scholarly journals The Autoimmune Disease Risk Allele of UBE2L3 in African American Patients with Systemic Lupus Erythematosus: A Recessive Effect Upon Subphenotypes

2011 ◽  
Vol 39 (1) ◽  
pp. 73-78 ◽  
Author(s):  
SANDRA AGIK ◽  
BEVERLY S. FRANEK ◽  
AKAASH A. KUMAR ◽  
MARISSA KUMABE ◽  
TAMMY O. UTSET ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
African American ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Disease Risk ◽  
Case Control ◽  
European Ancestry ◽  
Control Analysis ◽  
Systemic Lupus ◽  
Standard Case

Objective.UBE2L3 is associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis in European ancestry populations, and this locus has not been investigated fully in non-European populations. We studied the UBE2L3 risk allele for association with SLE, interferon-α (IFN-α), and autoantibodies in a predominantly African American SLE cohort.MethodsWe studied 395 patients with SLE and 344 controls. The UBE2L3 rs5754217 polymorphism was genotyped using Taqman primer-probe sets, and IFN-α was measured using a reporter cell assay.Results.The UBE2L3 rs5754217 T allele was strongly enriched in African American patients with anti-La antibodies as compared to controls, and a recessive model was the best fit for this association (OR 2.55, p = 0.0061). Serum IFN-α also demonstrated a recessive association with the rs5754217 genotype in African American patients, and the TT/anti-La-positive patients formed a significantly high IFN-α subgroup (p = 0.0040). Similar nonstatistically significant patterns of association were observed in the European American patients with SLE. Case-control analysis did not show large allele frequency differences, supporting the idea that this allele is most strongly associated with anti-La-positive patients.Conclusion.This pattern of recessive influence within a subgroup of patients may explain why this allele does not produce a strong signal in standard case-control studies, and subphenotypes should be included in future studies of UBE2L3. The interaction we observed between UBE2L3 genotype and autoantibodies upon serum IFN-α suggests a biological role for this locus in patients with SLE in vivo.

Damage accrual related to pregnancies before and after diagnosis of systemic lupus erythematosus: a cross-sectional and nested case-control analysis from a lupus registry

Lupus ◽  
2020 ◽  
Vol 29 (2) ◽  
pp. 176-181
Author(s):  
M Morishita ◽  
K-E Sada ◽  
K Ohashi ◽  
Y Miyawaki ◽  
Y Asano ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Confidence Interval ◽  
Lupus Erythematosus ◽  
Odds Ratio ◽  
Case Control ◽  
Control Analysis ◽  
Systemic Lupus ◽  
Before And After ◽  
Case Control Analysis ◽  
Nested Case Control

Objective The objective of this study was to evaluate the chronic damage associated with pregnancies before and after the diagnosis of systemic lupus erythematosus (SLE). Methods Using childbearing-aged female SLE patient data registered at the Okayama and Showa University Hospitals, a nested case-control analysis was performed to investigate the relationship between pregnancy and chronic damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Results Pregnancy occurred in 22 patients before and 13 patients after the diagnosis of SLE in 104 eligible patients. Live births occurred in 82% (33/40) and 50% (9/18) of the pregnancies before and after the diagnosis of SLE, respectively. After matching age and disease duration, 33 case patients with chronic damage (SDI ≥ 1) and 33 control patients without chronic damage (SDI = 0) were selected. Hypertension was more frequent in cases than in controls (48% vs. 24%, p = 0.041). Pregnancies before and after the diagnosis of SLE were comparable between cases and controls (before the diagnosis: nine case patients and eight control patients; after the diagnosis: three case patients and five control patients; p = 1.00). Even after adjusting for hypertension using multivariate analysis, the pregnancies before and after the diagnosis were not significant predictors for chronic damage (odds ratio = 1.48 (95% confidence interval 0.33–6.65)), p = 0.60 of the pregnancy before the diagnosis; odds ratio = 0.78 (95% confidence interval 0.13–4.74), p = 0.78 of the pregnancy after the diagnosis). Conclusion Pregnancies, either before or after the diagnosis of SLE, did not show any differences in chronic damage. Our results help alleviate fears regarding childbearing in female patients with SLE and their families.

scholarly journals IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus

2011 ◽  
Vol 71 (3) ◽  
pp. 463-469 ◽  
Author(s):  
Timothy B Niewold ◽  
Jennifer A Kelly ◽  
Silvia N Kariuki ◽  
Beverly S Franek ◽  
Akaash A Kumar ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
African American ◽  
Lupus Erythematosus ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
European Ancestry ◽  
Functional Assay ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Genetic Elements

ObjectiveHigh serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.Methods1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.ResultsIn European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR>2.56, p<1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained >70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.ConclusionsThe authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.3 4

scholarly journals Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus

2021 ◽  
pp. annrheumdis-2020-218810
Author(s):  
Latanya N Coke ◽  
Hongxiu Wen ◽  
Mary Comeau ◽  
Mustafa H Ghanem ◽  
Andrew Shih ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Secretion ◽  
Lupus Erythematosus ◽  
Conditional Analysis ◽  
Hek293 Cells ◽  
Enzyme Function ◽  
European Ancestry ◽  
Risk Haplotype ◽  
Systemic Lupus ◽  
Risk Association

ObjectivesTo determine if the polymorphism encoding the Arg206Cys substitution in DNASE1L3 explains the association of the DNASE1L3/PXK gene locus with systemic lupus erythematosus (SLE) and to examine the effect of the Arg206Cys sequence change on DNASE1L3 protein function.MethodsConditional analysis for rs35677470 was performed on cases and controls with European ancestry from the SLE Immunochip study, and genotype and haplotype frequencies were compared. DNASE1L3 protein levels were measured in cells and supernatants of HEK293 cells and monocyte-derived dendritic cells expressing recombinant and endogenous 206Arg and 206Cys protein variants.ResultsConditional analysis on rs35677470 eliminated the SLE risk association signal for lead single-nucleotide polymorphisms (SNPs) rs180977001 and rs73081554, which are found to tag the same risk haplotype as rs35677470. The modest effect sizes of the SLE risk genotypes (heterozygous risk OR=1.14 and homozygous risk allele OR=1.68) suggest some DNASE1L3 endonuclease enzyme function is retained. An SLE protective signal in PXK (lead SNP rs11130643) remained following conditioning on rs35677470. The DNASE1L3 206Cys risk variant maintained enzymatic activity, but secretion of the artificial and endogenous DNASE1L3 206Cys protein was substantially reduced.ConclusionsSLE risk association in the DNASE1L3 locus is dependent on the missense SNP rs35677470, which confers a reduction in DNASE1L3 protein secretion but does not eliminate its DNase enzyme function.

scholarly journals Pesticide exposure and risk of systemic lupus erythematosus in an urban population of predominantly African-American women

Lupus ◽  
2018 ◽  
Vol 27 (13) ◽  
pp. 2129-2134 ◽  
Author(s):  
J N Williams ◽  
S-C Chang ◽  
C Sinnette ◽  
S Malspeis ◽  
C G Parks ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
African American ◽  
African American Women ◽  
Lupus Erythematosus ◽  
Urban Population ◽  
Pesticide Exposure ◽  
Adult Women ◽  
Systemic Lupus ◽  
Community Screening ◽  
American Women

Objective: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. Methods: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. Results: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty-three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28–3.93). Conclusion: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings.

scholarly journals Anthrax Vaccine and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus in the U.S. Military: A Case–Control Study

2016 ◽  
Vol 181 (10) ◽  
pp. 1348-1356 ◽  
Author(s):  
Barbara H. Bardenheier ◽  
Jonathan Duffy ◽  
Susan K. Duderstadt ◽  
Jay B. Higgs ◽  
Michael P. Keith ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Case Control Study ◽  
Case Control ◽  
Systemic Lupus ◽  
Anthrax Vaccine ◽  
Control Study ◽  
The U.S

scholarly journals Clinically diagnosed urticaria and risk of systemic lupus erythematosus in children: A nationwide population-based case-control study

2018 ◽  
Vol 29 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Chien-Hung Lin ◽  
Peir-Haur Hung ◽  
Hsiao-Yun Hu ◽  
Chi-Jung Chung ◽  
Tsung-Hsien Chen ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Case Control Study ◽  
Population Based ◽  
Case Control ◽  
Systemic Lupus ◽  
Control Study

scholarly journals Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis

2018 ◽  
Vol 77 (7) ◽  
pp. 1063-1069 ◽  
Author(s):  
Dag Leonard ◽  
Elisabet Svenungsson ◽  
Johanna Dahlqvist ◽  
Andrei Alexsson ◽  
Lisbeth Ärlestig ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
General Population ◽  
Lupus Erythematosus ◽  
Risk Allele ◽  
Snp Array ◽  
Inflammatory Rheumatic Diseases ◽  
Systemic Lupus ◽  
Increased Risk

ObjectivesPatients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.MethodsPatients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).ResultsWe identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.ConclusionsThe IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

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