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The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

ABSTRACT: 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-? (IFN-?), and autoantibodies in a predominantly African American SLE cohort.We studied 395 patients with SLE and 344 controls. The UBE2L3 rs5754217 polymorphism was genotyped using Taqman primer-probe sets, and IFN-? was measured using a reporter cell assay.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-? 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-? 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.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-? suggests a biological role for this locus in patients with SLE in vivo.

SUBMITTER: Agik S

PROVIDER: S-EPMC3304461 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

Agik Sandra S Franek Beverly S BS Kumar Akaash A AA Kumabe Marissa M Utset Tammy O TO Mikolaitis Rachel A RA Jolly Meenakshi M Niewold Timothy B TB

The Journal of rheumatology 20111101 1

<h4>Objective</h4>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.<h4>Methods</h4>We studied 395 patients with SLE and 344 controls. The UBE2L3 rs5754217 polymorphism was genotyped using ...[more]

PMID: 22045845

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Project description:Immune dysregulation in systemic lupus erythematosus (SLE) contributes to increased disease activity. African-American (AA) SLE patients have an increased prevalence of complications from disease flares and end-organ damage that leads to increased morbidity and early mortality. We previously reported alterations in inflammatory and regulatory immune mediator levels prior to disease flare in European American (EA) SLE patients. In the current study, we assessed baseline and follow-up plasma levels of 52 soluble mediators, including innate, adaptive, chemokine, and TNF superfamily members, in AA SLE patients who developed SELENA-SLEDAI defined flare 6 or 12 weeks after baseline assessment. These patients were compared to themselves during a comparable, clinically stable period (SNF, n = 18), or to demographically matched SLE patients without impending disease flare (NF, n = 13 per group). We observed significant (q < 0.05) alterations in 34 soluble mediators at baseline, with increased levels of both innate (IL-1α and type I interferons [IFN]) and adaptive cytokines (Th1-, Th2-, and Th17-type), as well as IFN-associated chemokines and soluble TNF superfamily members weeks before clinical disease flare. In contrast, stable SLE patients exhibited increased levels of the regulatory mediators IL-10 (q ≤ 0.0045) and TGF-β (q ≤ 0.0004). Because heterogeneous immune pathways were altered prior to clinical disease flare, we developed a soluble mediator score that encapsulates all mediators tested. This score is the sum of all log transformed, standardized soluble mediator levels assessed at baseline (pre-flare), weighted by their Spearman correlation coefficients for association with the SELENA-SLEDAI score at time of concurrent flare. While baseline SELENA-SLEDAI scores were similar between flare vs. NF (p = 0.7214) and SNF (p = 0.5387), the SMS was significantly higher in pre-flare SLE patients (Flare vs NF or SNF, p < 0.0001). By capturing alterations in the balance between inflammatory and regulatory mediators associated with SLE pathogenesis, the soluble mediator score approximates the immune status of SLE patients and provides a robust, predictive gauge of impending disease flare.

Project description:IntroductionSystemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking.MethodsThrough meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry.ResultsAll reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE.ConclusionsAssociation with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.

Project description:Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10?¹²?) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p?=?4 x 10??. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low)?=?2.36, p?=?9e-9), the immunologic criterion (OR(high-low)?=?2.23, p?=?3e-7), and age at diagnosis (OR(high-low)?=?1.45, p?=?0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR?=?1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR?=?0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

Project description:BackgroundHealthcare access, utilization, and quality play critical roles in shaping mortality and morbidity among patients diagnosed with systemic lupus erythematosus (SLE), and yet healthcare access, utilization, and quality can be suboptimal for many people living with SLE. The aim of this qualitative study was to explore the perceived impact of a peer-led, group-based educational intervention (the Chronic Disease Self-Management Program [CDSMP]) on healthcare engagement behaviors among African American women with SLE.MethodsParticipants were recruited from the WELL (Women Empowered to Live with Lupus) study, a behavioral trial of the effectiveness of the CDSMP on African American women diagnosed with SLE. We conducted two waves of qualitative, one-on-one, semi-structured interviews with 24 purposively sampled WELL participants; one interview was conducted before CDSMP participation and one after. Wave 1 interviews explored health service use behaviors at baseline; Wave 2 interviews focused on changes in these behaviors post-intervention and women's perceptions of whether and how the CDSMP shaped these changes. Transcripts were analyzed using thematic analysis methods.ResultsStudy participants perceived the CDSMP to be a valuable resource for supporting two distinct health service use behaviors: communicating with doctors (N = 16 [88.9%]) and managing medication side effects (N = 17 [41.2%]). Women perceived that the CDSMP had the most potent and widespread effects on patients' communication with doctors. Strategies that women believed generated improvements in patient-doctor communication included enhancing preparation for appointments and boosting patient participation during doctor's visits. Women's reported post-CDSMP improvements in health service use behaviors varied by disease severity and depression. Insurance coverage, while not probed directly during baseline interviews, emerged organically as a key factor affecting health service use behaviors; the CDSMP did not seem to improve participants' ability to circumvent insurance-related barriers to accessing care.ConclusionsOur findings suggest that the CDSMP may help enhance healthcare service utilization among African American women with SLE by improving doctor/patient communication and medication side effect management. If future research confirms this conclusion, African American women living with SLE should be encouraged to participate in CDSMP workshops to enhance health service use behaviors.Trial registrationNCT02988661 . Registered 12/07/2016.

Project description:ObjectiveAfrican American patients with systemic lupus erythematosus (SLE) are at high risk for poor outcomes. Both patient characteristics and the severity of the disease may influence physician-patient interactions, which in turn can impact disease outcomes. We aimed to examine whether patient perceptions of interpersonal processes of care (i.e. physician-patient interactions) varied by demographic characteristics, disease activity, and/or depression in African American patients with SLE.MethodsThe Georgians Organized Against Lupus (GOAL) is a cohort drawn from a population-based registry of people with SLE. We conducted a cross-sectional analysis of patient-reported data collected in 2016-17 among 698 African American participants (out of 863 GOAL participants). We assessed physician-patient interactions (communication, patient-centered decision making, and physician interpersonal style) through the Interpersonal Processes of Care survey (IPC-29), disease activity through the Systemic Lupus Activity Questionnaire, and depression through the Patient Health Questionnaire-9. Mean scores of the IPC-29 scales were compared by gender, age and educational attainment with Wilcoxon rank-sum 2-sample test or Kruskal Wallis test. We conducted linear trend test to examine demographic-adjusted scores of IPC across severity of disease activity and depression, and multivariate logistic regression analyses to examine the association of disease activity and depression with suboptimal IPC scores.ResultsOverall, the lowest mean scores were observed for the patient-centered decision making domain, and specifically about how often doctors assessed patients' problems to follow recommendations and treatment among females compared with males (mean scores 3.13 ± 1.42 and 3.64 ± 1.38, respectively; p = 0.015). Mean scores for the assumed socioeconomic level subdomain (how often doctors make assumptions about a patient's socioeconomic level) were worse in individuals aged 18-34 (mean score 1.59 ± 0.94), compared to those aged 35-55 (mean score 1.47 ± 0.94; p = 0.033). Patients with some college or higher educational attainment reported poorer mean scores for most communication and interpersonal style scales than those who reported high-school or less. We found significant linear trends of poorer scores for all communication scales across more severe disease activity and depression symptoms, and poorer scores for all interpersonal style scales across more severe disease activity. Multivariate models revealed that while depression was associated with suboptimal quality of both communication (OR 1.20; 95% CI 1.04-1.39) and interpersonal style (OR 1.12; 95% CI 1.01-1.25), disease activity only increased the odds of suboptimal interpersonal style (OR 1.13; 95% CI 1.03-1.25).ConclusionIn the African American population with SLE, suboptimal interactions with providers may be explained in part by the mental and physical symptoms of the patient, regardless of age, gender and education. In addition to standard of care treatment, SLE patients with more severe disease activity and depression might need provider-based interventions focused on communication and interpersonal style.

Dataset Information

The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

Publications

The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

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