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1.  European Population Substructure Correlates with Systemic Lupus Erythematosus Endophenotypes in North Americans of European Descent 
Genes and immunity  2009;11(6):515-521.
Previous work has demonstrated that northern and southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. Here, 1855 SLE cases of European descent were genotyped for 4965 single nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished northern from southern European ancestry, PC2 differentiated eastern from western European ancestry, and PC3 delineated Ashkenazi Jewish ancestry. Compared to northern European ancestry, southern European ancestry was associated with autoantibody production (OR=1.40, 95% CI 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.
doi:10.1038/gene.2009.80
PMCID: PMC3951966  PMID: 19847193
Systemic lupus erythematosus; epidemiology; population substructure; genetics
2.  Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus 
Nature genetics  2008;40(9):1062-1064.
The TNFAIP3 (tumor necrosis factor alpha–induced protein 3) gene encodes a ubiquitin editing enzyme, A20, that restricts NF-κB–dependent signaling and prevents inflammation. We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry. These findings provide critical links between A20 and the etiology of SLE.
doi:10.1038/ng.202
PMCID: PMC3897246  PMID: 19165919
3.  SNPs in VKORC1 are Risk Factors for Systemic Lupus Erythematosus in Asians 
Arthritis and rheumatism  2013;65(1):211-215.
OBJECTIVE
The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. In a case-control analysis, we investigated whether 33 established and novel single nucleotide polymorphisms (SNP) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis in the general population were risk factors for SLE development among Asians.
METHODS
Patients in the discovery cohort were enrolled in one of two North American SLE cohorts. Patients in the replication cohort were enrolled in one of four Asian or two North American cohorts. SLE cases met American College of Rheumatology classification criteria. We first genotyped 263 Asian SLE and 357 healthy Asian control individuals for 33 SNPs using Luminex multiplex technology in the discovery phase, and then used Taqman and Immunochip assays to examine 5 SNPs in up to an additional 1496 cases and 993 controls in the Replication phase. SLE patients were compared to healthy controls for association with minor alleles in allelic models. Principal components analysis was used to control for intra-Asian ancestry in an analysis of the replication cohort.
RESULTS
Two genetic variants in the gene VKORC1, rs9934438 and rs9923231, were highly significant in both the discovery and replication cohorts: OR(disc) = 2.45 (p=2×10−9), OR(rep) = 1.53 (p=5×10−6) and OR(disc) = 2.40 (p=6×10−9), OR(rep) = 1.53 (p=5×10−6), respectively. These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: rs9934438 OR(adj) = 1.34 (p=0.0029) and rs9923231 OR(adj) = 1.34 (p=0.0032).
CONCLUSION
Genetic variants in VKORC1, involved in vitamin K reduction and associated with DVT, are associated with SLE development in Asians. These results suggest intersecting genetic pathways for the development of SLE and thrombosis.
doi:10.1002/art.37751
PMCID: PMC3670944  PMID: 23124848
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
4.  Gender Differences in Assessment of Obesity in Rheumatoid Arthritis 
Arthritis care & research  2013;65(1):62-70.
Objective
Determine prevalence of obesity and how accurately standard anthropometric measures identify obesity among men and women with RA.
Methods
Dual-energy x-ray absorptiometry (DXA) was performed for 141 persons with RA (56 men, 85 women). Two anthropometric proxies of obesity (body mass index [BMI], waist circumference [WC]) were compared to a DXA-based obesity criterion. Receiver operating characteristic (ROC) curves determined optimal cut-points for each anthropometric measure, relative to DXA. Association of body fat and anthropometric obesity measures with disease status and cardiovascular risk was assessed in multiple regression analyses, controlling for age and glucocorticoid use. All analyses were performed separately for men and women.
Results
20%, 32%, and 44% of women, and 41%, 36%, and 80% of men were classified as obese by BMI, WC, and DXA, respectively. Cut-points were identified for anthropometric measures to better approximate DXA estimates of percent body fat (BMI: women, ≥26.1 kg/m2; men ≥24.7 kg/m2. WC: women, ≥83 cm; men, ≥96 cm). For women and men, higher % fat was associated with poorer RA status. Anthropometric measures were more closely linked to RA status for women, but identified cardiovascular risk for both women and men.
Conclusions
A large percentage of this RA sample was overfat; DXA-defined obesity was twice as common in men than in women. Utility of revised BMI and WC cut-points compared to traditional cut-points remains to be examined in prospective studies, but results suggest that lower, sex-specific cut-points may be warrented to better identify individuals at risk for poor RA and/or cardiovascular outcomes.
doi:10.1002/acr.21810
PMCID: PMC3501549  PMID: 22833513
5.  European Genetic Ancestry is Associated with a Decreased Risk of Lupus Nephritis 
Arthritis and rheumatism  2012;64(10):10.1002/art.34567.
Objective
African Americans, East Asians, and Hispanics with systemic lupus erythematosus (SLE) are more likely to develop renal disease than SLE patients of European descent. We investigated whether European genetic ancestry protects against the development of lupus nephritis and explored genetic and socioeconomic factors that might explain this effect.
Methods
This was a cross-sectional study of 1906 adults with SLE. Participants were genotyped for 126 single nucleotide polymorphisms (SNPs) informative for ancestry. A subset of participants was also genotyped for 80 SNPs in 14 candidate genes for renal disease in SLE. We used logistic regression to test the association between European ancestry and renal disease. Analyses adjusted for continental ancestries, socioeconomic status, and candidate genes.
Results
Participants (n=1906) had on average 62.4% European, 15.8% African, 11.5% East Asian, 6.5% Amerindian, and 3.8% South Asian ancestry. Among participants, 34% (n=656) had renal disease. A 10% increase in European ancestry was associated with a 15% reduction in the odds of having renal disease after adjustment for disease duration and sex (OR 0.85, 95% CI 0.82-0.87, p=1.9 × 10−30). Adjusting for other genetic ancestries, measures of socioeconomic status, or SNPs in genes most associated with renal disease (IRF5 (rs4728142), BLK (rs2736340), STAT4 (rs3024912), ITGAM (rs9937837) and HLA-DRB1*0301 and DRB1*1501, p<0.05) did not substantively alter this relationship.
Conclusion
European ancestry is protective against the development of renal disease in SLE, an effect independent of other genetic ancestries, common risk alleles, and socioeconomic status.
doi:10.1002/art.34567
PMCID: PMC3865923  PMID: 23023776
6.  Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(11):3695-3705.
Objective
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins.
Methods
We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines.
Results
We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.
Conclusion
Our results confirmed the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
doi:10.1002/art.34642
PMCID: PMC3485412  PMID: 22833143
7.  Impact of Genetic Ancestry and Socio-Demographic Status on the Clinical Expression of Systemic Lupus Erythematosus in Amerindian-European Populations 
Arthritis and rheumatism  2012;64(11):3687-3694.
Objective
Amerindian-Europeans, Asians and African-Americans have an excess morbidity from SLE and higher prevalence of lupus nephritis than Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and socio-demographic characteristics and clinical features in a large cohort of Amerindian-European SLE patients.
Methods
A total of 2116 SLE patients of Amerindian-European origin and 4001 SLE patients of European descent with clinical data were used in the study. Genotyping of 253 continental ancestry informative markers was performed on the Illumina platform. The STRUCTURE and ADMIXTURE software were used to determine genetic ancestry of each individual. Correlation between ancestry and socio-demographic and clinical data were analyzed using logistic regression.
Results
The average Amerindian genetic ancestry of 2116 SLE patients was 40.7%. There was an increased risk of having renal involvement (P<0.0001, OR= 3.50 95%CI 2.63-4.63) and an early age of onset with the presence of Amerindian genetic ancestry (P<0.0001). Amerindian ancestry protected against photosensitivity (P<0.0001, OR= 0.58 95%CI 0.44-0.76), oral ulcers (P<0.0001, OR= 0.55 95%CI 0.42-0.72), and serositis (P<0.0001, OR= 0.56 95%CI 0.41-0.75) after adjustment by age, gender and age of onset. However, gender and age of onset had stronger effects on malar rash, discoid rash, arthritis and neurological involvement than genetic ancestry.
Conclusion
In general, genetic Amerindian ancestry correlates with lower socio-demographic status and increases the risk for developing renal involvement and SLE at an earlier age of onset.
doi:10.1002/art.34650
PMCID: PMC3485439  PMID: 22886787
8.  Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression 
PLoS Genetics  2013;9(10):e1003870.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Author Summary
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
doi:10.1371/journal.pgen.1003870
PMCID: PMC3794920  PMID: 24130510
9.  Quality of Care in Systemic Lupus Erythematosus: Application of Quality Measures to Understand Gaps in Care 
Journal of General Internal Medicine  2012;27(10):1326-1333.
ABSTRACT
BACKGROUND
Systemic lupus erythematosus (SLE) affects 1 in 2500 Americans and is associated with significant morbidity and mortality. The recent development of SLE quality measures provides an opportunity to understand gaps in clinical care and to identify modifiable factors associated with variations in quality.
OBJECTIVE
To evaluate performance on SLE quality measures as well as differences in quality of care by demographic, socioeconomic, disease, and health system characteristics.
DESIGN AND PATIENTS
Cross-sectional analysis of data derived from the Lupus Outcomes Study, a prospective, longitudinal study of 814 individuals. Principal data collection was through annual structured telephone surveys between 2009–2010. Data on 13 SLE quality measures was collected. We used regression models to estimate demographic, socioeconomic, disease, and health system characteristics associated with performance on individual and overall quality measures.
OUTCOME MEASURES
Performance on each quality measure and overall performance on all measures for which participants were eligible (pass rate).
RESULTS
Participants were eligible for a mean of five measures (range 2–12). Performance varied from 29 % (assessment of cardiovascular risk factors) to 90 % (sun avoidance counseling). The overall pass rate was 65 % (95 % CI 64 %, 65 %). In unadjusted analyses, younger age, minority race/ethnicity, poverty, shorter disease duration, fewer physician visits, and lack of health insurance, were associated with lower pass rates. Receiving care in public sector managed care organizations was associated with higher pass rates. After adjustment, younger age, having fewer physician visits and lacking health insurance remained significantly associated with lower performance; receiving care in public sector managed care organizations remained associated with higher performance.
CONCLUSIONS
We identified a number of gaps in clinical care for SLE. Factors associated with the health care system, including presence and type of health insurance, were the primary determinants of performance on quality measures in SLE.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-012-2071-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-012-2071-z
PMCID: PMC3445683  PMID: 22588825
systemic lupus erythematosus; studies; outcomes; quality of health care
10.  Frequent Use of the Emergency Department Among Persons with Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(3):401-408.
PURPOSE
To describe characteristics of systemic lupus erythematosus (SLE) patients who are frequent users of the emergency department (ED) and to identify predictors of frequent ED use.
METHODS
Data for this study were derived from the University of California, San Francisco (UCSF) Lupus Outcomes Study (LOS), a large a cohort persons with SLE who undergo annual structured interviews. Participants were categorized into one of three levels of ED utilization: non-users, if they had no visits in the preceding year, occasional users, if they had 1–2 visits and frequent users if they had 3 or more visits. We compared characteristics of the three groups and determined predictors of frequent ED use (≥3 visits) using multivariate logistic regression, adjusting for a variety of potential confounding covariates.
RESULTS
Of 807 study participants, 499 (62%) had no ED visits; 230 (28%) had occasional ED visits (1–2 visits); and 78 (10%) had frequent (≥3 visits) ED visits. Frequent ED users were younger, less likely to be employed, and less likely to have completed college. They also had greater disease activity, worse general health status, and more depressive symptoms. Frequent ED users were more likely to have Medicaid as their principal insurance. In multivariate logistic regression, older age predicted a lower likelihood of frequent ED visits whereas greater disease activity and having Medicaid insurance predicted a higher likelihood of frequent ED visits.
CONCLUSION
In persons with SLE, greater disease activity and Medicaid insurance are associated with more frequent ED use.
doi:10.1002/acr.20107
PMCID: PMC3759153  PMID: 20391487
11.  Cardiovascular Disease and Cognitive Dysfunction in Systemic Lupus Erythematosus 
Arthritis care & research  2012;64(9):1328-1333.
OBJECTIVE
Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE.
METHODS
Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test – Revised (HVLT-R) and the Controlled Oral Word Association Test (COWAT) were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction (MI), stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies (aPL), disease activity, disease duration) associated with cognitive impairment in year seven of the LOS.
RESULTS
The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (OR=2.10, 95% CI 1.3-3.41), hypertension (OR=2.06, 95% CI 1.19-3.56), and a history of stroke (OR=2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (p=0.036).
CONCLUSIONS
These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk.
doi:10.1002/acr.21691
PMCID: PMC3705733  PMID: 22549897
12.  Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations 
Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case–control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.
doi:10.1038/ejhg.2012.277
PMCID: PMC3746253  PMID: 23249952
systemic lupus erythematosus; genetic-association study; Asian; Caucasian
13.  Childhood-Onset Disease Predicts Mortality in an Adult Cohort of Patients with Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(8):1152-1159.
Objective
To examine childhood-onset disease as a predictor of mortality in a cohort of adult patients with systemic lupus erythematosus (SLE).
Methods
Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 957 adult subjects with SLE that includes 98 subjects with childhood-onset SLE. Baseline and follow-up data were obtained via telephone interviews conducted between 2002-2007. The number of deaths during 5 years of follow-up was determined and standardized mortality ratios (SMRs) for the cohort, and across age groups, were calculated. Kaplan-Meier life table analysis was used to compare mortality rates between childhood (defined as SLE diagnosis <18 years) and adult-onset SLE. Multivariate Cox proportional hazard models were used to determine predictors of mortality.
Results
During the median follow-up period of 48 months, 72 deaths (7.5% of subjects) occurred, including 9 (12.5%) among those with childhood-onset SLE. The overall SMR was 2.5 (CI 2.0-3.2). In Kaplan-Meier survival analysis, after adjusting for age, childhood-onset subjects were at increased risk for mortality throughout the follow-up period (p<0.0001). In a multivariate model adjusting for age, disease duration and other covariates, childhood-onset SLE was independently associated with an increased mortality risk (hazard ratio [HR]: 3.1; 95% confidence interval [CI]: 1.3-7.3), as was low socioeconomic status measured by education (HR: 1.9; 95% CI 1.1-3.2) and end stage renal disease (HR: 2.1; 95% CI 1.1-4.0).
Conclusion
Childhood-onset SLE was a strong predictor of mortality in this cohort. Interventions are needed to prevent early mortality in this population.
doi:10.1002/acr.20179
PMCID: PMC3755501  PMID: 20235215
14.  Variable association of reactive intermediate genes with systemic lupus erythematosus (SLE) in populations with different African ancestry 
The Journal of rheumatology  2013;40(6):842-849.
Objective
Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate related genes biological candidates for disease susceptibility. This study analyzed variation in reactive intermediate genes for association with SLE in two populations with African ancestry.
Methods
A total of 244 SNPs from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls) and. Single-marker, haplotype, and two-locus interaction tests were computed for these populations.
Results
The glutathione reductase gene GSR (rs2253409, P=0.0014, OR [95% CI]=1.26 [1.09–1.44]) was the most significant single-SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.23–3.59]) and nitric oxide synthase gene NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [0.44–0.88]) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26 [1.10–1.44]). Haplotype and two-locus interaction analyses also uncovered different loci in each population.
Conclusion
These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
doi:10.3899/jrheum.120989
PMCID: PMC3735344  PMID: 23637325
systemic lupus erythematosus; African Americans; genetic association studies; oxygen compounds; single nucleotide polymorphism
15.  Using the Center for Epidemiologic Studies Depression Scale to Screen for Depression in Systemic Lupus Erythematosus 
Arthritis care & research  2011;63(6):884-890.
Objective
Identifying persons with systemic lupus erythematosus (SLE) at risk for depression would facilitate the identification and treatment of an important comorbidity conferring additional risk for poor outcomes. The purpose of this study was to determine the utility of a brief screening measure, the Center for Epidemiologic Studies Depression Scale (CES-D), in detecting mood disorders in persons with SLE.
Methods
This cross-sectional study examined 150 persons with SLE. Screening cut points were empirically derived using threshold selection methods, and receiver operating characteristic curves were estimated. The empirically derived cut points of the CES-D were used as the screening measures and were compared to other commonly used CES-D cut points in addition to other commonly used methods to screen for depression. Diagnoses of major depressive disorder or other mood disorders were determined using a “gold standard” structured clinical interview.
Results
Of the 150 persons with SLE, 26% of subjects met criteria for any mood disorder and 17% met criteria for major depressive disorder. Optimal threshold estimations suggested a CES-D cut score of 24 and above, which yielded adequate sensitivity and specificity in detecting major depressive disorder (88% and 93%, respectively) and correctly classified 92% of participants. To detect the presence of any mood disorder, a cut score of 20 and above was suggested, yielding sensitivity and specificity of 87% and correctly classifying 87%.
Conclusion
These results suggest the CES-D may be a useful screening measure to identify patients at risk for depression.
doi:10.1002/acr.20447
PMCID: PMC3719846  PMID: 21312347
16.  Role of Community and Individual Characteristics in Physician Visits for Persons With Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(6):888-895.
Objective
To examine the effects of individual and local level socioeconomic status (SES) and health care access characteristics on the number of self-report physician visits for systemic lupus erythematosus (SLE).
Methods
Data derived from 755 adult participants from the 2004 to 2007 Lupus Outcomes Study (LOS) resulted in a sample of 2,926 repeated-measures observations. The outcome measure was the number of physician visits in the prior 12 months. Information on disease activity and manifestations, demographics, health insurance, and specialty of the participants’ main SLE physician was collected through yearly LOS interviews. Local area measures including neighborhood poverty, the number of subspecialists per capita, and hospital market areas were added from secondary data sources. We used a mixed model with repeated measures to estimate the number of physician visits for SLE by SES and health care access characteristics, as well as the extent of concentrated poverty and number of subspecialists per capita in the local community, and whether these relationships varied by specific hospital market area. Multivariate models were adjusted for demographic and health status covariates.
Results
LOS respondents reported a mean ± SD of 11.8 ± 10.7 (range 0–52) physician visits for SLE. After adjustment, having less than a high school education, receiving care in a health maintenance organization, being treated by a generalist, and living in a community of concentrated poverty were associated with a significantly lower number of physician visits for SLE. These relationships varied by hospital market areas.
Conclusion
Beyond health status, the number of physician visits for SLE varies by SES, neighborhood poverty, and characteristics of the health care system.
doi:10.1002/acr.20125
PMCID: PMC3715029  PMID: 20535800
17.  CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B cell signaling and activation 
Nature genetics  2012;44(11):1227-1230.
C-src tyrosine kinase, Csk, physically interacts with the intracellular phosphatase Lyp (PTPN22) and can modify the activation state of downstream Src kinases, such as Lyn, in lymphocytes. We identified an association of Csk with systemic lupus erythematosus (SLE) and refined its location to an intronic polymorphism rs34933034 (OR 1.32, p = 1.04 × 10−9). The risk allele is associated with increased CSK expression and augments inhibitory phosphorylation of Lyn. In carriers of the risk allele, B cell receptor (BCR)-mediated activation of mature B cells, as well as plasma IgM, are increased. Moreover, the fraction of transitional B cells is doubled in the cord blood of carriers of the risk allele compared to non-risk haplotypes due to an expansion of the late transitional cells, a stage targeted by selection mechanisms. This suggests that the Lyp-Csk complex increases susceptibility to lupus at multiple maturation and activation points of B cells.
doi:10.1038/ng.2439
PMCID: PMC3715052  PMID: 23042117
18.  Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4 
PLoS Genetics  2013;9(7):e1003554.
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10−34, OR = 1.43[1.26–1.60]) and rs1234317-T (P = 1.16×10−28, OR = 1.38[1.24–1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
Author Summary
Systemic lupus erythematosus (SLE/lupus) is a complex disease in which the body's immune cells cause inflammation in one or more systems to cause the associated morbidity. Hormones, the environment and genes are all causal contributors to SLE and over the past several years the genetic component of SLE has been firmly established. Several genes which are regulators of the immune system are associated with disease risk. We have established one of these, the tumour-necrosis family superfamily member 4 (TNFSF4) gene, as a lupus susceptibility gene in Northern Europeans. A major obstacle in pinpointing the marker(s) at TNFSF4 which best explain the risk of SLE has been the strong correlation (linkage disequilibrium, LD) between adjacent markers across the TNFSF4 region in this population. To address this, we have typed polymorphisms in several populations in addition to the European groups. The mixed ancestry of these populations gives a different LD pattern than that found in Europeans, presenting a method of pinpointing the section of the TNFSF4 region which results in SLE susceptibility. The Non-European populations have allowed identification of a polymorphism likely to regulate expression of TNFSF4 to increase susceptibility to SLE.
doi:10.1371/journal.pgen.1003554
PMCID: PMC3715547  PMID: 23874208
19.  Cardiovascular and Disease Related Predictors of Depression in SLE 
Arthritis care & research  2011;63(4):542-549.
OBJECTIVE
Depression and cardiovascular disease are common and debilitating comorbidities associated with systemic lupus erythematosus (SLE). In this study, history of cardiovascular events, cardiovascular risk factors and SLE disease related factors were evaluated as longitudinal predictors of depression in a large cohort of patients with SLE.
METHODS
Data derive from 663 adult participants in the 2004-2008 Lupus Outcomes Study, followed for up to 5 annual interviews. Multivariate logistic regression analyses using generalized estimating equations were used to determine predictors of the development of increased depressive symptom severity over a 12 month period (Center for Epidemiological Studies – Depression, CES-D, Score of 23 or greater), yielding 2,224 paired observations. Predictors included sociodemographics, traditional cardiovascular risk factors (reported presence of heart disease, history of stroke or myocardial infarction, hypertension, hypercholesterolemia, diabetes, obesity, smoking status, and family history), and SLE-specific risk factors (glucocorticoid use, renal involvement, disease duration, and disease activity).
RESULTS
Annual incidence of depression was 12% in this cohort. Multivariate predictors of new onset depression included younger age (age 20-39 OR 2.3; 1.3, 3.9; age 40-59 OR 1.8; 1.1, 2.7), Hispanic/ Latino ethnicity (OR 1.8; 1.2, 2.8) having some college education (OR 1.8; 1.1, 3.0), baseline CES-D(OR per point 1.1; 1.1, 1.2), presence of diabetes (OR 1.8; CI 1.1, 2.8), and baseline SLE disease activity (OR 1.2; CI 1.1, 1.4).
CONCLUSION
These results suggest that in addition to known sociodemographic factors, the presence of diabetes and SLE disease activity may play a role in the development of depression in SLE.
doi:10.1002/acr.20426
PMCID: PMC3713607  PMID: 21452266
20.  Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci 
Nature genetics  2008;40(2):204-210.
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (λS = ~30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 × 10−7 < Poverall < 1.6 × 10−23; odds ratio 0.82–1.62)in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 × 10−5) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at ≥9 other loci (P < 2 × 10−7). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.
doi:10.1038/ng.81
PMCID: PMC3712260  PMID: 18204446
21.  Validity of Brief Screening Tools for Cognitive Impairment in Rheumatoid Arthritis and Systemic Lupus Erythematosus 
Arthritis care & research  2012;64(3):448-454.
Objective
To determine the validity of standardized screening assessments of cognitive functioning to detect neuropsychological impairment evaluated using a comprehensive battery in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Methods
This is a cross-sectional study using a combined cohort of 139 persons with SLE and 82 persons with RA. Screening cut points were empirically derived using receiver operating characteristic curves and threshold selection methods. Screening measures included the Hopkins Verbal Learning Test-Revised (HVLT-R) learning and delayed recall indices and phonemic fluency, a composite measure of the 3 cognitive screening tests, and the Perceived Deficits Questionnaire-Short Form (PDQ-SF), a self-report measure of cognitive symptoms. A comprehensive neuropsychological battery was administered as the “gold standard” index of neuropsychological impairment.
Results
Rates of neuropsychological impairment were 27% and 15% for the SLE and RA cohorts, respectively. Optimal threshold estimations were derived for 5 screening techniques. The HVLT-R learning and phonemic fluency indices yielded the greatest sensitivity at 81%. The PDQ-SF yielded the lowest sensitivity at 52%. All measures were significantly associated with neuropsychological impairment after controlling for relevant sociodemographic covariates and depression.
Conclusion
These results suggest that telephone-administered screening techniques may be useful measures to identify persons with neuropsychological impairment. Specifically, measures of phonemic fluency and verbal learning appeared to be most sensitive and least likely to misclassify impaired individuals as cognitively intact. Self-reported questionnaires may have relatively decreased sensitivity compared to standardized interviewer-administered cognitive measures.
doi:10.1002/acr.21566
PMCID: PMC3705711  PMID: 22162414
22.  Evaluation of TRAF6 in a Large Multi-Ancestral Lupus Cohort 
Arthritis and Rheumatism  2012;64(6):1960-1969.
Objective
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Methods
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Results
Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Conclusion
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
doi:10.1002/art.34361
PMCID: PMC3380425  PMID: 22231568
TRAF6; polymorphism; systemic lupus erythematosus
23.  Primary Sjögren’s Syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s Syndrome registry 
Arthritis care & research  2012;64(6):911-918.
Objective
To study the prevalence of extra-glandular manifestations (EGM) in primary Sjögren’s Syndrome (pSS) among participants enrolled in the Sjögren’s International Collaborative Clinical Alliance (SICCA) registry.
Methods
1927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European consensus group (AECG) criteria for pSS, 830 “intermediate” cases who had some objective findings of pSS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities; specific rheumatologic examination findings; and physician confirmed thyroid, liver, kidney disease and lymphoma among SICCA participants.
Results
Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia and hypocomplementemia, frequently occurred among pSS cases, and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among pSS cases. In contrast, the frequency of physician confirmed diagnoses of thyroid, liver and kidney disease, and lymphoma was low and only primary biliary cirrhosis was associated with pSS cases status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status.
Conclusions
Data from the international SICCA registry support the systemic nature of pSS, manifest primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic or other systemic manifestations.
doi:10.1002/acr.21610
PMCID: PMC3595164  PMID: 22238244
24.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
25.  Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2011;71(5):694-699.
Objectives
Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci.
Methods
A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex–gene interaction was further validated using parametric and nonparametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients.
Results
A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P = 4.52×10−8) A significant sex–gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men.
Conclusions
The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.
doi:10.1136/annrheumdis-2011-200385
PMCID: PMC3324666  PMID: 22110124

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