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1.  Risk Factors in the Progression of Subclinical Atherosclerosis in Women with Systemic Lupus Erythematosus 
Arthritis care & research  2014;66(8):1177-1185.
To investigate risk factors in the subclinical atherosclerosis progression as measured by coronary artery calcium (CAC) and aorta calcium (AC) in women with Systemic Lupus Erythematosus (SLE) (cases) and in comparison with a control population.
A cohort of 149 cases and 124 controls participated in the Study of Lupus Vascular and Bone Long-term Endpoints (SOLVABLE). Demographic information, cardiovascular and SLE risk factors, and laboratory assessments were collected at an initial visit. CAC and AC were measured by electron beam computed tomography (CT) or multi-detector CT at an initial and a follow-up visit. Logistic regression models were used to identify predictors of progression in CAC and AC; multivariate models were adjusted for age, hypertension, and total cholesterol/HDL ratio.
Higher modified ACR/SLICC-DI (OR 2.15, 95%CI 1.33–3.57), use of a corticosteroid (OR 2.93, 95%CI 1.14–7.86), and use of aspirin (OR 4.23, 95%CI 1.53–11.74) were associated with CAC progression in multivariate models. Presence of SLE (OR 2.64, 95%CI 1.26–5.72), lower C3 (OR 0.54, 95%CI 0.33–0.87), lower C4 (OR 0.49, 95% CI 0.27–0.86), use of a corticosteroid (OR 2.73, 95%CI 1.03–7.64), higher corticosteroid dose (OR 1.77, 95%CI 1.12–3.00), higher lipoprotein(a) (OR 1.80, 95%CI 1.11–2.98), higher homocysteine (OR 2.06, 95%CI 1.06–4.29) were associated with AC progression in multivariate models.
Higher disease damage at the first study visit, as measured by the modified ACR/SLICC-DI, may predict increased risk in CAC progression, whereas higher disease activity at the first study visit, as measured by hypocomplementemia and use of corticosteroids, may predict increased risk in AC progression.
PMCID: PMC4069201  PMID: 24376005
2.  FcγRIIIa SNPs and haplotypes affect human IgG binding and association with lupus nephritis in African Americans 
To investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
PMCID: PMC4069204  PMID: 24782186
3.  Lupus risk variants in the PXK locus alter B-cell receptor internalization 
Frontiers in Genetics  2015;5:450.
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
4.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
PMCID: PMC3855611  PMID: 23303389
5.  Dialogue: what can we learn about the relationship between systemic lupus erythematosus and haematological malignancies from linking disease registries? 
Lupus Science & Medicine  2014;1(1):e000068.
PMCID: PMC4276294  PMID: 25553253
Systemic Lupus Erythematosus; Treatment; Disease Activity
6.  A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus 
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes, with pathogenesis of thrombosis.
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64 ancestry-informative markers (AIMs). We first analyzed association with arterial and venous thrombosis in the combined population via logistic regression, adjusting for top principal components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to meta-analysis (after stratification by ethnicity and study population) to confirm the association and to test for study population or ethnicity effects.
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was significantly associated with arterial thrombosis (logistic P = 6.4 × 10−5, false discovery rate P = 0.0044). Two additional SNPs in TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval 1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the effect was most significant among African Americans (OR 2.42, P = 3.5 × 10−4) and European Americans (OR 3.47, P = 0.024).
TLR2 gene variation is associated with thrombosis in SLE, particularly among African Americans and European Americans. There was no evidence of association among Hispanics, and results in Asian Americans were limited due to insufficient sample size. These results may help elucidate the pathogenesis of this important clinical manifestation.
PMCID: PMC4269184  PMID: 24578102
7.  Major Pathogenic Steps in Human Lupus Can be Effectively Suppressed by Nucleosomal Histone Peptide Epitope-Induced Regulatory Immunity 
Clinical immunology (Orlando, Fla.)  2013;149(3):10.1016/j.clim.2013.08.008.
Low-dose tolerance therapy with nucleosomal histone peptide epitopes blocks lupus disease in mouse models, but effect in humans is unknown. Herein, we found that CD4+CD25highFoxP3+ or CD4+CD45RA+FoxP3low T-cells, and CD8+CD25+FoxP3+ T-cells were all induced durably in PBMCs from inactive lupus patients and healthy subjects by the histone peptide/s themselves, but in active lupus, dexamethasone or hydroxychloroquine unmasked Treg-induction by the peptides. The peptide-induced Treg depended on TGFβ/ALK-5/ pSmad 2/3 signaling, and they expressed TGF-β precursor LAP. Lupus patients’ sera did not inhibit Treg induction. The peptide epitope-induced T cells markedly suppressed type I IFN related gene expression in lupus PBMC. Finally, the peptide epitopes suppressed pathogenic autoantibody production by PBMC from active lupus patients to baseline levels by additional mechanisms besides Treg induction, and as potently as anti-IL6 antibody. Thus, low-dose histone peptide epitopes block pathogenic autoimmune response in human lupus by multiple mechanisms to restore a stable immunoregulatory state.
PMCID: PMC3849335  PMID: 24211843
Systemic Lupus Erythematosus; Human, T cells; Peptide epitopes; Tolerance; Autoimmunity
8.  Non-Lymphoma Hematological Malignancies in Systemic Lupus Erythematosus 
Oncology  2013;85(4):10.1159/000350165.
To describe non-lymphoma hematological malignancies in SLE.
A large SLE cohort was linked to cancer registries. We examined the types of non-lymphoma hematological cancers.
In 16, 409 patients, 115 hematological cancers (including myelodysplastic syndrome) occurred. Among these, 33 were non-lymphoma. Of the 33 non-lymphoma cases, 13 were of lymphoid lineage: multiple myeloma (N=5), plasmacytoma (N=3), B-cell chronic lymphocytic leukemia, B-CLL (N=3), precursor cell lymphoblastic leukemia (N=1), and unspecified lymphoid leukemia (N=1). The remaining 20 cases were of myeloid lineage: myelodysplastic syndrome, MDS (N=7), acute myeloid leukemia, AML (N=7), chronic myeloid leukemia, CML (N=2), and 4 unspecified leukemias. Most of these malignancies occurred in female Caucasians, except for plasma cell neoplasms (4/5 multiple myeloma and 1/3 plasmacytoma cases occurred in blacks).
In this large SLE cohort, the most common non-lymphoma hematological malignancies were myeloid types (MDS and AML). This contrasts to the general population, where lymphoid types are 1.7 times more common than myeloid non-lymphoma hematological malignancies. Most (80%) multiple myeloma cases occurred in blacks, which requires further investigation.
PMCID: PMC3880772  PMID: 24107608
Systemic lupus erythematosus; malignancy; cancer
9.  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
10.  Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements 
Lupus Science & Medicine  2014;1(1):e000056.
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).
CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
PMCID: PMC4225732  PMID: 25396070
Autoimmune Diseases; Systemic Lupus Erythematosus; Autoantibodies
14.  Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis 
Arthritis Research & Therapy  2014;16(4):R147.
Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes’ expression is related to atherosclerosis in SLE.
Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.
Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.
Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis.
PMCID: PMC4227297  PMID: 25011540
15.  Allelic Dependent Expression of an Activating Fc receptor on B cells Enhances Humoral Immune Responses 
Science translational medicine  2013;5(216):216ra175.
B cells are pivotal regulators of acquired immune responses and recent work in both experimental murine models and humans has demonstrated that subtle changes in the regulation of B cell function can significantly alter immunological responses. The balance of negative and positive signals in maintaining an appropriate B cell activation threshold is critical in B lymphocyte immune tolerance and autoreactivity. FcγRIIb (CD32B), the only recognized Fcγ receptor on B cells, provides IgG-mediated negative modulation through a tyrosine-based inhibition motif which down-regulates B cell receptor initiated signaling. These properties make FcγRIIb a promising target for antibody-based therapy. Here we report the discovery of allele-dependent expression of the activating FcγRIIc on B cells. Identical to FcγRIIb in the extracellular domain, FcγRIIc has a tyrosine-based activation motif in its cytoplasmic domain. In both human B cells and in B cells from mice transgenic for human FcγRIIc, FcγRIIc expression counterbalances the negative feedback of FcγRIIb and enhances humoral responses to immunization in mice and to BioThrax® vaccination in a human Anthrax vaccine trial. Moreover, the FCGR2C-ORF allele is associated with the risk of development of autoimmunity in humans. FcγRIIc expression on B cells challenges the prevailing paradigm of uni-directional negative feedback by IgG immune complexes via the inhibitory FcγRIIb, is a previously unrecognized determinant in human antibody/autoantibody responses, and opens the opportunity for more precise personalized use of B cell targeted antibody-based therapy.
PMCID: PMC3982386  PMID: 24353158
16.  Telomere length in patients with systemic lupus erythematosus and its associations with carotid plaque 
Rheumatology (Oxford, England)  2013;52(6):1101-1108.
Objective. To evaluate telomere length (TL) between patients with SLE and healthy controls and to test if TL is associated with carotid plaque.
Methods. A pilot study of 154 patients with SLE and 152 controls was performed from the SOLVABLE (Study of Lupus Vascular and Bone Long-Term Endpoints) cohort. Demographic and cardiovascular disease (CVD) factors were collected at baseline. The presence or absence of plaque was evaluated by B-mode US. Genomic DNA was isolated from whole peripheral blood. TL was quantified using real-time quantitative PCR.
Results. SLE women had a short TL compared with healthy controls (4.57 vs 5.44 kb, P = 0.03). SLE women showed shorter TL than controls across all age groups: <35 years (4.38 vs 6.37 kb), 35–44 years (4.52 vs 5.30 kb), 45–54 years (4.77 vs 5.68 kb) and ≥55 years (4.60 vs 4.71 kb). Among patients with SLE and carotid plaque there was a trend towards shorter TL at a younger age and it was significantly lower in the 35- to 44-year age group when compared with controls (P = 0.025). Multiple logistic regression analysis indicated a risk of carotid plaque with older age [odds ratio (OR) 1.09; 95% CI 1.06, 1.12] but not with TL (OR 1.05; 95% CI 0.97, 1.13).
Conclusion. SLE women had significantly shorter TL than controls. SLE women trended towards shorter TL at a younger age. When carotid plaque was identified, the younger SLE women had shorter TL. Only older age but not shorter TL was independently associated with carotid plaque. Additional studies are needed to confirm if TL is a novel biomarker for cardiovascular disease in SLE.
PMCID: PMC3651615  PMID: 23382361
systemic lupus erythematosus; cardiovascular disease; telomere length
17.  Adverse pregnancy outcomes and subsequent risk of cardiovascular disease in women with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000024.
Patients with systemic lupus erythematosus (SLE) are at increased risk for adverse pregnancy outcomes and cardiovascular disease (CVD). The objective of this exploratory study was to investigate the association between a history of adverse pregnancy outcomes and subsequent risk of subclinical CVD assessed by imaging studies and verified clinical CVD events in 129 women with SLE.
The occurrence of adverse pregnancy outcomes, specifically pre-eclampsia, preterm birth and low birth weight was ascertained by questionnaire. Subclinical CVD was assessed by coronary artery calcium (CAC) as measured by electron beam CT and carotid plaque measured by B mode ultrasound. Clinical CVD events were verified by medical record review. Logistic regression was used to estimate the association of pregnancy complications with occurrence of subclinical CVD and clinical CVD with a priori adjustment for age, which is associated with CVD and SLE disease duration as a measure of SLE disease burden.
Fifty-six women reported at least one pregnancy complication while 73 had none. Twenty-six women had at least one pregnancy complicated by pre-eclampsia and were more likely to have a CAC score greater than or equal to 10 (adjusted OR=3.7; 95% CI 1.2 to 11.9), but the presence of plaque was not associated with this pregnancy complication, OR=1.1, (95% CI 0.4 to 2.8). Low birth weight and preterm birth were not associated with CAC or plaque.
Patients with SLE with a history of pre-eclampsia had a higher rate of subclinical CVD as measured by CAC score. Future studies are needed to confirm the relationship between adverse pregnancy outcomes and subsequent subclinical CVD and clinical CVD events.
PMCID: PMC4213826  PMID: 25379191
Cardiovascular Disease; Systemic Lupus Erythematosus; Pregnancy; Pre-eclampsia
18.  Cancer risk in systemic lupus: An updated international multi-centre cohort study 
Journal of autoimmunity  2013;42:130-135.
To update estimates of cancer risk in SLE relative to the general population.
A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers.
Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin’s lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61–0.88), endometrial (SIR 0.44, 95% CI 0.23–0.77), and possibly ovarian cancers (0.64, 95% CI 0.34–1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23).
These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.
PMCID: PMC3646904  PMID: 23410586
Systemic Lupus Erythematosus; Epidemiology; Treatment; Disease Activity
19.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
PMCID: PMC4002759  PMID: 24504811
20.  Malignancies in systemic lupus erythematosus 
Autoimmunity reviews  2009;9(4):10.1016/j.autrev.2009.07.004.
The purpose of this review is to underline important advancements in the understanding of cancer risks in systemic lupus erythematosus (SLE). In SLE, there is an increased risk of specific kinds of malignancy. For example, the risk of non-Hodgkin’s lymphoma is increased several-fold in SLE versus the general population. In addition, heightened risks for lung cancer, thyroid cancer and cervical dysplasia in SLE have been found. Some have postulated that immunosuppressive drugs play a role, as well as other important mediators, such as lupus disease activity itself. One new frontier being explored is the significant finding of a decreased risk of certain nonhematologic cancers (e.g., breast, ovarian, endometrial and prostate) in SLE. The reasons for this are currently under study.
PMCID: PMC3880771  PMID: 19643208
cancer; immunosuppressive drug; malignancy; risk; systemic lupus erythematosus
21.  SNPs in VKORC1 are Risk Factors for Systemic Lupus Erythematosus in Asians 
Arthritis and rheumatism  2013;65(1):211-215.
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.
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.
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).
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.
PMCID: PMC3670944  PMID: 23124848
systemic lupus erythematosus; single nucleotide polymorphisms; genetic risk factors
22.  Cancer risk in childhood-onset systemic lupus 
Arthritis Research & Therapy  2013;15(6):R198.
The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE).
We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population.
There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis.
These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care.
PMCID: PMC3978586  PMID: 24267155
23.  Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(11):3695-3705.
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.
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.
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.
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.
PMCID: PMC3485412  PMID: 22833143
24.  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.
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.
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.
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.
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.
PMCID: PMC3485439  PMID: 22886787
25.  Measures of Adult Systemic Lupus Erythematosus 
Arthritis care & research  2011;63(0 11):10.1002/acr.20572.
PMCID: PMC3812450  PMID: 22588757

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