Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes.

OBJECTIVE: Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. METHODS: We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. RESULTS: The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. CONCLUSIONS: Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Identification of new susceptibility loci associated with rheumatoid arthritis.

OBJECTIVES: The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA). METHODS: We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function. RESULTS: We identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta <5.00E-08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets. CONCLUSION: This study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

Discovery of new serum biomarker panels for systemic lupus erythematosus diagnosis.

OBJECTIVE: Clinical diagnosis of SLE is currently challenging due to its heterogeneity. Many autoantibodies are associated with SLE and are considered potential diagnostic markers, but systematic screening and validation of such autoantibodies is lacking. This study aimed to systematically discover new autoantibodies that may be good biomarkers for use in SLE diagnosis. METHODS: Sera from 15 SLE patients and 5 healthy volunteers were analysed using human proteome microarrays to identify candidate SLE-related autoantibodies. The results were validated by screening of sera from 107 SLE patients, 94 healthy volunteers and 60 disease controls using focussed arrays comprised of autoantigens corresponding to the identified candidate antibodies. Logistic regression was used to derive and validate autoantibody panels that can discriminate SLE disease. Extensive ELISA screening of sera from 294 SLE patients and 461 controls was performed to validate one of the newly discovered autoantibodies. RESULTS: A total of 31, 11 and 18 autoantibodies were identified to be expressed at significantly higher levels in the SLE group than in the healthy volunteers, disease controls and healthy volunteers plus disease control groups, respectively, with 25, 7 and 13 of these differentially expressed autoantibodies being previously unreported. Diagnostic panels comprising anti-RPLP2, anti-SNRPC and anti-PARP1, and anti-RPLP2, anti-PARP1, anti-MAK16 and anti- RPL7A were selected. Performance of the newly discovered anti-MAK16 autoantibody was confirmed by ELISA. Some associations were seen with clinical characteristics of SLE patients, such as disease activity with the level of anti-PARP1 and rash with the level of anti-RPLP2, anti-MAK16 and anti- RPL7A. CONCLUSION: The combined autoantibody panels identified here show promise for the diagnosis of SLE and for differential diagnosis of other major rheumatic immune diseases.

Combination of Percutaneous Rotational Thrombectomy and Drug-Coated Balloon for Treatment of Femoropopliteal Artery Nonembolic Occlusion: 12-Month Follow-up.

PURPOSE: To evaluate safety and efficacy of percutaneous mechanical thrombectomy using the Rotarex catheter combined with drug-coated balloon (DCB) in treatment of femoropopliteal artery occlusive disease. MATERIALS AND METHODS: Between January 2016 and February 2018, 81 patients with acute or subacute femoropopliteal artery occlusions were treated with the Rotarex catheter combined with DCB. Lesions were classified according to the onset of symptoms as acutely (< 14 d) or subacutely (14 d to 3 mo) occluded. The mean lesion length was 12.1 cm ± 6.7. The primary endpoint was target lesion patency at 1 year as evaluated by duplex ultrasound (peak systolic velocity ratio < 2.4) and freedom from clinically indicated target lesion revascularization. Amputation rate, major adverse events, and ankle-brachial index at 12 months were evaluated. RESULTS: Technical success rate was 100% (n = 81). Bailout stents were necessary in 14 patients owing to residual stenosis or flow-limiting dissection. Additional thrombolysis was applied in 10 interventions. No major adverse events occurred during hospital stay. There were 9 restenosis cases during the 12-month follow-up period. Primary patency rate was 87.3% (62/71), and freedom from target lesion revascularization rate was 90.1% (64/71). Ankle-brachial index significantly increased from 0.46 ± 0.15 to 0.77 ± 0.14 during follow-up. The amputation rate was 1.4% at 12 months. CONCLUSIONS: These initial data from 2 centers suggest that the combination of the Rotarex catheter and DCB may be safe and effective for treatment of acute or subacute thrombotic femoropopliteal occlusion with superior immediate and midterm results achieved.

Circular RNA expression profile and potential function of hsa_circ_0045272 in systemic lupus erythematosus.

Circular RNAs (circRNAs) represent a class of non-coding RNAs that form covalently closed RNA circles with extensive expression and conservation in mammals. Circular RNAs regulate gene expression through acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Accumulating evidence supports the implication of circRNAs in a variety of human diseases, but studies of circRNA role in systemic lupus erythematosus (SLE) are lacking. The present study measured the circRNA expression profiles in T cells from patients with SLE and healthy controls with human circRNA microarray and identified 127 differentially expressed circRNAs in SLE patients. Down-regulation of hsa_circ_0045272 in SLE T cells was verified with quantitative PCR. Jurkat cells with stable hsa_circ_0045272 knockdown were generated using specific lentiviral short hairpin RNA for functional studies. Flow cytometric analysis indicated that hsa_circ_0045272 knockdown significantly up-regulated the early apoptosis of Jurkat cells. Meanwhile, ELISA showed that hsa_circ_0045272 knockdown significantly enhanced interleukin-2 production of activated Jurkat cells. Then, ceRNAs were predicted for hsa_circ_0045272 and the significant down-regulation of two mRNAs predicted as ceRNAs, NM_003466 (PAX8) and NM_015177 (DTX4), but not their corresponding proteins, was validated. Furthermore, dual luciferase reporter assay indicated binding of hsa_circ_0045272 with hsa-miR-6127. Circular RNA-mRNA co-expression networks showed the correlation of circRNAs with mRNAs and provided additional clues to circRNA functions. Our study demonstrated dysregulated circRNAs in SLE and revealed the function of hsa_circ_0045272 in negatively regulating apoptosis and interleukin-2 secretion and its potential mechanism. The implication of hsa_circ_0045272 and other abnormal circRNAs in SLE merits further investigation.

The expression levels of long noncoding RNAs lnc0640 and lnc5150 and its gene single-nucleotide polymorphisms in rheumatoid arthritis patients.

OBJECTIVES: The aim of our study was to evaluate two lncRNAs (lnc0640 and lnc5150) expressions and gene single-nucleotide polymorphisms (SNPs) in rheumatoid arthritis (RA) patients. METHODS: The expressions of lncRNAs in peripheral blood mononuclear cells (PBMCs) were examined by quantitative real-time reverse transcription polymerase chain reaction from 65 RA patients and 54 controls. Simultaneously, three SNPs (rs13039216, rs6085189, and rs6085190) of lnc0640, three SNPs (rs1590666, rs141561256, and rs144047453) of lnc5150 were genotyped using TaqMan SNP-genotyping assays in 627 RA patients and 590 controls. RESULTS: The lnc0640 level in PBMCs from RA patients was significantly increased (P = 0.001), whereas the lnc5150 level was significantly reduced (P < 0.001) compared to controls. There were significant associations of lnc0640 and lnc5150 levels with C-reactive protein in RA patients (P = 0.011 and P = 0.014, respectively), while lnc5150 level was associated with erythrocyte sedimentation rate (P = 0.022). TT genotype of rs13039216 in lnc0640 gene was statistically associated with a reduced risk of RA (TT vs CC; P = 0.046), and a decreased risk of rs13039216 variant was observed under the recessive model (P = 0.038). In addition, the G allele of rs141561256 polymorphism in lnc5150 gene was significantly associated with rheumatoid factor in RA patients (P = 0.034). There were no associations between lnc0640 and lnc5150 levels and their respective genotype in RA patients. CONCLUSIONS: The expressions of lnc0640 and lnc5150 were alternated in the RA patients, suggesting that these lncRNAs may involve in the development of RA.

Association between HLA-DQB1 polymorphisms and pemphigus vulgaris: A meta-analysis.

OBJECTIVE: This study was performed to systematically summarize the results on the association of HLA-DQB1 polymorphisms with pemphigus vulgaris (PV) and other related factors. METHODS: A comprehensive literature search of PubMed, The Cochrane Library, Embase, and Google Scholar database was conducted to identify relevant articles in English, with the last report up to November 1, 2016. Heterogeneity test was performed, and publication bias was evaluated. Stata software 12.0 was used to perform the meta-analysis. Odds ratios (ORs) and 95% confidence intervals (CI) were used to describe the correlation by random-effects model. RESULTS: 18 studies were obtained after searching databases: 10 studies were about Caucasian, and 8 articles were about non-Caucasian. Meta-analysis revealed that the allele and phenotype frequencies of DQB1*05 were markedly higher in PV patients than in controls [P < 0.001, OR: 2.640, 95%CI: 1.570-4.441; P = 0.030, OR 3.688, 95%CI: 1.138-11.946]. In addition, DQB1*03 was significantly increased at the allele level [P < 0.001, OR: 2.080, 95%CI: 1.507-2.869], and DQB1*02 was significantly decreased in PV at the allele and phenotype levels [P = 0.002, OR: 0.450, 95%CI: 0.289-0.702; P = 0.001, OR: 0.293, 95%CI: 0.146-0.587]. When based on each subtype of HLA-DQB1, DQB1*05:03 and DQB1*03:02 may play susceptibility roles in PV, and DQB1*03:03, DQB1*05:01 and DQB1*06:01 are negatively associated with PV. CONCLUSION: In summary, our study suggests that alleles from the groups DQB1*05 and DQB1*03, concretely DQB1*05:03 and DQB1*03:02, respectively, may be the susceptibility factors for PV at allele and phenotype levels, whereas DQB1*05:01, DQB1*02, DQB1*06:01, and DQB1*03:03 are negatively associated with PV.

Translation of noncoding RNAs: Focus on lncRNAs, pri-miRNAs, and circRNAs.

Mammalian genome is pervasively transcribed, producing large number of noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), primary miRNAs (pri-miRNA), and circular RNAs (circRNAs). The translation of these ncRNAs has long been overlooked. Increasing studies, however, based on ribosome profiling in various organisms provide important clues to unanticipated translation potential of lncRNAs. Moreover, a few functional peptides encoded by lncRNAs and pri-miRNAs underline the significance of their translation. Recently, several novel researches also evidence the translation of endogenous circRNAs. Given the functional significance exemplified by peptides translated by some ncRNAs and their pervasive translation, it is not too far-fetched to image that abnormal translation of ncRNAs may contribute to human diseases. Through challenging, deciphering ncRNA translation is required for comprehensive understanding of biology and medicine. In this review, we firstly present evidence concerning translation potential of lncRNAs and go on to introduce a few functional short peptides encoded by lncRNAs. Then, salient observations showing translation of pri-miRNAs and circRNAs are described in detail. We end by discussing the impact of ncRNA translation beyond producing peptides and referring briefly to the potential role of abnormal ncRNA translation in human diseases.

Association of leptin and leptin receptor gene polymorphisms with systemic lupus erythematosus in a Chinese population.

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.

Comprehensive long non-coding RNA expression profiling reveals their potential roles in systemic lupus erythematosus.

Long non-coding RNAs can regulate gene transcription, modulate protein function, and act as competing endogenous RNA. Yet, their roles in systemic lupus erythematosus remain to be elucidated. We determined the expression profiles of lncRNAs in T cells of SLE patients and healthy controls using microarrays. Up to 1935 lncRNAs and 1977 mRNAs were differentially expressed. QRT-PCR showed downregulated uc001ykl.1 and ENST00000448942 in SLE patients. Expression of uc001ykl.1 correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein, whereas ENST00000448942 level correlated with ESR and anti-Sm antibodies. Short time-series expression miner analysis revealed some lncRNAs whose expressions might correlate with disease activity of SLE patients. Coding-non-coding gene coexpression analyses showed differential lncRNAs might operate via modulating expressions of their correlated, relevant mRNAs in SLE. Differential lncRNAs might also function through their ceRNAs. Our study established that the aberrant expression profiles of lncRNAs may play a role in SLE and thus warrant further investigation.

Associated Variables of Myositis in Systemic Lupus Erythematosus: A Cross-Sectional Study.

BACKGROUND This study aimed to estimate the point prevalence of myositis and identify associated variables of myositis in systemic lupus erythematosus (SLE). MATERIAL AND METHODS Clinical date of patients hospitalized with lupus at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital were collected. Patients were defined as having myositis if they reported the presence of persistent invalidating muscular weakness combined with increased levels of creatine phosphokinase (CPK) and abnormal electromyography (EMG). RESULTS The study sample comprised 1701 lupus patients, of which 44 had myositis. Patients with SLE-associated myositis are more likely to have skin rash, alopecia, pericarditis, vasculitis, anti-Sm, anti-RNP, anti-dsDNA, thrombocytopenia, leukopenia, low C3, low C4, high erythrocyte sedimentation rate (ESR), high D-dimer, and active disease. Multivariate logistic regression found positive associations between leukopenia, alopecia, and active disease with myositis. Negative associations between myositis with the use of corticosteroids or immunosuppressive drugs were revealed in univariate and multivariate analysis. CONCLUSIONS The point prevalence of myositis was 2.6% in SLE patients. The significant association of alopecia, leukopenia, and active disease with myositis suggests that organ damage, hematological abnormality, and high disease activity promote the progression of myositis in lupus patients.

The prevalence and risk factors for serositis in patients with systemic lupus erythematosus: a cross-sectional study.

This study aims to estimate the prevalence of serositis and identify risk factors for serositis in a large cohort of systemic lupus erythematosus (SLE) patients. A cross-sectional study was conducted based on the medical records of patients hospitalized with SLE at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital. Patients were diagnosed with serositis when they presented with symptoms and signs of pleuritis or/and pericarditis. We explored factors associated with the generation and quantity of serositis by using binary and ordinal logistic regression analysis. Among the 1668 lupus patients, 298 have serositis. Active lupus disease, fever (≥38 °C) and high D-dimer were all significantly associated with the generation and quantity of serositis. Male gender was independent significant risk factor for pleuritis but not for pericarditis, while low complement C4 and high erythrocyte sedimentation rate (ESR) were risk factors for pericarditis rather than for pleuritis. The possible prevalence of serositis in patients with SLE was 17.9%. The significant associations of active lupus disease, fever (≥38 °C) and high D-dimer with serositis suggest that higher disease activity and hypercoagulability may both contribute to the generation and development of serositis in SLE. The risk factors for pleuritis and pericarditis in SLE are similar but not identical.

Comparison of plasma/serum levels of procalcitonin between infection and febrile disease flare in patients with systemic lupus erythematosus: a meta-analysis.

Currently published data regarding the potential role of procalcitonin (PCT) for the discrimination between systemic lupus erythematosus (SLE) flare and infection are contradictory. To derive a more precise evaluation, a meta-analysis was performed. Published literatures from PubMed, Embase, and the Cochrane Library were obtained. The Newcastle-Ottawa Scale was used to assess the study quality. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by random-effect model analysis. Heterogeneity test was performed by the Q statistic and quantified using I 2. Eight studies including 205 SLE flare patients and 198 SLE patients with infection were finally incorporated in the meta-analysis after examining title, type, abstracts, and full text. No significant differences in plasma/serum PCT levels were found between SLE patients with flare and SLE patients with infection when all studies were pooled into the meta-analysis (pooled SMD = - 0.45, 95% CI = - 0.96 to 0.06). However, subgroup analysis showed that Asian SLE patients with infection had higher plasma/serum PCT levels when compared with SLE patients with flare (p < 0.001). Overall, there is no significant difference in plasma/serum PCT levels between SLE patients with flare and SLE patients with infection. However, plasma/serum PCT levels are significantly higher in Asian SLE patients with infection.

Decreased flow-mediated dilatation in patients with rheumatoid arthritis: a meta-analysis.

OBJECTIVES: To derive a more precise comparison of flow-mediated dilatation (FMD%) of the brachial artery between patients with rheumatoid arthritis (RA) and normal controls by performing a meta-analysis of appropriate studies. METHODS: PubMed and EMBASE databases were searched for all relevant articles. STATA (V.12.0) software was used to perform the meta-analysis. Quality estimation of all appropriate studies was evaluated according to the Newcastle-Ottawa Scale (NOS). Standardised mean difference (SMD) with 95% CIs were calculated with a random-effects model. The Cochrane Q test and I2 statistic were used to evaluate the heterogeneity. Funnel plot and Egger's test were conducted to assess the publication bias. RESULTS: In total, 464 articles were obtained after searching the two databases. Ten studies were included in the meta-analysis on the basis of the inclusion and exclusion criteria. Significant heterogeneity was observed among these 10 studies (Q=102.89, p<0.001, I2=91.3%) with random-effects modelling. The results showed that the RA group had significantly lower FMD% (SMD: -1.405; 95% CI -1.992 to -0.817; p<0.001) than the control group. Egger's test (p=0.004) indicated that the funnel plot showed a skewed or asymmetrical shape and publication bias existed. Sensitivity analyses suggested the robustness and credibility of our results. CONCLUSIONS: FMD% in patients with RA is significantly decreased compared with healthy controls. FMD% is an important early marker of atherosclerosis. It may be used as a parameter to forecast cardiovascular disease in patients with RA.

Evidence of epistatic interaction between DPP4 and CCR6 in patients with rheumatoid arthritis.

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.

Plasma levels of adipokines in systemic lupus erythematosus patients.

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.

Genetic Polymorphism (rs329498) in the Pellino-1 Gene as Possible Predisposal Factor for Systemic Lupus Erythematosus in a Chinese Population.

OBJECTIVE: The purpose of this study was to analyze the association of two single nucleotide polymorphisms (SNPs) in Peli-1 gene with systemic lupus erythematosus (SLE) in a Chinese population. METHODS: We conducted a case-control study and a total of 738 SLE patients and 827 healthy controls were finally recruited. Peli-1 rs329498 and rs10496105 polymorphisms were specified from genomic DNA using TaqMan genotyping assay on Fluidigm 192.24 system. RESULTS: Allele contrast showed the minor allele C was associated with decreased risk for SLE when compared with the A allele (OR = 0.851, 95% CI = 0.737-0.983, p = 0.028). Significant difference was observed in genotype distribution of rs329498 polymorphism between lupus nephritis (LN) patients and non-LN patients (χ(2) = 8.18, p = 0.017). Furthermore, we also found a decreased frequency of the minor allele C in LN patients (29.2%) than in non-LN patients (37.7%) (χ(2) = 8.67, p = 0.003). Moreover, a significant difference was also detected under a dominant model with regard to the distribution of genotype frequencies between LN patients and non-LN patients (CC + AC vs. AA: OR = 0.632, 95% CI = 0.451-0.884, p = 0.007). Clinical features analysis showed a significant difference in the distribution of genotypic frequencies between patients with malar rash and patients without this feature (χ(2) = 6.63, p = 0.036). Unfortunately, we failed to find any significant results between Peli-1 gene rs10496105 and SLE susceptibility. CONCLUSIONS: Our observations suggested that Peli-1 gene polymorphism rs329498 might contribute to SLE susceptibility in Chinese Han Population. Likewise, the rs329498 SNP was also associated with the clinical features LN and malar rash in SLE patients.

Association between CARD8 rs2043211 polymorphism and inflammatory bowel disease: a meta-analysis.

OBJECTIVE: The aim of this study was to determine whether caspase recruitment domain-containing protein 8 (CARD8) rs2043211 polymorphism was associated with susceptibility to inflammatory bowel disease (IBD). METHODS: Relevant studies were searched using PubMed and Embase up to February 2014. A meta-analysis was conducted on the association between rs2043211 polymorphism and IBD using: (1) allele contrast, (2) the dominant model, (3) the recessive model, and (4) homozygote contrast. The pooled estimated of risk was obtained by random-effects model or fixed-effects model. Publication bias was assessed by Egger's test. RESULTS: Eight relevant articles with a total of 10 534 IBD patients [6785 Crohn's disease (CD), 3713 ulcerative colitis (UC) and 36 indeterminate colitis (IC)] and 6755 healthy controls were included in the meta-analysis, which consisted of 12 studies, 12 for CD, 10 for UC, 2 for IC. There was no significant association between rs2043211 polymorphism and IBD, CD, and IC in overall population. However, stratified meta-analysis by ethnicity showed significant association between rs2043211 polymorphism and CD in the European population under the dominant model [odds ratio (OR) = 1.210, 95% confidence interval (CI) = 1.013-1.445, p = 0.036] and homozygote contrast (OR = 1.212, 95% CI = 1.005-1.461, p = 0.044). CONCLUSIONS: Our meta-analysis results indicated significant association between rs2043211 polymorphism and the susceptibility to CD under the dominant model and homozygote contrast in the European population.