scholarly journals Causal Effects of Gut Microbiome on Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun Xiang ◽  
Peng Wang ◽  
Zhiwei Xu ◽  
Yu-Qian Hu ◽  
Yi-Sheng He ◽  
...  
Keyword(s):  
Instrumental Variables ◽  
Lupus Erythematosus ◽  
Gut Microbiome ◽  
Mendelian Randomization ◽  
Statistical Significance ◽  
Causal Effects ◽  
Systemic Lupus ◽  
Significance Level ◽  
Significance Threshold ◽  
Genome Wide

The observational association between gut microbiome and systemic lupus erythematosus (SLE) has been well documented. However, whether the association is causal remains unclear. The present study used publicly available genome-wide association study (GWAS) summary data to perform two-sample Mendelian randomization (MR), aiming to examine the causal links between gut microbiome and SLE. Two sets of MR analyses were conducted. A group of single nucleotide polymorphisms (SNPs) that less than the genome-wide statistical significance threshold (5 × 10-8) served as instrumental variables. To obtain a comprehensive conclusion, the other group where SNPs were smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. Based on the locus-wide significance level, the results indicated that there were causal effects of gut microbiome components on SLE risk. The inverse variance weighted (IVW) method suggested that Bacilli and Lactobacillales were positively correlated with the risk of SLE and Bacillales, Coprobacter and Lachnospira were negatively correlated with SLE risk. The results of weighted median method supported that Bacilli, Lactobacillales, and Eggerthella were risk factors for SLE and Bacillales and Coprobacter served as protective factors for SLE. The estimates of MR Egger suggested that genetically predicted Ruminiclostridium6 was negatively associated with SLE. Based on the genome-wide statistical significance threshold, the results showed that Actinobacteria might reduce the SLE risk. However, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) detected significant horizontal pleiotropy between the instrumental variables of Ruminiclostridium6 and outcome. This study support that there are beneficial or detrimental causal effects of gut microbiome components on SLE risk.

scholarly journals Association between Systemic Lupus Erythematosus and Coronary Heart Disease: a retrospective case-control analysis and Mendelian Randomization Study

2021 ◽  
Author(s):  
Jinyun Chen ◽  
Junmei Tian ◽  
Wen Wang ◽  
Shiliang Zhou ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Coronary Heart Disease ◽  
Lupus Erythematosus ◽  
Coronary Atherosclerosis ◽  
Mendelian Randomization ◽  
Hdl Cholesterol ◽  
Systemic Lupus ◽  
Cholesterol Levels ◽  
Apolipoprotein A ◽  
Genome Wide

Objectives To appraise the causal effect of systemic lupus erythematosus (SLE) for risk of Coronary heart disease (CHD). Methods We selected single nucleotide polymorphisms (SNPs) associated with SLE as instrumental variables (IVs) from three independent genome-wide association studies (GWAS), the three largest to date for SLE of European ancestry. Then we conducted two-sample Mendelian randomization (2SMR) analyses to estimate the effects of IVs on the odds of CHD and traditional coronary risk factors (including high LDL cholesterol levels, low HDL cholesterol levels, Apolipoprotein A-I, Apolipoprotein B, diabetes mellitus, and hypertension). Additionally, we searched for common risk loci between SLE and premature coronary atherosclerosis. Furthermore, we retrospectively reviewed the lipid profile of treatment-naïve SLE patients and age-matched healthy controls. Results Genetically predicted SLE did not increase the odds of CHD. Nevertheless, we found mild causal relationships between SLE and decreased HDL cholesterol levels, and between SLE and decreased apolipoprotein A-I. There was one common risk locus (rs597808) between SLE and premature coronary atherosclerosis at a genome-wide significance level (P<5 ×10−8). Retrospective analysis showed decreased HDL-cholesterol (0.98±0.516mmol/L vs. 1.46±0.307mmol/L in female, 0.76±0.199mmol/L vs. 1.19±0.257mmol/L in male; both P<0.001) and apolipoprotein A-I (1.06±0.314g/L vs. 1.37±0.205g/L in female, 0.87±0.174g/L vs. 1.24±0.200g/L in male; both P<0.001) in naïve SLE patients. Conclusion SLE may accelerate coronary atherosclerosis in young patients by reducing HDL cholesterol and apolipoprotein A-I intrinsically, but it seems not to play a predominant role in CHD development in old patients.

Alcohol intake and risk of systemic lupus erythematosus: a Mendelian randomization study

Lupus ◽  
2018 ◽  
Vol 28 (2) ◽  
pp. 174-180 ◽  
Author(s):  
S C Bae ◽  
Y H Lee
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Alcohol Intake ◽  
Mendelian Randomization ◽  
Inverse Association ◽  
Causal Association ◽  
Systemic Lupus ◽  
Regression Methods ◽  
Genome Wide ◽  
Weighted Median

Objectives This study aimed to examine whether alcohol intake is causally associated with systemic lupus erythematosus (SLE). Methods We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and an SLE GWAS consisting of 1311 SLE and 1783 control subjects of European descent as the outcome. Results We selected 20 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables to improve inference. The IVW method found no evidence to support a causal association between alcohol intake and SLE (beta = –0.413, SE = 0.513, p = 0.421). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.031, p = 0.582). The MR-Egger analysis found no causal association between alcohol intake and SLE (beta = –1.494, SE = 1.996, p = 0.464). Likewise, the weighted median approach also did not provide evidence of a causal association between alcohol intake and SLE (beta = –0.538, SE = 0.574, p = 0.349). The MR estimates determined using the IVW, weighted median, and MR-Egger regression methods were consistent and results from a “leave-one-out” analysis demonstrated that no single SNP was driving the IVW point estimate. Conclusions The results of MR analysis do not support a causal inverse association between alcohol intake and SLE occurrence.

scholarly journals POS0765 LABORATORY RATIOS: A SUBROGATE BIOMARKER FOR DETECTION OF INFECTION IN SLE PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 636.1-636
Author(s):  
Y. Santamaria-Alza ◽  
J. Sanchez-Bautista ◽  
T. Urrego Callejas ◽  
J. Moreno ◽  
F. Jaimes ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Logistic Regression ◽  
Roc Curve ◽  
Lupus Erythematosus ◽  
Statistical Significance ◽  
C Reactive Protein ◽  
Systemic Lupus ◽  
Predictive Capacity ◽  
Cross Sectional ◽  
Reactive Protein

Background:The most common complication in patients with SLE is infection, and its clinical presentation is often indistinguishable from SLE flares. Therefore, laboratory ratios have been evaluated to differentiate between those events. Among them, ESR/CRP1, neutrophil/lymphocyte (NLR)2, and platelet/lymphocyte (PLR)3 ratios have been previously assessed with acceptable performance; however, there is no validation of those ratios in our SLE population.Objectives:To examine the predictive capacity of infection of the lymphocyte/C4 (LC4R), lymphocyte/C3 (LC3R), and ferritin/ESR (FER) ratios in SLE patients, and to evaluate the performance of ESR/CRP, NLR, AND PLR ratios in our SLE population.Methods:We conducted a cross-sectional study of SLE patients admitted to the emergency service at Hospital San Vicente Fundación (HSVF). The HSVF ethics committee approved the execution of the project.Patients were categorized into four groups according to the main cause of hospitalization: (1) infection, (2) flare, (3) infection and flare and, (4) neither infection nor flare.We calculated the median values of the ratios and their respective interquartile ranges for each group. Then, we compared those summary measures using the Kruskal-Wallis test. Subsequently, we assessed the predictive capacity of infection of each ratio using ROC curve. Finally, we carried out a logistic regression model.Results:A total of 246 patients were included, among them 90.7% were women. The median age was 28 years (IQR: 20-35 years). Regarding the outcomes, 37.0% of the patients had flares, 30.9% had neither infection nor flare, 16.7% had an infection and, 15.5% had simultaneously infection and flare. When compared the four groups, statistical significance (p<0.05) was observed. Area under the ROC curve (AUC) for infection prediction was as follows: 0.752 (sensitivity 60.5%, specificity 80.5%) for LC4R, 0.740 (sensitivity 73.2%, specificity 68.3%) for FER, 0.731 (sensitivity 77.6%, specificity 80.5%) for LC3R.In the logistic regression modeling, we observed that an increase in the risk of infection was associated with an LC4R below 66.7 (OR: 6.3, CI: 2.7 – 14.3, p <0.0001), a FER greater than 13.6 (OR: 5.9, CI: 2.8 – 12.1, p <0.0001) and an LC3R below 11.2 (OR: 4.9, CI: 2.4 – 9.8, p <0.0001).The ESR/CRP and PLR performed poorly with an AUC of 0.580 and 0.655, respectively. In contrast, the NLR showed better performance (AUC of 0.709, with a sensitivity of 80.2% and specificity of 55.7%).Figure 1.ROC curves of the evaluated ratiosConclusion:These laboratory ratios could be easy to assay and inexpensive biomarkers to differentiate between infection and activity in SLE patients. The LC4R, FER, and LC3R have a significant diagnostic performance for detecting infection among SLE patients. Of the ratios previously evaluated, ESR/CRP, LPR, NLR, only the latest has an adequate performance in our population.References:[1]Littlejohn E, Marder W, Lewis E, et al. The ratio of erythrocyte sedimentation rate to C-reactive protein is useful in distinguishing infection from flare in systemic lupus erythematosus patients presenting with fever. Lupus. 2018;27(7):1123-1129.[2]Broca-Garcia BE, Saavedra MA, Martínez-Bencomo MA, et al. Utility of neutrophil-to-lymphocyte ratio plus C-reactive protein for infection in systemic lupus erythematosus. Lupus. 2019;28(2):217-222.[3]Soliman WM, Sherif NM, Ghanima IM, EL-Badawy MA. Neutrophil to lymphocyte and platelet to lymphocyte ratios in systemic lupus erythematosus: Relation with disease activity and lupus nephritis. Reumatol Clin. 2020;16(4):255-261s.Disclosure of Interests:None declared

scholarly journals AB0013 ASSOCIATION BETWEEN STAT4 POLYMORPHISM AND MANIFESTATIONS OF SLE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1041.1-1041
Author(s):  
V. Agarwal ◽  
S. Kakati ◽  
P. Debbaruah
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Indian Population ◽  
Association Studies ◽  
Statistical Significance ◽  
Elevated Serum ◽  
Systemic Lupus ◽  
Cutaneous Manifestations ◽  
Genotype Group ◽  
Dsdna Antibody

Background:SNP rs7574865, located within the third intron of STAT4 gene at chromosome 2, has been associated with susceptibility to SLE among different ethnic groups.1,2 Interestingly, we recently have documented an association between this gene and susceptibility to systemic lupus erythematosus (SLE) in Indian population.3Objectives:To determine whether the STAT4 (rs7574865) SNP is associated with clinical and immunological manifestations in SLE.Methods:The study was carried out on 100 unrelated SLE (SLICC criteria 2012) patients from North-East India. Genotyping of STAT4 rs7574865 SNP was done using Taqman probe and Real-Time Polymerase chain reaction. An association study was performed between the alleles and genotypes of STAT4 rs7574865 with the clinical and immunological manifestations included in the SLE SLICC classification criteria. For all analysis, the statistical significance was fixed at 5% level of significance (p < 0.05).Results:The mean duration of illness was 2.69±2.55 years. Cases and Controls remained in Hardy-Weinberg equilibrium.The occurrence of Photosensitivity and hyperpigmentation was significantly higher in TT genotype group (97.22% and 77.77%, respectively) with p <0.001 in each case.SLE patients with nephritis (Albuminuria >500mg/24 hours) and elevated serum creatinine were both significantly higher in TT genotype group as compared to GT and GG (p< 0.001 and p=0.001 respectively).The Anti-dsDNA antibody was significantly associated with TT genotype (p <0.001).Conclusion:Our study provides evidence regarding the association between STAT4 rs7574865 gene polymorphism is risk factor for cutaneous manifestations, Lupus nephritis and Anti ds-DNA positivity in SLE. So, our findings reinforce the need for further association studies including prospective studies with larger subjects in order to replicate such findings.References:[1]Graham RR, Ph D, Hom G, Ph D, Behrens TW, Bakker PIW De, et al. and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus. N Engl J Med. 2007;357(10):977–86.[2]Yuan H, Feng JB, Pan HF, Qiu LX, Li LH, Zhang N, et al. A meta-analysis of the association of STAT4 polymorphism with systemic lupus erythematosus. Mod Rheumatol. 2010;20(3):257–62.[3]Gupta V, Kumar S, Pratap A, Singh R, Kumari R, Kumar S, et al. Association of ITGAM, TNFSF4, TNFAIP3 and STAT4 gene polymorphisms with risk of systemic lupus erythematosus in a North Indian population. Lupus. 2018;27(12):1973–9.Disclosure of Interests:None declared

scholarly journals Prevalence of Hyposalivation in Patients with Systemic Lupus Erythematosus in a Brazilian Subpopulation

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Cristhiane Almeida Leite ◽  
Marcial Francis Galera ◽  
Mariano Martínez Espinosa ◽  
Paulo Ricardo Teles de Lima ◽  
Vander Fernandes ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Salivary Flow ◽  
Cross Sectional Study ◽  
Systemic Lupus ◽  
Cross Sectional ◽  
Mato Grosso ◽  
Significance Level ◽  
Factors Associated ◽  
Study Population

Background.Systemic lupus erythematosus (SLE) is a chronic inflammatory, multisystem, and autoimmune disease.Objective.The aim of this study was to describe the prevalence of hyposalivation in SLE patients and evaluate factors associated.Methods.This is a cross-sectional study developed at the Cuiaba University General Hospital (UNIC-HGU), Mato Grosso, Brazil. The study population consisted of female SLE patients treated at this hospital from 06/2010 to 12/2012. Unstimulated salivary flow rates (SFRs) were measured. Descriptive and inferential analyses were performed in all cases using a significance levelP<0.05.Results.The results showed that 79% of patients with systemic lupus erythematosus suffered from hyposalivation and that the disease activity and age in years were the factors that resulted in statistically significant differences.Conclusion.The activity of the disease, age >27 years, and the drugs used were factors associated with hyposalivation, resulting in a statistically significant decrease in saliva production.

scholarly journals AB0815 FIRST DEGREE RELATIVES OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS - CLINICAL, SEROLOGICAL AND IMMUNOLOGICAL CORRELATIONS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1432.2-1432
Author(s):  
B. Penev ◽  
G. Vasilev ◽  
D. Kyurkchiev ◽  
S. Monov
Keyword(s):  
Risk Factors ◽  
Systemic Lupus Erythematosus ◽  
Connective Tissue ◽  
Lupus Erythematosus ◽  
Current Knowledge ◽  
Statistical Significance ◽  
Clinical Signs ◽  
Connective Tissue Diseases ◽  
Pharmaceutical Products ◽  
Systemic Lupus

Background:Antinuclear antibodies (ANA) have been unequivocally recognized as essential for diagnosis and play both pathogenic and diagnostic roles in systemic lupus erythematosus (SLE). SLE and ANA have also been found to be more often among relatives of SLE patients. ANA and other immunological changes are known to appear prior to the clinical onset of the disease and thus can be used as predictors. Studies have reported that relatives of SLE patients who later transitioned to SLE displayed more lupus-associated autoantibody specificities and had early clinical signs. They also displayed elevated baseline plasma levels of inflammatory mediators, including B-lymphocyte stimulator (BLyS) and interferon-associated chemokines, with concurrent decreases in levels of regulatory mediators, e.g. tumor growth factor (TGF)-β. Commonly recognized risk factors for SLE are signs of past Epstein-Barr (EBV) infection, use of estrogen drugs and current smoking. It seems that ANA, immunologic changes and risk factors have not been investigated together in relatives of SLE patients.Objectives:The aim of the study was to determine the relative prevalence of clinical signs of SLE or connective tissue disease (CTD), smoking, use of estrogen drugs and levels of circulating ANA, BLyS, IFN-α, TGF-β, anti-EBV viral capsid antigen (VCA) IgM and IgG antibodies among sera of FDR, non-FDR healthy individuals and SLE patients.Methods:Forty three FDRs of SLE patients were studied along with 15 SLE patients and 15 clinically healthy subjects as control groups. The FDRs and the healthy answered a questionnaire about early clinical signs of CTD, smoking and estrogen use history. The questionnaire was developed based on the existing Screening Questionnaire for Connective Tissue Diseases and current knowledge of most early signs of CTD. Blood samples were obtained and tested for ANA, both by indirect immunofluorescence and immunoblot, anti-dsDNA by ELISA. ELISA was also performed to measure levels of BLys, IFN-α, TGF-β, anti-EBV IgM and IgG.Results:More than half of the FDRs displayed ANA in titer 1:160 or more, with predominately AC-4 type of fluorescence according to International Classification on ANA Patterns (ICAP) compared to only AC-1 and AC-0 among patients and controls respectively. A correlation between the ANA titer and the number of complaints was found. This was particularly valid or reported skin complaints and oral ulcers which appeared more frequently when ANA was 1:320 or above (p=0,018 and 0,038 respectively). Furthermore, oral ulcerations showed positive correlation with the presence of anti-Ro60. No associations were found in the healthy group between reported complaints and ANA titers. Smoking and estrogen use did not differ across the three groups. Patients showed significant differences in levels of BLys (p=0,027), TGF-β (p=0,019) and anti-EBV IgG (p=0.041) compared to both FDRs and controls. Without reaching statistical significance, levels of TGF-β tend to split the FDR group into “healthy-like” and “SLE-like”.Conclusion:Our results show that FDR ANA levels are between those of SLE patients and healthy subject groups. This is consistent with previous studies. The data also suggest that ANA positivity correlates with reported complaints, some of which could be interpreted as very early clinical signs of SLE. Of note, anti-Ro60 is known to be among the earliest ANA that appear in “future” SLE patients and in this study they are related to oral complaints that could be caused by early sicca phenomena. Immunologically, our data support previous findings [1] that the FDRs are a heterogenic group with different “lupus-developing” potential.References:[1]Munroe МE. et al, Soluble Mediators and Clinical Features Discern Risk of Transitioning to Classified Disease in Relatives of Systemic Lupus Erythematosus Patients, Arthritis Rheumatol. 2017 March; 69(3): 630–642.Disclosure of Interests:Bogdan Penev: None declared, Georgi Vasilev: None declared, Dobroslav Kyurkchiev: None declared, Simeon Monov Speakers bureau: I have been paid for giving lectures on statistical data on efficacy of many pharmaceutical products on various companies

scholarly journals Causal Effect Between Total Cholesterol and HDL Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Liu Miao ◽  
Yan Min ◽  
Chuan-Meng Zhu ◽  
Jian-Hong Chen ◽  
Bin Qi ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Causal Effects ◽  
Lipid Levels ◽  
Serum Lipid Levels ◽  
Genome Wide ◽  
Mr Study

Abstract Background/Aims: While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. Methods: To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample Mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with plasma serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187365), triglyceride (TG, n = 177861), HDL cholesterol (HDL-C, n = 187167), LDL cholesterol (LDL-C, n = 173082), apolipoprotein A1 (ApoA1, n = 20687), apolipoprotein B (ApoB, n = 20690) and CKD (n = 117165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). Results: MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. Conclusions: The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

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