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1.  Perivascular Adipose Tissue of the Descending Thoracic Aorta is Associated with Systemic Lupus Erythematosus and Vascular Calcification in Women 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.004.
Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Traditional CVD and SLE-disease related risk factors do not fully account for this increased risk. Perivascular adipose tissue (PVAT) is a visceral adipose depot in close proximity to blood vessels possibly influencing CVD. We hypothesized that women with SLE have an increased volume of descending thoracic aortic PVAT (aPVAT) associated with increased vascular calcification.
Using electron beam computed tomography, we quantified the aPVAT in clinically CVD-free SLE women (n=135) and age-/race-matched healthy controls (HC, n=152). Coronary artery calcification (CAC) and aortic calcification (AC) were quantified using Agatston scores and the aPVAT was quantified using standard Hounsfield Units (HU) for adipose tissue.
Women with SLE had greater median aPVAT (32.2 cm3 vs. HC aPVAT 28.6 cm3, p=0.0071) and greater median AC (26.0 vs HC AC 6.0, p=0.0013) than the healthy control women. Total aPVAT (per 25 cm3) remained significantly associated with SLE after adjusting for CVD risk factors (Odds Ratio 1.74 [95% Confidence Interval: 1.04-2.9], p=0.034), but was attenuated when adjusting for circulating inflammatory markers (p=0.34). In a logistic regression analysis, SLE aPVAT (per 25 cm3) was associated with AC (6.78 [2.0-23], p=0.0019), which remained significant after adjusting for circulating inflammatory markers (p=0.0074), and CAC (2.66 [1.4-5.0], p=0.0028).
Total aPVAT is greater in clinically CVD-free SLE women than in age-/race-matched controls and is associated with calcification in different vascular beds.
PMCID: PMC3831349  PMID: 24125423
atherosclerosis; adipose; systemic lupus erythematosus; calcification
2.  Relation of Carotid Intima-Media Thickness and Plaque With Incident Cardiovascular Events in Women With Systemic Lupus Erythematosus 
The American journal of cardiology  2013;112(7):1025-1032.
Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.
PMCID: PMC3779482  PMID: 23827400
3.  Citrullination within the atherosclerotic plaque: A potential target for the anti-citrullinated protein antibody response in rheumatoid arthritis 
Arthritis and rheumatism  2013;65(7):1719-1724.
Patients with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, an observation not explained by traditional cardiac risk factors and generally limited to those with RA-associated autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies (ACPA). We hypothesized that citrullinated proteins within the atherosclerotic plaque can be targeted by ACPA, forming stimulatory immune complexes which propagate the progression of atherosclerosis.
Methods and Results
Protein lysates prepared from atherosclerotic segments of human aorta were investigated for the presence of citrulline-modified proteins and specifically citrullinated fibrinogen (cFb) by immunoprecipitation and/or immunoblotting followed by mass spectrometry. Immunohistochemistry was performed in coronary artery plaques for the presence of citrullinated proteins and the PAD4 enzyme. Levels of anti-cyclic citrullinated peptide (CCP), anti-citrullinated vimentin (cVim), and anti-cFb antibodies were measured in 134 women with seropositive RA previously characterized for the presence of subclinical atherosclerosis by electron beam CT scan (EBCT). Western analysis of atherosclerotic plaque lysates demonstrated several citrullinated proteins and the presence of cFb was confirmed by immunoprecipitation, and mass spectroscopy. Immunohistochemistry demonstrated co-localization of citrullinated proteins and the PAD4 enzyme within the coronary artery plaque. In age-adjusted regression models, antibodies targeting cFb and cit-vimentin, but not CCP2, were associated with an increased aortic plaque burden.
Citrullinated proteins are prevalent within the atherosclerotic plaque, and certain ACPAs are associated with atherosclerotic burden. These observations suggest that targeting of citrullinated epitopes, specifically cFb, within the atherosclerotic plaque could provide a mechanism for accelerated atherosclerosis observed in patients with RA.
PMCID: PMC3731137  PMID: 23553485
4.  Erythrocyte C3d and C4d for Monitoring Disease Activity in Systemic Lupus Erythematosus 
Arthritis and rheumatism  2010;62(3):837-844.
Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE.
The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).
At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and E-C4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti–double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA–SLEDAI. In a multivariable analysis, E-C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA–SLEDAI.
Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.
PMCID: PMC2917974  PMID: 20187154
5.  C-reactive Protein and Coronary Artery Calcium in Asymptomatic Women with Systemic Lupus Erythematosus or Rheumatoid Arthritis 
The American journal of cardiology  2008;102(6):755-760.
Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. We compared the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, RA, and healthy controls without diabetes mellitus or history of myocardial infarct, angina pectoris or stroke, and investigated its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. Both female patient groups had similar prevalence and extent of CAC as well as a significant increased odds of having any CAC (odds ratio 1.87, 95% CI 1.09-3.21) and more extensive CAC (odds ratio 4.04, 95% CI 1.42-11.56 for CAC score>100) when compared to healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC when compared to controls. In conclusion, asymptomatic and non-diabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC when compared to age- and race-matched healthy controls. The increased odds for coronary artery calcium may in part result from higher levels of inflammation and endothelial activation in these patients.
PMCID: PMC2563802  PMID: 18774002
6.  Biomarkers in systemic lupus erythematosus: challenges and prospects for the future 
The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.
PMCID: PMC3728979  PMID: 23904865
biomarker; lupus; systemic lupus erythematosus; SLE
7.  Association Between Depression and Vascular Disease in Systemic Lupus Erythematosus 
The Journal of rheumatology  2011;39(2):262-268.
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with increased prevalence of cardiovascular disease (CVD) and depression. Although depression may contribute to CVD risk in population-based studies, its influence on cardiovascular morbidity in SLE has not been evaluated. We evaluated the association between depression and vascular disease in SLE.
A cross-sectional study was conducted from 2002–2005 in 161 women with SLE and without CVD. The primary outcome measure was a composite vascular disease marker consisting of the presence of coronary artery calcium and/or carotid artery plaque.
In total, 101 women met criteria for vascular disease. In unadjusted analyses, several traditional cardiovascular risk factors, inflammatory markers, adiposity, SLE disease-related factors, and depression were associated with vascular disease. In the final multivariable model, the psychological variable depression was associated with nearly 4-fold higher odds for vascular disease (OR 3.85, 95% CI 1.37, 10.87) when adjusted for other risk factors of age, lower education level, hypertensive status, waist-hip ratio, and C-reactive protein.
In SLE, depression is independently associated with vascular disease, along with physical factors.
PMCID: PMC3632335  PMID: 22174200
8.  Genome-Wide Association Study of Antiphospholipid Antibodies 
Autoimmune Diseases  2013;2013:761046.
Background. The persistent presence of antiphospholipid antibodies (APA) may lead to the development of primary or secondary antiphospholipid syndrome. Although the genetic basis of APA has been suggested, the identity of the underlying genes is largely unknown. In this study, we have performed a genome-wide association study (GWAS) in an effort to identify susceptibility loci/genes for three main APA: anticardiolipin antibodies (ACL), lupus anticoagulant (LAC), and anti-β2 glycoprotein I antibodies (anti-β2GPI). Methods. DNA samples were genotyped using the Affymetrix 6.0 array containing 906,600 single-nucleotide polymorphisms (SNPs). Association of SNPs with the antibody status (positive/negative) was tested using logistic regression under the additive model. Results. We have identified a number of suggestive novel loci with P < E − 05. Although they do not meet the conservative threshold of genome-wide significance, many of the suggestive loci are potential candidates for the production of APA. We have replicated the previously reported associations of HLA genes and APOH with APA but these were not the top loci. Conclusions. We have identified a number of suggestive novel loci for APA that will stimulate follow-up studies in independent and larger samples to replicate our findings.
PMCID: PMC3595708  PMID: 23509613
9.  Hydroxychloroquine and Glycemia in Women with Rheumatoid Arthritis and Systemic Lupus Erythematosus 
The Journal of rheumatology  2010;37(6):1136-1142.
To determine the relationship between current hydroxychloroquine (HCQ) use and 2 indicators of glycemic control, fasting glucose and insulin sensitivity, in nondiabetic women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
Nondiabetic women with SLE (n = 149) or RA (n = 177) recruited between 2000 and 2005 for a cross-sectional evaluation of cardiovascular risk factors were characterized by HCQ usage status. Unadjusted and multivariately adjusted mean fasting glucose, median insulin, and insulin resistance [assessed by the homeostasis model assessment (HOMA-IR) calculation] were compared among HCQ users and nonusers for disease-specific groups.
More women with SLE were taking HCQ than those with RA (48% vs 18%; p < 0.0001; mean dose ~ 400 mg vs ~ 200 mg). For women with SLE or RA, after adjustment for age, waist circumference, disease duration, prednisone dosage, C-reactive protein, menopausal status, nonsteroidal antiinflammatory drugs, and disease-specific indicators, serum glucose was lower in HCQ users than in nonusers (SLE: 85.9 vs 89.3 mg/dl, p = 0.04; RA: 82.5 vs 86.6 mg/dl, p = 0.05). In women with SLE, HCQ use also was associated with lower logHOMA-IR (0.97 vs 1.12, p = 0.09); in those with RA, no differences in logHOMA-IR were seen. HCQ usage was not associated with fasting insulin levels in either patient group.
HCQ use was associated with lower fasting glucose in women with SLE or RA and also lower logHOMA-IR in the SLE group. The use of HCQ may be beneficial for reducing cardiovascu lar risk by improving glycemic control in these patients.
PMCID: PMC3457696  PMID: 20436082
10.  Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus (SLE) 
The Journal of rheumatology  2011;38(4):652-657.
Two F2 functional polymorphisms, rs1799963 (G20210A) and rs3136516 (A19911G), are known to be associated with elevated prothrombin (encoded by F2) levels/activity and thrombosis risk. Since systemic lupus erythematosus (SLE) patients have high risk of thrombosis and accelerated atherosclerosis and also high prevalence of anti-prothrombin antibodies, we hypothesized that these two F2 polymorphisms could affect SLE risk.
We investigated these polymorphisms in 627 women with SLE (84% Caucasian Americans, 16% African Americans) and 657 female controls (78% Caucasian Americans, 22% African Americans).
While the rs1799963 A allele was almost absent in African Americans, it was present at ~2% frequency in Caucasian Americans and showed no significant association with SLE. The rs3136516 G allele frequency was significantly higher in Caucasian SLE cases than controls (48.4% vs. 43.7%) with a covariate-adjusted odds ratio (OR) of 1.22 (95%CI: 1.03–1.46; P = 0.023). The association was replicated in African Americans (rs3136516 G allele frequency: 91.2% in cases vs. 82.2% in controls) with an adjusted OR of 1.96 (95%CI: 1.08–3.58; P = 0.022). Stratification of Caucasian SLE patients based on the presence or absence of cardiac and vascular events (CVE) revealed stronger association with the CVE-positive SLE subgroup than the CVE-negative SLE subgroup (OR: 1.42 vs. 1.20). Prothrombin activity measurements in a subset of SLE cases demonstrated higher activity in the carriers of the rs3136516 G allele.
Our results suggest a potential role for prothrombin and the crosstalk between hemostatic and immune/inflammatory systems in SLE and SLE-associated cardiovascular events, which warrant further investigation in independent samples.
PMCID: PMC3073870  PMID: 21239755
lupus; prothrombin; F2; polymorphism; A19911G; G20210A
11.  Neuropsychiatric Systemic Lupus Erythematosus 
Current Neuropharmacology  2011;9(3):449-457.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is the least understood, yet perhaps the most prevalent manifestation of lupus. The pathogenesis of NPSLE is multifactorial and involves various inflammatory cytokines, autoantibodies, and immune complexes resulting in vasculopathic, cytotoxic and autoantibody-mediated neuronal injury. The management of NPSLE is multimodal and has not been subjected to rigorous study. Different treatment regimens include nonsteroidal anti-inflammatory drugs, anticoagulation, and immunosuppressives such as cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate. For refractory NPSLE, intravenous immunoglobulin (IVIG), plasmapheresis, and rituximab have been used. Adjunctive symptomatic treatment complements these therapies by targeting mood disorders, psychosis, cognitive impairment, seizures or headaches. Several new biological agents are being tested including Belimumab, a human monoclonal antibody that targets B lymphocyte stimulator. This review focuses on the pathophysiology, treatment, and new potential therapies for neuropsychiatric manifestations of systemic lupus erythematosus.
PMCID: PMC3151599  PMID: 22379459
SLE; neuropsychiatric lupus; immunosuppression; autoimmunity; autoantibody.
13.  Association analysis of PON2 genetic variants with serum paraoxonase activity and systemic lupus erythematosus 
BMC Medical Genetics  2011;12:7.
Low serum paraoxonase (PON) activity is associated with the risk of coronary artery disease, diabetes and systemic lupus erythematosus (SLE). Our prior studies have shown that the PON1/rs662 (p.Gln192Arg), PON1/rs854560 (p.Leu55Met), PON3/rs17884563 and PON3/rs740264 SNPs (single nucleotide polymorphisms) significantly affect serum PON activity. Since PON1, PON2 and PON3 share high degree of structural and functional properties, in this study, we examined the role of PON2 genetic variation on serum PON activity, risk of SLE and SLE-related clinical manifestations in a Caucasian case-control sample.
PON2 SNPs were selected from HapMap and SeattleSNPs databases by including at least one tagSNP from each bin defined in these resources. A total of nineteen PON2 SNPs were successfully genotyped in 411 SLE cases and 511 healthy controls using pyrosequencing, restriction fragment length polymorphism (RFLP) or TaqMan allelic discrimination methods.
Our pair-wise linkage disequilibrium (LD) analysis, using an r2 cutoff of 0.7, identified 14 PON2 tagSNPs that captured all 19 PON2 variants in our sample, 12 of which were not in high LD with known PON1 and PON3 SNP modifiers of PON activity. Stepwise regression analysis of PON activity, including the known modifiers, identified five PON2 SNPs [rs6954345 (p.Ser311Cys), rs13306702, rs987539, rs11982486, and rs4729189; P = 0.005 to 2.1 × 10-6] that were significantly associated with PON activity. We found no association of PON2 SNPs with SLE risk but modest associations were observed with lupus nephritis (rs11981433, rs17876205, rs17876183) and immunologic disorder (rs11981433) in SLE patients (P = 0.013 to 0.042).
Our data indicate that PON2 genetic variants significantly affect variation in serum PON activity and have modest effects on risk of lupus nephritis and SLE-related immunologic disorder.
PMCID: PMC3030528  PMID: 21223581
14.  Lymphocyte-Bound Complement Activation Products as Biomarkers for Diagnosis of Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is frequently misdiagnosed due to the lack of definitive diagnostic tests. The purpose of this study was to determine specifically whether complement activation products (CAP) are deposited on lymphocytes of SLE patients and whether lymphocyte-bound CAP (LB-CAP) may serve as novel biomarkers for the diagnosis of SLE. We conducted a cross-sectional study of 224 patients with SLE, 179 patients with other diseases, and 114 healthy controls. LB-CAP on peripheral blood lymphocytes was measured by flow cytometry. Diagnostic utility of LB-CAP was determined by receiver operating characteristic (ROC) analysis. Significantly elevated levels of C4d and C3d were detected specifically on T and B lymphocytes (designated T-C4d, T-C3d, B-C4d, and B-C3d) of SLE patients. As diagnostic tools, T-C4d and B-C4d, respectively, were 56% sensitive/80% specific and 60% sensitive/82% specific in differentiating SLE from other diseases. Moreover, compared with measurement of anti-dsDNA, serum C3, or serum C4, measurement of T-C4d/B-C4d was significantly more sensitive in identifying SLE patients during a single clinic visit. This is the first investigation of lymphocytes bearing complement activation products in human disease. T-C4d and B-C4d have high diagnostic sensitivity and specificity for SLE and may have added value to current laboratory tests for SLE diagnosis.
PMCID: PMC2790176  PMID: 20161444
systemic lupus erythematosus; SLE; lupus; complement; biomarker
15.  Association between C-reactive Protein and Depressive Symptoms in Women with Rheumatoid Arthritis 
Biological psychology  2009;81(2):131-134.
Converging lines of evidence support an association between systemic inflammation and depressive symptoms. Neuroimmune pathways may account for the high prevalence of depression in individuals with inflammatory conditions such as rheumatoid arthritis (RA). However, this relationship is complicated by factors linked to both inflammatory disease activity and mood, such as pain and physical disability. The goal of this cross-sectional study was to examine the relationship between C-reactive protein (CRP) and depressive symptoms among 173 women with RA. Somatic symptoms of depression and circulating CRP were significantly associated in regression analyses adjusted for body mass index (β= .19, p < 0.05), but this relationship was attenuated when pain and disability were included as covariates (β= .09, p = 0.24). CRP was not significantly associated with negative mood symptoms of depression. Findings suggest that depression in the context of RA may result from the overlap of somatic depressive and RA symptoms rather than neuroimmune pathways.
PMCID: PMC2680764  PMID: 19428978
Rheumatoid arthritis; Autoimmune disorders; Inflammation; C-reactive protein; Depression
16.  Association between depression and coronary artery calcification in women with systemic lupus erythematosus 
Rheumatology (Oxford, England)  2009;48(5):576-581.
Objectives. To determine the associations between depression, cardiovascular risk factors and coronary artery calcification (CAC) in women with SLE and controls.
Methods. CAC was measured using electron-beam CT (EBCT). Traditional, inflammatory and lupus-related risk factors as well as depressive symptoms (Center for Epidemiologic Studies Depression Scale—CES-D) were measured at a single study visit in 161 women with SLE and 161 age- and race frequency-matched female healthy controls.
Results. Women with SLE reported more depressive symptoms than controls, with 27% of SLE and 15% of controls having CES-D scores suggestive of clinical depression. SLE women were more likely to have CAC, as well as more severe CAC compared with controls. Among the SLE women, depression was associated with greater than 2-fold odds of having any CAC [odds ratio (OR) 2.48; 95% CI 1.05, 5.87; P = 0.04], independent of traditional risk factors (age, hypertension and triglycerides) and inflammatory markers. However, when BMI was included among the covariates, the association between depression and CAC was attenuated, indicating the potential mediating role of BMI. Depression was not a risk factor for CAC in controls.
Conclusions. In women with SLE, depression was associated with CAC. This association was mediated by BMI. Depression and adiposity may add to the inflammatory burden of SLE, thus contributing to cardiovascular disease risk.
PMCID: PMC2669765  PMID: 19286698
Systemic lupus erythematosus; Calcified tissue; Cardiovascular; Depression; CT scanning; Adipose tissue; Psychosocial factors; Risk factors; Inflammation
17.  Differences in Subclinical Cardiovascular Disease between African American and Caucasian Women with Systemic Lupus Erythematosus 
Racial differences exist in disease rates and mortality in both cardiovascular disease (CVD) and Systemic Lupus Erythematosus (SLE). The objective of this cross-sectional study was to compare the frequency of and risk factors for subclinical CVD in African-American (AA) and Caucasian women with SLE and no prior CVD events.
Traditional CVD risk factors and SLE-related factors were assessed in 309 SLE women. Subclinical CVD was assessed by carotid ultrasound to measure intima-medial thickness (IMT) and plaque, and electron beam computed tomography (EBCT) to measure coronary artery calcium (CAC).
AA had less education, higher body mass index, blood pressure, lipoprotein(a), CRP, fibrinogen, and ESR, but lower albumin; more and longer duration of corticosteroid use; higher SLE disease activity and damage; and more had dsDNA antibodies compared to Caucasian women, after adjustment for age and study-site. More AA had carotid plaque (adjusted OR 1.94, 95%CI 1.03, 3.65) and higher carotid IMT (0.620 vs. 0.605mm, p=0.07) compared with Caucasians, but similar CAC. Multivariate analysis included risk factor variables significantly different between the racial groups and associated with plaque: blood pressure, current corticosteroid use, SLE disease activity and damage. All factors contributed, but no individual risk factor fully accounted for the association between race and plaque.
In conclusion, the presence of carotid plaque was higher in AA compared with Caucasian women with SLE, in contrast to studies of non-SLE subjects, where AA have similar or less plaque than Caucasians. A combination of SLE-related and traditional CVD risk factors explained the racial difference in plaque burden.
PMCID: PMC2674850  PMID: 19138649
Systemic Lupus Erythematosus; Race; Cardiovascular Disease
18.  APOH Promoter Polymorphisms in Relation to Lupus and Lupus-Related Phenotypes 
The Journal of rheumatology  2009;36(2):315-322.
Sequence variation in gene promoters is often associated with disease risk. In this study, we tested the hypothesis that common promoter variation in the APOH gene (encoding for β2-glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort.
We used a case-control design and genotyped 345 SLE women and 454 healthy control women for 8 APOH promoter single nucleotide polymorphisms (SNPs) (−1284C>G, −1219G>A, −1190G>C, −759 A>G, − 700C>A, −643T>C, −38G>A, and −32C>A). Association analyses were performed on single SNPs and haplotypes. Haplotype analyses were performed using EH (Estimate Haplotype-frequencies) and Haploview programs. In vitro reporter gene assay was performed in COS-1 cells. Electrophoretic mobility shift assay (EMSA) was performed using HepG2 nuclear cells.
Overall haplotype distribution of the APOH promoter SNPs was significantly different between cases and controls (P = 0.009). The −643C allele was found to be protective against carotid plaque formation (adjusted OR = 0.37, P = 0.013) among SLE patients. The −643C allele was associated with a ~ 2-fold decrease in promoter activity as compared to wild-type −643T allele (mean ± standard deviation: 3.94 ± 0.05 vs. 6.99 ± 0.68, P = 0.016). EMSA showed that the −643T>C SNP harbors a binding site for a nuclear factor. The −1219G>A SNP showed a significant association with the risk of lupus nephritis (age-adjusted OR = 0.36, P = 0.016).
Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.
PMCID: PMC2667221  PMID: 19132787
APOH; β2-glycoprotein I; promoter; SLE; lupus; polymorphism
19.  Do Carotid Artery Diameters Manifest Early Evidence of Atherosclerosis in Women with Rheumatoid Arthritis? 
Journal of Women's Health  2009;18(1):21-29.
Given the high incidence of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA), we examined the associations between RA diagnosis and characteristics and evidence of carotid atherosclerosis. We take a unique approach by evaluating lumen and interadventitial diameters in addition to intima-media thickness and plaque.
Ninety-three women with RA were matched with 93 healthy women by age, race, and menopause status. In cross-sectional analyses, we compared common carotid artery measures between groups and examined their relationships with measures of RA severity and activity.
Mean age was 53.3 years, and median RA duration was 14 years. Lumen diameter in patients was significantly greater than in healthy women (5.50 vs. 5.19 mm, p < 0.001), as was interadventitial diameter (6.92 vs. 6.61 mm, p < 0.001). Having RA also was independently associated with greater lumen (β = 0.256, p < 0.01) and interadventitial (β = 0.261, p < 0.01) diameters, after controlling for cardiovascular risk factors and intima-media thickness. Carotid intima-media thickness (0.70 vs. 0.71 mm) was similar, and the prevalence of carotid plaque in patients (21%) was higher but not statistically different from healthy women (15%). In patients with RA, we found positive associations between methotrexate dose and interadventitial diameter, between hypothyroidism and intima-media thickness, and between hypothyroidism and soluble endothelial adhesion molecule and plaque, independent of cardiovascular risk factors.
Women with RA have increased carotid artery diameters compared with healthy women. This may reflect premature vascular aging and may be an early indicator of increased cardiovascular risk.
PMCID: PMC2897697  PMID: 19105681
20.  Genetic Variation in the C-Reactive Protein (CRP) Gene may be Associated with the Risk of Systemic Lupus Erythematosus and CRP Levels 
The Journal of rheumatology  2008;35(11):2171-2178.
The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, two SNPs in the CRP gene (+838, +2043) have been shown to be associated with CRP levels and/or SLE risk in a British family-based cohort. The current study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the impact of three additional CRP tagSNPs (-861, -390, +90) on SLE risk and serum CRP levels.
DNA from 337 white women who met the ACR criteria for definite (n = 324) or probable (n = 13) SLE and 448 white female healthy controls was genotyped for five CRP tagSNPs (-861, -390, +90, +838, +2043). Genotyping was performed using PCR-RFLP, pyrosequencing or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the χ2 distribution, Z-test, Fisher's exact test and ANOVA. Haplotype analysis was performed using EH software and haplo.stats package in R 2.1.2.
While none of the SNPs were found to be associated with SLE risk individually, there was an association with the five-SNP haplotypes (p<0.000001). Three SNPs (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes.
Our data suggests that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.
PMCID: PMC2582591  PMID: 18793001
21.  Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus 
PLoS Genetics  2008;4(5):e1000084.
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r2 = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10−16). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10−19), nephritis (MAF = 34.3%, OR = 1.80, p<10−11), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10−13). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10−4 in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
Author Summary
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the STAT4 gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
PMCID: PMC2377340  PMID: 18516230

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