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1.  Pregnancy outcomes among African–American patients with systemic lupus erythematosus compared with controls 
Lupus science & medicine  2014;1(1):e000020.
Objective
In a study of Gullah African–Americans, we compared pregnancy outcomes before and after systemic lupus erythematosus (SLE) diagnosis to controls to test whether there is a predisease state that negatively affects pregnancy outcomes.
Design
Cases and controls reporting at least one pregnancy were included. Controls were all Gullah African-American females. We collected demographic, socioeconomic and pregnancy data. We modelled pregnancy outcome associations with case status using multiple logistic regression to calculate ORs.
Results
After adjustment for age, years of education, medical coverage and pregnancy number, compared with controls, cases were more likely to have any adverse outcome (OR 2.35, 95% CI 1.78 to 3.10), including stillbirth (OR 4.55, 95% CI 1.53 to 13.50), spontaneous abortion (OR 2.05, 95% CI 1.40 to 3.00), preterm birth (OR 2.58, 95% CI 1.58 to 4.20), low birth weight (OR 2.64, 95% CI 1.61 to 4.34) and preeclampsia (OR 1.80, 95% CI 1.08 to 3.01). The odds of adverse pregnancy outcomes all increased after SLE diagnosis compared with before diagnosis, even after adjustment for age, years of education, pregnancy number and medical coverage.
Conclusion
From a large cohort of African–American women, our findings suggest there may be a predisease state that predisposes to adverse pregnancy outcomes.
doi:10.1136/lupus-2014-000020
PMCID: PMC4211631  PMID: 25360323
2.  Vitamin D in Lupus 
Vitamin D is an essential steroid hormone, with well-established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease flare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases.
PMCID: PMC4185297  PMID: 20969555
3.  Pregnancy outcomes among African–American patients with systemic lupus erythematosus compared with controls 
Lupus Science & Medicine  2014;1(1):e000020.
Objective
In a study of Gullah African–Americans, we compared pregnancy outcomes before and after systemic lupus erythematosus (SLE) diagnosis to controls to test whether there is a predisease state that negativelyaffects pregnancy outcomes.
Design
Cases and controls reporting at least one pregnancy were included. Controls were all Gullah African-American females. We collected demographic, socioeconomic and pregnancy data. We modelled pregnancy outcome associations with case status using multiple logistic regression to calculate ORs.
Results
After adjustment for age, years of education, medical coverage and pregnancy number, compared with controls, cases were more likely to have any adverse outcome (OR 2.35, 95% CI 1.78 to 3.10), including stillbirth (OR 4.55, 95% CI 1.53 to 13.50), spontaneous abortion (OR 2.05, 95% CI 1.40 to 3.00), preterm birth (OR 2.58, 95% CI 1.58 to 4.20), low birth weight (OR 2.64, 95% CI 1.61 to 4.34) and preeclampsia (OR 1.80, 95% CI 1.08 to 3.01). The odds of adverse pregnancy outcomes all increased after SLE diagnosis compared with before diagnosis, even after adjustment for age, years of education, pregnancy number and medical coverage.
Conclusion
From a large cohort of African–American women, our findings suggest there may be a predisease state that predisposes to adverse pregnancy outcomes.
doi:10.1136/lupus-2014-000020
PMCID: PMC4211631  PMID: 25360323
systemic lupus erythematosus; pregnancy
4.  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.
doi:10.3389/fgene.2014.00450
PMCID: PMC4288052  PMID: 25620976
lupus; PXK; fine-mapping; B cells; BCR
5.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
Objective
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1136/annrheumdis-2012-202099
PMCID: PMC3855611  PMID: 23303389
7.  Self-Reported Versus Objectively Assessed Exercise Adherence 
In a 10-wk Wii Fit™ home-based program, exercise logs exhibited marginally acceptable agreement with Wii estimation of exercise duration at a group level, illustrating the tendency of participants to overreport.
OBJECTIVE. We examined agreement of data between self-reported and objectively assessed exercise adherence among women with systemic lupus erythematosus.
METHOD. Eleven participants completed weekly exercise logs on date and duration of exercise during a 10-wk Wii Fit™ home-based program. Afterward, exercise data from the log were compared with those recorded in the Wii console.
RESULTS. Of the paired data, the mean duration of exercise recorded in the Wii was 29.5 min and that recorded in the log was 33.3 min. The composite intraclass correlation for exercise duration between exercise log and the Wii Fit was 0.4. The 95% limits of agreement indicated large between-subjects variability.
CONCLUSION. Exercise logs exhibit a marginally acceptable agreement with Wii estimation of exercise duration at a group level. However, caution should be applied when using the exercise log as a measure of a person’s exercise behavior because of the tendency to overreport.
doi:10.5014/ajot.2013.007575
PMCID: PMC3722661  PMID: 23791324
exercise therapy; home care services; lupus erythematosus, systemic; patient compliance; self report
11.  Potential benefits of vitamin D for patients with systemic lupus erythematosus 
Dermato-endocrinology  2012;4(2):146-151.
Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease. Vitamin D deficiency has been proposed as an environmental trigger of disease onset and as a contributor to increased SLE activity. SLE patients are prone to develop vitamin D deficiency because of photosensitivity leading to sun avoidance and other sun protective measures. The impact of vitamin D on immune function previously seen in vitro and in cross-sectional studies has now been shown in prospective human studies, strengthening the evidence that there is a connection between SLE and vitamin D status. This review describes the role of vitamin D on immune function, prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency in SLE patients, and review current vitamin D recommendations for patients with SLE.
doi:10.4161/derm.20443
PMCID: PMC3427193  PMID: 22928070
systemic lupus erythematosus; vitamin D; autoimmune disease; review
12.  Cancer risk in systemic lupus: An updated international multi-centre cohort study 
Journal of autoimmunity  2013;42:130-135.
OBJECTIVE
To update estimates of cancer risk in SLE relative to the general population.
METHODS
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.
RESULTS
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).
CONCLUSION
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.
doi:10.1016/j.jaut.2012.12.009
PMCID: PMC3646904  PMID: 23410586
Systemic Lupus Erythematosus; Epidemiology; Treatment; Disease Activity
13.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1002/art.38220
PMCID: PMC4002759  PMID: 24504811
14.  Vitamin D Deficiency in a Multiethnic Healthy Control Cohort and Altered Immune Response in Vitamin D Deficient European-American Healthy Controls 
PLoS ONE  2014;9(4):e94500.
Objective
In recent years, vitamin D has been shown to possess a wide range of immunomodulatory effects. Although there is extensive amount of research on vitamin D, we lack a comprehensive understanding of the prevalence of vitamin D deficiency or the mechanism by which vitamin D regulates the human immune system. This study examined the prevalence and correlates of vitamin D deficiency and the relationship between vitamin D and the immune system in healthy individuals.
Methods
Healthy individuals (n = 774) comprised of European-Americans (EA, n = 470), African–Americans (AA, n = 125), and Native Americans (NA, n = 179) were screened for 25-hydroxyvitamin D [25(OH)D] levels by ELISA. To identify the most noticeable effects of vitamin D on the immune system, 20 EA individuals with severely deficient (<11.3 ng/mL) and sufficient (>24.8 ng/mL) vitamin D levels were matched and selected for further analysis. Serum cytokine level measurement, immune cell phenotyping, and phosphoflow cytometry were performed.
Results
Vitamin D sufficiency was observed in 37.5% of the study cohort. By multivariate analysis, AA, NA, and females with a high body mass index (BMI, >30) demonstrate higher rates of vitamin D deficiency (p<0.05). Individuals with vitamin D deficiency had significantly higher levels of serum GM-CSF (p = 0.04), decreased circulating activated CD4+ (p = 0.04) and CD8+ T (p = 0.04) cell frequencies than individuals with sufficient vitamin D levels.
Conclusion
A large portion of healthy individuals have vitamin D deficiency. These individuals have altered T and B cell responses, indicating that the absence of sufficient vitamin D levels could result in undesirable cellular and molecular alterations ultimately contributing to immune dysregulation.
doi:10.1371/journal.pone.0094500
PMCID: PMC3984168  PMID: 24727903
15.  Spatial Environmental Modeling of Autoantibody Outcomes among an African American Population 
In this study of autoimmunity among a population of Gullah African Americans in South Carolina, the links between environmental exposures and autoimmunity (presence of antinuclear antibodies (ANA)) have been assessed. The study population included patients with systemic lupus erythematosus (n = 10), their first degree relatives (n = 61), and unrelated controls (n = 9) where 47.5% (n = 38) were ANA positive. This paper presents the methodology used to model ANA status as a function of individual environmental influences, both self-reported and measured, while controlling for known autoimmunity risk factors. We have examined variable dimension reduction and selection methods in our approach. Following the dimension reduction and selection methods, we fit logistic spatial Bayesian models to explore the relationship between our outcome of interest and environmental exposures adjusting for personal variables. Our analysis also includes a validation “strip” where we have interpolated information from a specific geographic area for a subset of the study population that lives in that vicinity. Our results demonstrate that residential proximity to exposure site is important in this form of analysis. The use of a validation strip network demonstrated that even with small sample numbers some significant exposure-outcome relationships can be detected.
doi:10.3390/ijerph110302764
PMCID: PMC3987002  PMID: 24608900
lupus; autoimmunity; African Americans; environmental metals; soil; groundwater; spatial
16.  The process associated with motivation of a home-based Wii Fit exercise program among sedentary African American women with systemic lupus erythematosus 
Disability and health journal  2012;6(1):63-68.
Objective
To explore the process associated with the motivation for playing Wii Fit among patients with systemic lupus erythematosus (SLE).
Methods
Individual in-depth semi-structured telephone interviews were conducted with 14 sedentary African American women with SLE to explore their experiences and reflect on their motivation for playing Wii Fit after completing a 10-week home-based Wii Fit exercise program. Interviews were audio-recorded, transcribed verbatim, and analyzed using the constant comparative method to identify categories related to participants’ motivation. Three authors independently sorted, organized and coded transcript text into categories, then combined the categories into themes and subthemes.
Results
In addition to the two themes (Ethical principal of keeping a commitment, and Don’t want to let anyone down) generic to home-based exercise trials, we identified five themes (Enjoyment, Health Benefits, Sense of Accomplishment, Convenience, and Personalized) that revealed why the participants were motivated to play the Wii Fit. Enjoyment had three subthemes: Interactive, Challenging, and Competitive with an embedded social element. However, several participants commented they were not able to do many activities, master certain games, or figure out how to play some; as a result, they were bored with the limited selection of activities that they could do.
Conclusions
The motivational elements of the Wii Fit may contribute to improved exercise motivation and adherence in select sedentary African American women with SLE. Results provide a better understanding on the important elements to incorporate in the development of sustainable home-based exercise programs with interactive health video games for this population.
doi:10.1016/j.dhjo.2012.08.003
PMCID: PMC3539138  PMID: 23260612
Exergames; Exercise adherence; Qualitative study
17.  A Meta-Analysis Identifies New Loci Associated with Body Mass index in Individuals of African Ancestry 
Monda, Keri L. | Chen, Gary K. | Taylor, Kira C. | Palmer, Cameron | Edwards, Todd L. | Lange, Leslie A. | Ng, Maggie C.Y. | Adeyemo, Adebowale A. | Allison, Matthew A. | Bielak, Lawrence F. | Chen, Guanji | Graff, Mariaelisa | Irvin, Marguerite R. | Rhie, Suhn K. | Li, Guo | Liu, Yongmei | Liu, Youfang | Lu, Yingchang | Nalls, Michael A. | Sun, Yan V. | Wojczynski, Mary K. | Yanek, Lisa R. | Aldrich, Melinda C. | Ademola, Adeyinka | Amos, Christopher I. | Bandera, Elisa V. | Bock, Cathryn H. | Britton, Angela | Broeckel, Ulrich | Cai, Quiyin | Caporaso, Neil E. | Carlson, Chris | Carpten, John | Casey, Graham | Chen, Wei-Min | Chen, Fang | Chen, Yii-Der I. | Chiang, Charleston W.K. | Coetzee, Gerhard A. | Demerath, Ellen | Deming-Halverson, Sandra L. | Driver, Ryan W. | Dubbert, Patricia | Feitosa, Mary F. | Freedman, Barry I. | Gillanders, Elizabeth M. | Gottesman, Omri | Guo, Xiuqing | Haritunians, Talin | Harris, Tamara | Harris, Curtis C. | Hennis, Anselm JM | Hernandez, Dena G. | McNeill, Lorna H. | Howard, Timothy D. | Howard, Barbara V. | Howard, Virginia J. | Johnson, Karen C. | Kang, Sun J. | Keating, Brendan J. | Kolb, Suzanne | Kuller, Lewis H. | Kutlar, Abdullah | Langefeld, Carl D. | Lettre, Guillaume | Lohman, Kurt | Lotay, Vaneet | Lyon, Helen | Manson, JoAnn E. | Maixner, William | Meng, Yan A. | Monroe, Kristine R. | Morhason-Bello, Imran | Murphy, Adam B. | Mychaleckyj, Josyf C. | Nadukuru, Rajiv | Nathanson, Katherine L. | Nayak, Uma | N’Diaye, Amidou | Nemesure, Barbara | Wu, Suh-Yuh | Leske, M. Cristina | Neslund-Dudas, Christine | Neuhouser, Marian | Nyante, Sarah | Ochs-Balcom, Heather | Ogunniyi, Adesola | Ogundiran, Temidayo O. | Ojengbede, Oladosu | Olopade, Olufunmilayo I. | Palmer, Julie R. | Ruiz-Narvaez, Edward A. | Palmer, Nicholette D. | Press, Michael F. | Rampersaud, Evandine | Rasmussen-Torvik, Laura J. | Rodriguez-Gil, Jorge L. | Salako, Babatunde | Schadt, Eric E. | Schwartz, Ann G. | Shriner, Daniel A. | Siscovick, David | Smith, Shad B. | Wassertheil-Smoller, Sylvia | Speliotes, Elizabeth K. | Spitz, Margaret R. | Sucheston, Lara | Taylor, Herman | Tayo, Bamidele O. | Tucker, Margaret A. | Van Den Berg, David J. | Velez Edwards, Digna R. | Wang, Zhaoming | Wiencke, John K. | Winkler, Thomas W. | Witte, John S. | Wrensch, Margaret | Wu, Xifeng | Yang, James J. | Levin, Albert M. | Young, Taylor R. | Zakai, Neil A. | Cushman, Mary | Zanetti, Krista A. | Zhao, Jing Hua | Zhao, Wei | Zheng, Yonglan | Zhou, Jie | Ziegler, Regina G. | Zmuda, Joseph M. | Fernandes, Jyotika K. | Gilkeson, Gary S. | Kamen, Diane L. | Hunt, Kelly J. | Spruill, Ida J. | Ambrosone, Christine B. | Ambs, Stefan | Arnett, Donna K. | Atwood, Larry | Becker, Diane M. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Borecki, Ingrid B. | Bottinger, Erwin P. | Bowden, Donald W. | Burke, Gregory | Chanock, Stephen J. | Cooper, Richard S. | Ding, Jingzhong | Duggan, David | Evans, Michele K. | Fox, Caroline | Garvey, W. Timothy | Bradfield, Jonathan P. | Hakonarson, Hakon | Grant, Struan F.A. | Hsing, Ann | Chu, Lisa | Hu, Jennifer J. | Huo, Dezheng | Ingles, Sue A. | John, Esther M. | Jordan, Joanne M. | Kabagambe, Edmond K. | Kardia, Sharon L.R. | Kittles, Rick A. | Goodman, Phyllis J. | Klein, Eric A. | Kolonel, Laurence N. | Le Marchand, Loic | Liu, Simin | McKnight, Barbara | Millikan, Robert C. | Mosley, Thomas H. | Padhukasahasram, Badri | Williams, L. Keoki | Patel, Sanjay R. | Peters, Ulrike | Pettaway, Curtis A. | Peyser, Patricia A. | Psaty, Bruce M. | Redline, Susan | Rotimi, Charles N. | Rybicki, Benjamin A. | Sale, Michèle M. | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Strom, Sara S. | Thun, Michael J. | Vitolins, Mara | Zheng, Wei | Moore, Jason H. | Williams, Scott M. | Zhu, Xiaofeng | Zonderman, Alan B. | Kooperberg, Charles | Papanicolaou, George | Henderson, Brian E. | Reiner, Alex P. | Hirschhorn, Joel N. | Loos, Ruth JF | North, Kari E. | Haiman, Christopher A.
Nature genetics  2013;45(6):690-696.
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
doi:10.1038/ng.2608
PMCID: PMC3694490  PMID: 23583978
18.  Epidemiology of Environmental Exposures and Human Autoimmune Diseases: Findings from a National Institute of Environmental Health Sciences Expert Panel Workshop 
Journal of autoimmunity  2012;39(4):259-271.
Autoimmune diseases (AID) are a collection of many complex disorders of unknown etiology resulting in immune responses to self-antigens and are thought to result from interactions between genetic and environmental factors. Here we review the epidemiologic evidence for the role of environmental factors in the development of human AID, the conclusions that can be drawn from the existing data, critical knowledge gaps, and research needed to fill these gaps and to resolve uncertainties. We specifically summarize the state of knowledge and our levels of confidence in the role of specific agents in the development of autoimmune diseases, and we define the areas of greatest impact for future investigations. Among our consensus findings we are confident that: 1) crystalline silica exposure can contribute to the development of several AID; 2) solvent exposure can contribute to the development of systemic sclerosis; 3) smoking can contribute to the development of seropositive rheumatoid arthritis; and 4) an inverse association exists between ultraviolet radiation exposure and the risk of development of multiple sclerosis. We suggest that more studies of phenotypes, genotypes, and multiple exposures are needed. Additional knowledge gaps needing investigation include: defining important windows in the timing of exposures and latencies relating to age, developmental state, and hormonal changes; understanding dose-response relationships; and elucidating mechanisms for disease development. Addressing these essential issues will require more resources to support research, particularly of rare AID, but knowledge of the risks conferred by environmental factors in specific genetic contexts could pave the way for prevention of AID in the future.
doi:10.1016/j.jaut.2012.05.002
PMCID: PMC3496812  PMID: 22739348
autoimmune disease; environmental risk factors; biologic agents; chemical agents; physical factors; research priorities
19.  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
20.  Comparison of autoantibody specificities between traditional and bead-based assays in a large, diverse collection of SLE patients and family members 
Arthritis and rheumatism  2012;64(11):3677-3686.
Objective
The replacement of standard immunofluorescence anti-nuclear antibody (ANA) methods with bead-based assays is a new clinical option. A large, multi-racial cohort of SLE patients, blood relatives and unaffected control individuals was evaluated for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods.
Methods
Serum samples (1,540 SLE patients, 1,127 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead-based assay, immunofluorescence, and immunodiffusion. Autoantibody prevalence, disease sensitivity, clustering, and association with standard immunodiffusion results were evaluated.
Results
ANA frequency in SLE patient sera were 89%, 73%, and 67% by BioPlex 2200 and 94%, 84%, and 86% by immunofluorescence in African-American, Hispanic, and European-American patients respectively. 60kD Ro, La, Sm, nRNP A, and ribosomal P prevalence were compared across assays, with sensitivities ranging from 0.92 to 0.83 and specificities ranging from 0.90 to 0.79. Cluster autoantibody analysis showed association of three subsets: 1) 60kD Ro, 52kD Ro and La, 2) spliceosomal proteins, and 3) dsDNA, chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60kD Ro in SLE patient sibling pairs was observed (p ≤ 0.004). Simplex pedigree patients had a greater prevalence for dsDNA (p=0.0003) and chromatin (p=0.005) autoantibodies than multiplex patients.
Conclusion
ANA frequencies detected by a bead-based assay are lower in European-American SLE patients compared to immunofluorescence. These assays have strong positive predictive values across racial groups, provide useful information for clinical care, and provide unique insights to familial aggregation and autoantibody clustering.
doi:10.1002/art.34651
PMCID: PMC3490432  PMID: 23112091
systemic lupus erythematosus; autoantibodies; ancestry
21.  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
22.  Premature atherosclerosis is associated with hypovitaminosis D and angiotensin converting enzyme inhibitor non-use in lupus patients 
Our ultimate goal is to identify and target modifiable risk factors that will reduce major cardiovascular events in African-American lupus patients. As a first step toward achieving this goal, this study was designed to explore risk factor models of preclinical atherosclerosis in a predominantly African-American group of SLE patients using variables historically associated with endothelial function in non-lupus populations.
51 subjects with SLE but without a history of clinical cardiovascular events were enrolled. At entry, a Framingham risk factor history and medication list were recorded. Sera and plasma samples were analyzed for lipids, lupus activity markers, and total 25-hydroxyvitamin D (25(OH)D) levels. Carotid ultrasound measurements were performed to determine total plaque area (TPA) in both carotids. Cases had TPA values above age-matched controls from a vascular prevention clinic population. Logistic regression and machine learning analyses were performed to create predictive models.
25(OH)D levels were significantly lower and SLE disease duration was significantly higher in cases. 25(OH)D levels inversely correlated with age-adjusted TPA. ACE-inhibitor non-use associated with case status. Logistic regression models containing ACE-inhibitor use, 25(OH)D levels, and LDL levels had a diagnostic accuracy of 84% for predicting accelerated atherosclerosis. Similar results were obtained with machine learning models, but hydroxychloroquine use associated with controls in these models.
This is the first study to demonstrate an association between atherosclerotic burden and 25(OH)D insufficiency or ACE-inhibitor non-use in lupus patients. These findings provide strong rationale for the study of ACE-inhibitors and vitamin D replenishment as preventive therapies in this high-risk population.
doi:10.1097/MAJ.0b013e31823fa7d9
PMCID: PMC3323721  PMID: 22222338
Systemic lupus erythematosus; Atherosclerosis; Vitamin D deficiency; Angiotensin converting enzyme inhibitors; Hypercholesterolemia
23.  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
24.  Derivation and Validation of Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus 
Arthritis and rheumatism  2012;64(8):2677-2686.
Objective
The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology.
Methods
The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls.
Results
Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001).
Conclusions
The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification.
doi:10.1002/art.34473
PMCID: PMC3409311  PMID: 22553077
25.  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

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