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Phenome-Wide Association Studies Uncover a Novel Association of Increased Atrial Fibrillation in Male Patients With Systemic Lupus Erythematosus.
Barnado A, Carroll RJ, Casey C, Wheless L, Denny JC, Crofford LJ
(2018) Arthritis Care Res (Hoboken) 70: 1630-1636
MeSH Terms: Adult, Aged, Atrial Fibrillation, Humans, Lupus Erythematosus, Systemic, Male, Middle Aged, Retrospective Studies, Sex Characteristics
Show Abstract · Added March 14, 2018
OBJECTIVE - Phenome-wide association studies (PheWAS) scan across billing codes in the electronic health record (EHR) and re-purpose clinical EHR data for research. In this study, we examined whether PheWAS could function as an EHR-based discovery tool for systemic lupus erythematosus (SLE) and identified novel clinical associations in male versus female patients with SLE.
METHODS - We used a de-identified version of the Vanderbilt University Medical Center EHR, which includes more than 2.8 million subjects. We performed EHR-based PheWAS to compare SLE patients with age-, sex-, and race-matched control subjects and to compare male SLE patients with female SLE patients, controlling for multiple testing using a false discovery rate (FDR) P value of 0.05.
RESULTS - We identified 1,097 patients with SLE and 5,735 matched control subjects. In a comparison of patients with SLE and matched controls, SLE patients were shown to be more likely to have International Classification of Diseases, Ninth Revision codes related to the SLE disease criteria. In the PheWAS of male versus female SLE patients, with adjustment for age and race, male patients were shown to be more likely to have atrial fibrillation (odds ratio 4.50, false discovery rate P = 3.23 × 10 ). Chart review confirmed atrial fibrillation, with the majority of patients developing atrial fibrillation after the SLE diagnosis and having multiple risk factors for atrial fibrillation. After adjustment for age, sex, race, and coronary artery disease, SLE disease status was shown to be significantly associated with atrial fibrillation (P = 0.002).
CONCLUSION - Using PheWAS to compare male and female patients with SLE, we identified a novel association of an increased incidence of atrial fibrillation in male patients. SLE disease status was shown to be independently associated with atrial fibrillation, even after adjustment for age, sex, race, and coronary artery disease. These results demonstrate the utility of PheWAS as an EHR-based discovery tool for SLE.
© 2018, American College of Rheumatology.
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9 MeSH Terms
Developing Electronic Health Record Algorithms That Accurately Identify Patients With Systemic Lupus Erythematosus.
Barnado A, Casey C, Carroll RJ, Wheless L, Denny JC, Crofford LJ
(2017) Arthritis Care Res (Hoboken) 69: 687-693
MeSH Terms: Adult, Aged, Algorithms, Antibodies, Antinuclear, Antirheumatic Agents, Electronic Health Records, Female, Humans, International Classification of Diseases, Lupus Erythematosus, Systemic, Male, Middle Aged, Predictive Value of Tests, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added March 14, 2018
OBJECTIVE - To study systemic lupus erythematosus (SLE) in the electronic health record (EHR), we must accurately identify patients with SLE. Our objective was to develop and validate novel EHR algorithms that use International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification codes, laboratory testing, and medications to identify SLE patients.
METHODS - We used Vanderbilt's Synthetic Derivative, a de-identified version of the EHR, with 2.5 million subjects. We selected all individuals with at least 1 SLE ICD-9 code (710.0), yielding 5,959 individuals. To create a training set, 200 subjects were randomly selected for chart review. A subject was defined as a case if diagnosed with SLE by a rheumatologist, nephrologist, or dermatologist. Positive predictive values (PPVs) and sensitivity were calculated for combinations of code counts of the SLE ICD-9 code, a positive antinuclear antibody (ANA), ever use of medications, and a keyword of "lupus" in the problem list. The algorithms with the highest PPV were each internally validated using a random set of 100 individuals from the remaining 5,759 subjects.
RESULTS - The algorithm with the highest PPV at 95% in the training set and 91% in the validation set was 3 or more counts of the SLE ICD-9 code, ANA positive (≥1:40), and ever use of both disease-modifying antirheumatic drugs and steroids, while excluding individuals with systemic sclerosis and dermatomyositis ICD-9 codes.
CONCLUSION - We developed and validated the first EHR algorithm that incorporates laboratory values and medications with the SLE ICD-9 code to identify patients with SLE accurately.
© 2016, American College of Rheumatology.
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15 MeSH Terms
Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction.
Stocks BT, Wilhelm AJ, Wilson CS, Marshall AF, Putnam NE, Major AS, Moore DJ
(2016) Am J Transplant 16: 334-41
MeSH Terms: Animals, Autoantibodies, Autoimmunity, Cells, Cultured, Dendritic Cells, Graft Rejection, Graft Survival, Islets of Langerhans Transplantation, Lupus Erythematosus, Systemic, Lupus Nephritis, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Inbred NOD, T-Lymphocytes, Regulatory, Transplantation Tolerance
Show Abstract · Added September 16, 2015
The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
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17 MeSH Terms
Genetics of serum concentration of IL-6 and TNFα in systemic lupus erythematosus and rheumatoid arthritis: a candidate gene analysis.
Solus JF, Chung CP, Oeser A, Li C, Rho YH, Bradley KM, Kawai VK, Smith JR, Stein CM
(2015) Clin Rheumatol 34: 1375-82
MeSH Terms: Adult, Aged, Alleles, Arthritis, Rheumatoid, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Interleukin-6, Lupus Erythematosus, Systemic, Male, Middle Aged, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha
Show Abstract · Added February 19, 2015
Elevated concentrations of inflammatory mediators are characteristic of autoimmune disease accompanied by chronic or recurrent inflammation. We examined the hypothesis that mediators of inflammation known to be elevated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with genetic polymorphism previously identified in studies of inflammatory disease. Serum interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) concentrations in patients with SLE (n = 117) or RA (n = 164) and in inflammatory disease-free control subjects (n = 172) were measured by multiplex ELISA. Candidate genes were chosen from studies of autoimmune and inflammatory disease. Genotypes were determined for 345 SNP markers in 75 genes. Association between serum analytes and single alleles was tested by linear regression. Polymorphisms in several genes were associated with IL-6 levels (including IL10, TYK2, and CD40L in SLE and DRB1, NOD2, and CSF1 in RA) or with TNFα levels (including TNFSF4 and CSF2 in SLE and PTPN2, DRB1, and NOD2 in RA). Some associations were shared between disease and control groups or between IL-6 and TNFα within a group. In conclusion, variation in genes implicated in disease pathology is associated with serum IL-6 or TNFα concentration. Some genetic associations are more apparent in healthy controls than in SLE or RA, suggesting dysregulation of the principal mediators of chronic inflammation in disease. Susceptibility genes may affect inflammatory response with variable effect on disease etiology.
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15 MeSH Terms
Dysregulation of T lymphocyte proliferative responses in autoimmunity.
Elizer SK, Marshall AF, Moore DJ
(2014) PLoS One 9: e106347
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Death, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Lupus Erythematosus, Systemic, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Inbred NOD
Show Abstract · Added October 15, 2014
T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains-NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.
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12 MeSH Terms
Alpha-chlorofatty Acid and coronary artery or aorta calcium scores in women with systemic lupus erythematosus. A pilot study.
Mahieu MA, Guild CP, Albert CJ, Kondos GT, Carr JJ, Edmundowicz D, Ford DA, Ramsey-Goldman R
(2014) J Rheumatol 41: 1834-42
MeSH Terms: Adult, Aged, Aorta, Aortography, Biomarkers, Calcium, Cardiovascular Diseases, Coronary Vessels, Fatty Acids, Female, Humans, Lupus Erythematosus, Systemic, Middle Aged, Pilot Projects, Risk Factors
Show Abstract · Added October 10, 2014
OBJECTIVE - Alpha-chlorofatty acid (α-ClFA) is one product of myeloperoxidase activity in vivo during atherogenesis and may be a biomarker for cardiovascular disease (CVD). We investigated if serum α-ClFA is associated with subclinical CVD as measured by coronary artery and aorta calcium scores (CAC and AC, respectively) in women with and without systemic lupus erythematosus (SLE).
METHODS - This pilot project analyzed baseline data from 173 women with SLE and 186 women without SLE participating in a 5-year longitudinal investigation of the Study of Lupus Vascular and Bone Long-term Endpoints (SOLVABLE). Data collection included demographic information, CVD and SLE risk factors, and laboratory assessments. Alpha-ClFA was measured in stored serum by liquid chromatography-mass spectrometry. CAC and AC were measured by computed tomography. Outcome measures were CAC and AC present (CAC > 0 or AC > 0) versus absent (CAC = 0 or AC = 0). Associations between risk factors and CAC or AC were tested with descriptive statistics and multivariate analyses.
RESULTS - Women with SLE had higher α-ClFA levels than women without SLE (42.0 fmol/25 µl ± 37.3 vs 34.5 fmol/25 µl ± 21.9; p = 0.020). In analyses including individual CVD risk factors, having SLE was independently associated with the presence of CAC (OR 3.42, 95% CI 1.72 to 6.78) but not AC. Alpha-ClFA was not associated with the presence of CAC or AC in patients with SLE.
CONCLUSION - SLE, but not serum α-ClFA, was associated with the presence of CAC in this pilot project.
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15 MeSH Terms
Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus.
Chung CP, Solus JF, Oeser A, Li C, Raggi P, Smith JR, Stein CM
(2014) Lupus 23: 876-80
MeSH Terms: Adult, Coronary Artery Disease, Female, Genetic Variation, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, Risk Factors
Show Abstract · Added February 19, 2015
Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in 20 of the candidate genes (ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC (p-values = 0.001-0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.
© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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9 MeSH Terms
Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice.
Wilhelm AJ, Rhoads JP, Wade NS, Major AS
(2015) Ann Rheum Dis 74: 778-85
MeSH Terms: Animals, Atherosclerosis, CD4-Positive T-Lymphocytes, Disease Models, Animal, Forkhead Transcription Factors, Lupus Erythematosus, Systemic, Mice, Mice, Inbred Strains, Mice, Knockout, Receptors, Interleukin-10, Receptors, LDL, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory
Show Abstract · Added February 11, 2014
OBJECTIVE - Accelerated atherosclerosis is a major source of morbidity in systemic lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis remains unclear.
METHODS - CD4(+) T cells from C57/Bl/6 (B6) or SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr(-/-), Rag(-/-) mice. T cells were examined for cytokine production and expression of interleukin-10 receptor (IL-10R) and functional markers. T cells were isolated based on FoxP3(GFP) expression and transferred to LDLr(-/-), Rag(-/-) mice to establish a role for B6.SLE effector T cells (Teff) in atherosclerosis.
RESULTS - Mice receiving whole B6.SLE CD4(+) T cells displayed no other SLE phenotype; however, atherosclerosis was increased nearly 40%. We noted dysregulated IL-17 production and reduced frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6 Treg. Transfer experiments with CD4(+)FoxP3(-) Teff and CD4(+)FoxP3(+) Treg from B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff with B6 Treg had increased production of IL-17 and fewer expressed IL-10R compared with B6 Teff and Treg transfer.
CONCLUSIONS - Transfer of B6.SLE Teff to LDLr(-/-), Rag(-/-) mice results in accelerated atherosclerosis independent of the source of Treg. In addition, the presence of B6.SLE Teff resulted in more IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may mediate phenotypic changes in Treg. To our knowledge, this is the first study to provide direct evidence of the role of B6.SLE Teff in accelerating atherosclerosis through resistance to Treg suppression.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
0 Communities
2 Members
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13 MeSH Terms
Suboptimal inhibition of platelet cyclooxygenase 1 by aspirin in systemic lupus erythematosus: association with metabolic syndrome.
Kawai VK, Avalos I, Oeser A, Oates JA, Milne GL, Solus JF, Chung CP, Stein CM
(2014) Arthritis Care Res (Hoboken) 66: 285-92
MeSH Terms: Adult, Aspirin, Biomarkers, Blood Platelets, C-Reactive Protein, Chi-Square Distribution, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Female, Humans, Lupus Erythematosus, Systemic, Male, Metabolic Syndrome, Middle Aged, Obesity, Prospective Studies, Thromboxane B2, Time Factors, Treatment Outcome
Show Abstract · Added March 7, 2014
OBJECTIVE - Low-dose aspirin prevents platelet aggregation by suppressing thromboxane A2 (TXA2 ) synthesis. However, in some individuals TXA2 suppression by aspirin is impaired, indicating suboptimal inhibition of platelet cyclooxygenase 1 (COX-1) by aspirin. Because patients with systemic lupus erythematosus (SLE) have increased risk of thrombotic events, many receive aspirin; however, the efficacy of aspirin in SLE has not been determined. We examined the hypothesis that aspirin response is impaired in SLE.
METHODS - We assessed the effect of aspirin by measuring concentrations of the stable metabolite of TXA2 , serum thromboxane B2 (sTXB2 ), before and after treatment with daily aspirin (81 mg) for 7 days in 34 patients with SLE and 36 control subjects. The inability to suppress sTXB2 synthesis to <10 ng/ml represents suboptimal inhibition of platelet COX-1 by aspirin.
RESULTS - Aspirin almost completely suppressed sTXB2 in control subjects to median 1.5 ng/ml (interquartile range [IQR] 0.8-2.7) but had less effect in patients with SLE (median 3.1 ng/ml [IQR 2.2-5.3]) (P = 0.002). A suboptimal effect of aspirin was present in 15% (5 of 34) of the patients with SLE but not in control subjects (0 of 36) (P = 0.023). Incomplete responders were more likely to have metabolic syndrome (P = 0.048), obesity (P = 0.048), and higher concentrations of C-reactive protein (CRP) (P = 0.018).
CONCLUSION - The pharmacologic effect of aspirin is suboptimal in 15% of patients with SLE but in none of the control subjects, and the suboptimal response was associated with metabolic syndrome, obesity, and higher CRP concentrations.
Copyright © 2014 by the American College of Rheumatology.
2 Communities
1 Members
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19 MeSH Terms
Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus.
Ormseth MJ, Swift LL, Fazio S, Linton MF, Raggi P, Solus JF, Oeser A, Bian A, Gebretsadik T, Shintani A, Stein CM
(2013) Lupus 22: 26-33
MeSH Terms: Adult, Biomarkers, Calcium, Case-Control Studies, Cholesterol, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Cross-Sectional Studies, Cytokines, Endothelial Cells, Fatty Acids, Nonesterified, Female, Humans, Immunosuppressive Agents, Inflammation, Inflammation Mediators, Insulin Resistance, Logistic Models, Lupus Erythematosus, Systemic, Male, Metabolic Syndrome, Middle Aged, Multivariate Analysis, Odds Ratio, Prevalence, Prognosis, Risk Factors, Tennessee, Tomography, X-Ray Computed, Triglycerides, Up-Regulation
Show Abstract · Added December 10, 2013
Free fatty acids (FFAs) are implicated in the pathogenesis of insulin resistance and atherosclerosis. Inflammatory cytokines promote lipolysis and increase FFAs, a cause of endothelial dysfunction and increased atherosclerosis risk. We hypothesized that increased inflammation is associated with increased FFAs, resulting in insulin resistance and atherosclerosis in patients with systemic lupus erythematosus (SLE). We measured clinical variables, serum FFAs, homeostasis model assessment for insulin resistance (HOMA), inflammatory cytokines, markers of endothelial activation, cholesterol concentrations and coronary artery calcium in 156 patients with SLE and 90 controls. We compared FFAs in patients with SLE and controls using Wilcoxon rank sum tests and further tested for the independent association between FFAs and disease status with adjustment for age, race and sex using multivariable regression models. We assessed the relationship between FFAs and continuous variables of interest using Spearman correlation and multivariable regression analysis. Levels of FFAs were higher in patients with SLE than controls (0.55 mmol/l (0.37-0.71) vs 0.44 mmol/l (0.32-0.60), P = 0.02). Levels of FFAs remained significantly higher among patients with SLE after adjustment for age, race and sex (P = 0.03) but not after further adjustment for body mass index (P = 0.13). FFA levels did not differ according to the usage of current immunosuppressive medications in univariate and adjusted analysis (all P > 0.05). Among patients with SLE, concentrations of FFAs were higher among those with metabolic syndrome compared to those without (0.66 mmol/l (0.46-0.81) vs 0.52 mmol/l (0.35-0.66), P < 0.001). FFAs were positively correlated with insulin resistance (HOMA) (rho = 0.23, P = 0.004, P adjusted = 0.006) and triglyceride levels (rho = 0.22, P = 0.01, P adjusted = 0.004). FFAs were not associated with inflammatory cytokines (IL-6, TNF-α) (all P > 0.05) but were positively associated with levels of E-selectin (rho = 0.33, P = < 0.001, P adjusted = 0.001) and ICAM-1 (rho = 0.35, P < 0.001, P adjusted = 0.001). FFAs were correlated with coronary artery calcium score (rho = 0.20, P = 0.01) but this was attenuated after adjustment for age, race and sex (P = 0.33). From our study we concluded that FFAs are elevated in patients with SLE, particularly those with metabolic syndrome. FFAs in patients with SLE are not associated with markers of generalized inflammation but are associated with insulin resistance and markers of endothelial activation.
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32 MeSH Terms