Project description:Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings.
Project description:Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems and varies in severity across different populations. To examine the clinical heterogeneity of SLE, we sought to identify different lupus subtypes within our multi-ethnic cohort using a clustering approach. Additionally, with genome-wide methylation and genotype data generated for our cohort, we applied integrative methods to investigate genetic and epigenetic risk factors. This integrative and computational approach revealed molecular differences associated with phenotypic clusters.
Project description:OBJECTIVE:Systemic lupus erythematosus (SLE), which is associated with increased stroke risk, is more prevalent and often more severe among Blacks, Asians, and Hispanics than Whites. We examined racial/ethnic variation in stroke rates and risks, overall and by hemorrhagic versus ischemic subtype, among SLE patients. METHODS:Within Medicaid (2000-2010), we identified patients aged 18-65 with SLE (? 3 ICD-9 710.0 codes, ? 30days apart) and ?12 months of continuous enrollment. Subjects were followed from index date to first stroke event, death, disenrollment, or end of follow-up. Race/ethnicity-specific annual event rates were calculated for stroke overall and by subtypes (hemorrhagic vs. ischemic). We used Cox proportional hazard models to estimate hazard ratios (HR) of stroke by race/ethnicity, adjusting for comorbidities and the competing risk of death. RESULTS:Of 65,788 SLE patients, 93.1% were female. Racial/ethnic breakdown was 42% Black, 38% White, 16% Hispanic, 3% Asian, and 1% American Indian/Alaska Natives. Mean follow-up was 3.7 ± 3.0years. After multivariable adjustment, Blacks were at increased risk of overall stroke (HR 1.34 [95%CI 1.18-1.53), hemorrhagic stroke (HR 1.42 [1.00-2.01]), and ischemic stroke (HR 1.33 [1.15-1.52]) compared to Whites. Hispanics were at increased risk of overall stroke (HR 1.25 [1.06-1.47)] and hemorrhagic stroke (HR 1.79 [95% CI 1.22-2.61]), but not ischemic stroke, compared to Whites. CONCLUSION:Among SLE patients enrolled in Medicaid, we observed elevated stroke risk (overall and by subtype) among Blacks and Hispanics compared to Whites, suggesting the importance of early recognition and screening for stroke risk factors among Blacks and Hispanics.
Project description:The objective of this study was to determine risk factors predicting seizures and damage caused by seizures in a multi-ethnic systemic lupus erythematosus cohort (PROFILE) that includes systemic lupus erythematosus patients (n = 1295) from five different US institutions. Only patients with seizures after systemic lupus erythematosus diagnosis (incident) were included in the analyses of clinical seizures (80/1295, 6.2%), but all patients (prevalent and incident) were included in the analyses of damage caused by seizures (51/1295, 3.9%). We examined socioeconomic-demographic, clinical, and genetic variables predictive of clinical seizures and damage from seizures by Cox proportional hazard ratios (HR) and 95% confidence intervals (CI). Independent predictors of a shorter time to the occurrence of clinical seizures were younger age (HR = 1.0; 95% CI 0.9-1.0), having Hispanic-Texan ethnicity (HR = 2.7; 95% CI 1.3-5.7) or African-American ethnicity (HR = 1.8; 95% CI 1.0-3.1), and the previous occurrence of a cerebrovascular accident (HR = 3.3; 95% CI 1.6-7.1) or an episode of psychosis (HR = 2.4; 95% CI 1.1-5.0), whereas the previous occurrence of photosensitivity (HR = 0.5; 95% CI 0.3-0.9) was the only independent predictor of a longer time to the occurrence of clinical seizures. Independent predictors of a shorter time to the occurrence of damage caused by seizures were younger age (HR = 1.0; 95% CI 0.9-1.0), male gender (HR = 2.4; 95% CI 1.1-5.4), and the occurrence of a previous cerebrovascular accident (HR = 2.7; 95% CI 1.0-7.0) or an episode of psychosis (HR = 4.7; 95% CI 2.3-9.9). No allele from the candidate genes examined (HLA-DRB1, HLA-DQB1, FCGR2A, FCGR3A, or FCG3B) predicted clinical seizures or damage caused by seizures.
Project description:T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction.A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ?2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007).Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians.
Project description:We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five 'tag' SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P=0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P=0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (?50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.