G/A polymorphism. The titer of anti-CCP during diagnosis of RA was high in the absence of the C allele of rs10754558 C/G polymorphisms in RA patients. Antinuclear antibody and anti-CCP were positively associated with the A allele of rs12079994 G/A polymorphism in primary SS. The C allele of rs4612666 C/T was negatively associated with ANA in primary SS. Conclusions: The results have shown that NLRP3 gene polymorphisms may play a role in the pathogenesis of RA and primary SS.

Gout and type 2 diabetes have a mutual inter-dependent effect on genetic risk factors and higher incidences.

OBJECTIVE: To explore the causal relationship between gout and Type 2 diabetes based on genetic evidence and national outpatient database. METHODS: Twenty male gout patients with early-onset, gout family history, without a habit of alcohol consumption or obesity before the first attack of gout were selected from hospital in 2010; and 42 unrelated male Chinese subjects were selected from HapMap as controls for genome-wide analysis study (GWAS). The comorbid diseases with gout were revealed by applying the significant single nucleotide polymorphisms (SNPs) to MetaCore platform, and the comorbid relationship was analysed by standardized incidence ratio (SIR) from outpatient database. RESULTS: A total of 334 SNPs were significantly related to gout in GWAS (P < 10(-7)), and Type 2 diabetes was the most significantly associated disease with gout as recognized by 36 gene symbols correspondent to the above significant SNPs. The analysis of national outpatient database showed that the overall incident Type 2 diabetes was 1.50 cases per 1000 person-months among gout patients, which was higher than the overall incident gout (1.06 cases) among Type 2 diabetes. The age-adjusted SIR of incident Type 2 diabetes among gout was 2.59 (95% CI 2.42, 2.78), whereas the age-adjusted SIR for incident gout among Type 2 diabetes was 1.61 (95% CI 1.48, 1.74). CONCLUSION: After excluding obesity and alcohol consumption behaviour, this study showed that patients with gout and Type 2 diabetes shared the common genetic factors most, and that there existed a mutual inter-dependent effect on higher incidences.