Promoter Variant of PIK3C3 Is Associated with Autoimmunity against Ro and Sm Epitopes in African-American Lupus Patients

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-α). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34–3.73), P = 2.0 × 10−3]. This autoantibody profile was associated with higher serum IFN-α (P = 7.6 × 10−6). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 × 10−5), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients

Osteopontin Alleles Are Associated with Clinical Characteristics in Systemic Lupus Erythematosus

Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3′ UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR = 3.2, 95% CI = 1.6–6.5, P = 1.0 × 10−3). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR = 2.1, P = 0.023) and hemolytic anemia (OR = 2.6, P = 0.036). These clinical associations with SNPs in the promoter and 3′ UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE

Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus

INTRODUCTION: Systemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE. METHODS: We undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2). RESULTS: SNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10(-4)). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10(-6 )and P = 2.6 × 10(-3 )respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE. CONCLUSIONS: This study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE

Gene-Expression-Guided Selection of Candidate Loci and Molecular Phenotype Analyses Enhance Genetic Discovery in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder characterized by differences in autoantibody profiles, serum cytokines, and clinical manifestations. We have previously conducted a case-case genome-wide association study (GWAS) of SLE patients to detect associations with autoantibody profile and serum interferon alpha (IFN-α). In this study, we used public gene expression data sets to rationally select additional single nucleotide polymorphisms (SNPs) for validation. The top 200 GWAS SNPs were searched in a database which compares genome-wide expression data to genome-wide SNP genotype data in HapMap cell lines. SNPs were chosen for validation if they were associated with differential expression of 15 or more genes at a significance of P<9×10−5. This resulted in 11 SNPs which were genotyped in 453 SLE patients and 418 matched controls. Three SNPs were associated with SLE-associated autoantibodies, and one of these SNPs was also associated with serum IFN-α (P<4.5×10−3 for all). One additional SNP was associated exclusively with serum IFN-α. Case-control analysis was insensitive to these molecular subphenotype associations. This study illustrates the use of gene expression data to rationally select candidate loci in autoimmune disease, and the utility of stratification by molecular phenotypes in the discovery of additional genetic associations in SLE

Assessing readability and comprehension of web-based patient education materials by American Heart Association (AHA) and CardioSmart online platform by American College of Cardiology (ACC): How useful are these websites for patient understanding?

Cardiovascular diseases (CVD) are a leading cause of morbidity &amp; mortality worldwide. Patient education materials help patients understand the disease and its management. Health literacy is an important challenge that may contribute to health inequities and disparities. The National Institute of Health and American Medical Association recommend patient education materials to be ≤6th-grade reading level. Objective: To evaluate readability and comprehension of patient education materials related to CVD, available at the American Heart Association (AHA) &amp; CardioSmart web platform by the American College of Cardiology (ACC) websites. Method: We examined the readability and comprehension of 63 patient education materials (accessed June 2022) using: (a) Flesch Kincaid Readability Ease (FKRE): measures readability (0–100, goal > 70), (b) Flesch Kincaid Grade Level (FKGL) (goal = grade 7). We compared the AHA and ACC scores using descriptive and t-tests. P-value ≤ 0.05 was significant. Results: Sixty-three web pages of patient education materials (AHA 24, ACC 39) were reviewed in June 2022. Mean ± standard deviation (SD) FKRE was 54.9 ± 6.8 for all the web pages. FKRE 50–60 equates to “fairly difficult to read.” Mean ± SD FKGL was 10.0 ± 1.3. AHA patient education materials content was significantly more difficult to read and comprehend, were longer, and had more complex words than ACC patient education materials. Conclusions: CVD-related patient education materials available online through leading national organizations are not congruent with the recommendations from national healthcare organizations. They are not as user-friendly as they can be. Urgent recognition of the gaps and unmet needs are indicated to optimize patient health literacy

Longitudinal Study of Fatigue, Stress, and Depression: Role of Reduction in Stress Toward Improvement in Fatigue

ObjectiveFatigue is common among individuals with systemic lupus erythematosus (SLE), but the causes are not well understood. Our objective was to examine perceived stress and depressive symptoms as predictors of fatigue in SLE.MethodsData from 2 years of the Lupus Outcomes Study (n = 650 patients), obtained through annual structured interviews, were used. Fatigue was measured with the Short Form 36 (SF-36) vitality scale along with a variety of self-report measures of disease, depression, and stress. Multivariate linear regression models examined predictors of changes in fatigue. Model 1 tested the association of time 1 (T1) depression with time 2 (T2) fatigue; model 2 added T1 perceived stress to model 1, and final models added T1-to-T2 decrease in stress. All analyses controlled for T1 fatigue, age, sex, self-report of fibromyalgia, pain, and SLE duration, activity, and damage.ResultsMean ± SD age was 51 ± 12 years, 92% of participants were women, and 68% were white. The mean ± SD SF-36 fatigue score was 55 ± 24. T1 depression significantly predicted T2 fatigue. When T1 stress was added, stress (β = 1.7 [95% confidence interval (95% CI) 1.1, 2.2]; P &lt; 0.0001) significantly predicted T2 fatigue, but depression was no longer significant. The addition of T1-to-T2 decrease in stress was associated with a clinically meaningful decline in fatigue (β = -11.8 [95% CI -15.6, -8.9]; P &lt; 0.0001).ConclusionWhile depressive symptoms initially predicted subsequent fatigue, the effects were mediated by stress. A decrease in stress, in addition, was associated with a clinically meaningful decrease in fatigue. These results suggest that perceived stress plays an important role in SLE fatigue and may be an important focus of interventions for fatigue

Performance and psychometric properties of lupus impact tracker in assessing patient-reported outcomes in pediatric lupus: Report from a pilot study

© The Author(s) 2020. Objective: To evaluate the reliability, validity, feasibility and psychometric performance of the Lupus Impact Tracker (LIT) as a patient reported outcome (PRO) measure tool in pediatric systemic lupus erythematosus (pSLE). Methods: This is a prospective, observational, pilot study where patients aged between 12 and 25 years, fulfilling the 1997 ACR classification criteria for SLE, were enrolled. Over 3 consecutive, routine, clinical visits, the patients completed the LIT alongside the Patient-Reported Outcomes Measurement Information System-Short Forms (PROMIS-SFs), Childhood Health Assessment Questionnaire (CHAQ). Rheumatologists completed the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index. Demographic, clinical and laboratory data were also collected. Results: Of 46 patients enrolled, 38 patients completed 2 visits and 31 completed all 3 visits. Seventy-eight percent were female, 33% African American, 28% Asian, 15% Caucasian and 17% Hispanic. The mean (SD) age was 17.2 (2.7) years, with a mean (SD) disease duration of 4.6 (3.1) years. The mean (SD) SLEDAI-2K at enrollment was 3.54 (2.96). In the 38 patients who completed two or more visits, intra-class correlation coefficient and Cronbach alpha were calculated to be 0.70 and 0.91 respectively, signifying good reliability of LIT. The LIT showed positive correlation with CHAQ-Disability Index and majority of the PROMIS-SFs parameters. Construct validity was established against clinical disease activity (SLEDAI-2K). Conclusion: The preliminary results indicate that the LIT is a reliable and valid instrument to capture PRO in p-SLE. Prospective validation with a larger, multicenter cohort is the next step