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109. Drivers of Satisfaction With Care for Patients With Lupus

Author

Jolly, Meenakshi, primary, Sethi, Bhavika, additional, O'Brien, Courtney, additional, Sequeira, Winston, additional, Block, Joel A., additional, Toloza, Sergio, additional, Bertoli, Ana, additional, Blazevic, Ivana, additional, Vilá, Luis M., additional, Moldovan, Ioana, additional, Torralba, Karina D., additional, Cicognani, Elvira, additional, Mazzoni, Davide, additional, Hasni, Sarfaraz, additional, Goker, Berna, additional, Haznedaroglu, Seminur, additional, Bourre‐Tessier, Josiane, additional, Navarra, Sandra V., additional, Mok, Chi Chiu, additional, Clarke, Ann, additional, Weisman, Michael, additional, and Wallace, Daniel, additional

Published
2019
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113. Drivers of Satisfaction With Care for Patients With Lupus

Author

Jolly, M, Sethi, B, O'Brien, C, Sequeira, W, Block, J, Toloza, S, Bertoli, A, Blazevic, I, Vilá, L, Moldovan, I, Torralba, K, Cicognani, E, Mazzoni, D, Hasni, S, Goker, B, Haznedaroglu, S, Bourre‐tessier, J, Navarra, S, Mok, C, Clarke, A, Weisman, M, Wallace, D, Jolly, Meenakshi, Sethi, Bhavika, O'Brien, Courtney, Sequeira, Winston, Block, Joel A., Toloza, Sergio, Bertoli, Ana, Blazevic, Ivana, Vilá, Luis M., Moldovan, Ioana, Torralba, Karina D., Cicognani, Elvira, Mazzoni, Davide, Hasni, Sarfaraz, Goker, Berna, Haznedaroglu, Seminur, Bourre‐Tessier, Josiane, Navarra, Sandra V., Mok, Chi Chiu, Clarke, Ann, Weisman, Michael, Wallace, Daniel, Jolly, M, Sethi, B, O'Brien, C, Sequeira, W, Block, J, Toloza, S, Bertoli, A, Blazevic, I, Vilá, L, Moldovan, I, Torralba, K, Cicognani, E, Mazzoni, D, Hasni, S, Goker, B, Haznedaroglu, S, Bourre‐tessier, J, Navarra, S, Mok, C, Clarke, A, Weisman, M, Wallace, D, Jolly, Meenakshi, Sethi, Bhavika, O'Brien, Courtney, Sequeira, Winston, Block, Joel A., Toloza, Sergio, Bertoli, Ana, Blazevic, Ivana, Vilá, Luis M., Moldovan, Ioana, Torralba, Karina D., Cicognani, Elvira, Mazzoni, Davide, Hasni, Sarfaraz, Goker, Berna, Haznedaroglu, Seminur, Bourre‐Tessier, Josiane, Navarra, Sandra V., Mok, Chi Chiu, Clarke, Ann, Weisman, Michael, and Wallace, Daniel

Abstract

Objective: Quality of life (QOL) and quality of care (QOC) in systemic lupus erythematosus (SLE) remains poor. Satisfaction with care (SC), a QOC surrogate, correlates with health behaviors and outcomes. This study aimed to determine correlates of SC in SLE. Methods: A total of 1262 patients with SLE were recruited from various countries. Demographics, disease activity (modified Systemic Lupus Erythematosus Disease Activity Index for the Safety of Estrogens in Lupus Erythematosus: National Assessment trial [SELENA-SLEDAI]), and QOL (LupusPRO version 1.7) were collected. SC was collected using LupusPRO version 1.7. Regression analyses were conducted using demographic, disease (duration, disease activity, damage, and medications), geographic (eg, China vs United States), and QOL factors as independent predictors. Results: The mean (SD) age was 41.7 (13.5) years; 93% of patients were women. On the univariate analysis, age, ethnicity, current steroid use, disease activity, and QOL (social support, coping) were associated with SC. On the multivariate analysis, Asian participants had worse SC, whereas African American and Hispanic patients had better SC. Greater disease activity, better coping, and social support remained independent correlates of better SC. Compared with US patients, patients from China and Canada had worse SC on the univariate analysis. In the multivariate models, Asian ethnicity remained independently associated with worse SC, even after we adjusted for geographic background (China). No associations between African American or Hispanic ethnicity and SC were retained when geographic location (Canada) was added to the multivariate model. Canadian patients had worse SC when compared with US patients. Higher disease activity, better social support, and coping remained associated with better SC. Conclusion: Greater social support, coping, and, paradoxically, SLE disease activity are associated with better SC. Social support and coping are modifiable factors

Published
2019

114. Efficacy of Cyclosporine in the Induction and Maintenance of Remission in a Systemic Lupus Erythematosus Patient Presenting with Macrophage-Activating Syndrome

Author

Cruz-Pérez, Franchesca, Vilá, Salvador, Ríos, Grissel, and Vilá, Luis M.

Subjects
Article Subject
Abstract

Macrophage-activating syndrome (MAS) is a rare condition characterized by dysfunctional macrophage activation leading to overproduction of cytokines and phagocytosis of erythrocytes, leukocytes, and platelets. MAS is associated with infectious diseases, malignancies, and autoimmune rheumatic disorders. Herein, we present a 22-year-old Hispanic woman with SLE who was hospitalized because of a three-week history of fever, fatigue, polyarthralgia, nausea, and abdominal pain. Initial laboratories showed severe pancytopenia with marked elevation of liver enzymes and ferritin levels. Bone marrow biopsy revealed macrophages with engulfed erythrocytes consistent with MAS. The patient was treated with high-dose corticosteroids, intravenous immunoglobulins, and cyclosporine 3 mg/kg/day. She had a remarkable clinical response to this therapy. She was continued on cyclosporine, and prednisone dose was gradually decreased to 7.5 mg daily without experiencing recurrent disease. She remained in full clinical remission for 12 months. Our case, together with other reports, suggests that combination therapy with corticosteroids, immunoglobulins, and cyclosporine appears to be effective for patients with SLE-associated MAS. Furthermore, cyclosporine seems to be a good drug for maintenance of remission.

Published
2018
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115. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

Langefeld, C. D., Ainsworth, H. C., Kelly, J. A., Comeau, M. E., Marion, M. C., Howard, T. D., Ramos, P. S., Croker, J. A., Morris, D. L., Sandling, J. K., Almlöf, J. C., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José Mario, Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjowall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusie-Luna, Teresa, Vasconcelos, C., Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvanen, Ann-Christine, Ronnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón-Riquelme, M. E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, P. M., Vyse, Timothy J., Acevedo-Vásquez, E. M., Alarcón, G. S., Babini, A. M., Baca, V., Bengtsson, A. A., Berbotto, G. A., Bij, l. M., Brown, E. E., Brunner, H.I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapaa, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rua Figueroa, Inigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emoke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, G. S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, D. L., Karp, David R., Kaufman, Kenneth M, Kottyan, Leah C., Kovacs, Laszlo, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Cecena, Marco A., Martín, J., McCune, Joseph M., McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, Jose F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, N., Petri, Michelle, Pineau, Christian A., National Institute for Health Research (UK), Arthritis Research UK, Alliance for Lupus Research, Junta de Andalucía, National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), National Institutes of Health (US), RILITE Foundation, and Genentech Foundation

Subjects
skin and connective tissue diseases
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE., We gratefully acknowledge the Alliance for Lupus Research for funding and support. The research was supported in part by awards from the Arthritis Research UK Special Strategic Award (ref. 19289) and from George Koukis (T.J.V.). In addition, the research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London (T.J.V.). The work would not be possible without funding from the NIH grants AR049084 (RPK, EEB); the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) AI083194 (J.B.H.); CA141700, AR058621 Proyecto de Excelencia, Consejeria de Andalucia (M.E.A.R.); AR043814 and AR-065626 (B.P.T.); AR060366, MD007909, AI107176 (S.K.N.); AR-057172 (C.O.J.); RC2 AR058959, U19 A1082714, R01 AR063124, P30 GM110766, R01 AR056360 (P.M.G.); P60 AR053308 (L.A.C.), MUSC part is from UL1RR029882 (G.S.G., D.L.K.) and 5P60AR062755 (G.S.G., D.L.K., P.R.R.). Oklahoma Samples U19AI082714, U01AI101934, P30GM103510, U54GM104938 and P30AR053483 (J.A.J., J.M.G.); Northwestern P60 AR066464 and 1U54TR001018 (R.R.G.); This study was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) under Award Numbers K01 AR067280 and P60 AR062755 (PSR); N01AR22265 (funded collection of APPLE samples) (LES) and the APPLE Investigators; R01AR43727, NIH AR 043727 and 069572 (M.P.); NIAMS/NIH P50-AR055503 (D.R.K.). We would like to also thank the RILITE foundation for financial support (C.D.L.). Additional funding for Immunochip genotyping was provided by Genentech.

Published
2017

117. A plausibly causal functional lupus-associated risk variant in the STAT1–STAT4 locus

Author

Patel, Zubin H, primary, Lu, Xiaoming, additional, Miller, Daniel, additional, Forney, Carmy R, additional, Lee, Joshua, additional, Lynch, Arthur, additional, Schroeder, Connor, additional, Parks, Lois, additional, Magnusen, Albert F, additional, Chen, Xiaoting, additional, Pujato, Mario, additional, Maddox, Avery, additional, Zoller, Erin E, additional, Namjou, Bahram, additional, Brunner, Hermine I, additional, Henrickson, Michael, additional, Huggins, Jennifer L, additional, Williams, Adrienne H, additional, Ziegler, Julie T, additional, Comeau, Mary E, additional, Marion, Miranda C, additional, Glenn, Stuart B, additional, Adler, Adam, additional, Shen, Nan, additional, Nath, Swapan K, additional, Stevens, Anne M, additional, Freedman, Barry I, additional, Pons-Estel, Bernardo A, additional, Tsao, Betty P, additional, Jacob, Chaim O, additional, Kamen, Diane L, additional, Brown, Elizabeth E, additional, Gilkeson, Gary S, additional, Alarcón, Graciela S, additional, Martin, Javier, additional, Reveille, John D, additional, Anaya, Juan-Manuel, additional, James, Judith A, additional, Sivils, Kathy L, additional, Criswell, Lindsey A, additional, Vilá, Luis M, additional, Petri, Michelle, additional, Scofield, R Hal, additional, Kimberly, Robert P, additional, Edberg, Jeffrey C, additional, Ramsey-Goldman, Rosalind, additional, Bang, So-Young, additional, Lee, Hye-Soon, additional, Bae, Sang-Cheol, additional, Boackle, Susan A, additional, Cunninghame Graham, Deborah, additional, Vyse, Timothy J, additional, Merrill, Joan T, additional, Niewold, Timothy B, additional, Ainsworth, Hannah C, additional, Silverman, Earl D, additional, Weisman, Michael H, additional, Wallace, Daniel J, additional, Raj, Prithvi, additional, Guthridge, Joel M, additional, Gaffney, Patrick M, additional, Kelly, Jennifer A, additional, Alarcón-Riquelme, Marta E, additional, Langefeld, Carl D, additional, Wakeland, Edward K, additional, Kaufman, Kenneth M, additional, Weirauch, Matthew T, additional, Harley, John B, additional, and Kottyan, Leah C, additional

Published
2018
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118. Efficacy of Rituximab in a Systemic Lupus Erythematosus Patient Presenting with Diffuse Alveolar Hemorrhage

Author

Montes-Rivera, Gabriela, Ríos, Grissel, and Vilá, Luis M.

Subjects
Article Subject, immune system diseases
Abstract

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE). Although infrequent, its mortality is very high. While there are no established therapeutic guidelines, DAH has been traditionally managed with high-dose intravenous (IV) corticosteroids, cyclophosphamide, and plasma exchange. The efficacy of alternative therapies such as rituximab has been described only in a few cases. Herein, we report a 25-year-old Hispanic man who presented with acute-onset SLE manifested by polyarthralgia, nephritis, seizures, pancytopenia, severe hypocomplementemia, and elevated anti-dsDNA antibodies. His disease course was complicated by DAH. His condition was refractory to high-dose intravenous (IV) methylprednisolone pulses, IV cyclophosphamide, and plasmapheresis. Given the lack of clinical response, he was started on IV rituximab 375 mg/m2 weekly for a total of four courses. He rapidly improved after the first two doses. Over the next seven months, he did not present recurrent pulmonary symptoms. Follow-up chest computed tomography did not show residual abnormalities. This case, together with other reports, suggests that rituximab is an effective therapeutic option for DAH in SLE.

Published
2017
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119. Evaluation ofTRAF6in a large multiancestral lupus cohort

Author

Namjou, Bahram, Choi, Chan-Bum, Harley, Isaac T. W., Alarcón-Riquelme, Marta E., Kelly, Jennifer A., Glenn, Stuart B., Ojwang, Joshua O., Adler, Adam, Kwangwoo Kim, Gallant, Caroline J., Boackle, Susan A., Criswell, Lindsey A., Kimberly, Robert P., Brown, Elizabeth E., Edberg, Jeffrey, Alarcón, Graciela S., Stevens, Anne M., Jacob, Chaim O., Gilkeson, Gary S., Kamen, Diane L., Tsao, Betty P., Anaya, Juan-Manuel, Kim, Eun-Mi, Park, So-Yeon, Sung, Yoon-Kyoung, Guthridge, Joel M., Merrill, Joan T., Petri, Michelle, Ramsey-Goldman, Rosalind, Vilá, Luis M., Niewold, Timothy B., Martin, Javier, Pons-Estel, Bernardo A., Vyse, Timothy J., Freedman, Barry I., Moser, Kathy L., Gaffney, Patrick M., Williams, Adrienne H., Comeau, Mary E., Reveille, John D., Kang, Changwon, James, Judith A., Scofield, R. Hal, Langefeld, Carl D., Kaufman, Kenneth M., Harley, John B., Bae, Sang-Cheol, Junker, Peter, Voss, Anne, and Laustrup, Helle

Subjects
single nucleotide, Male, Linkage disequilibrium, Candidate gene, Heredity, Organogenesis, Tumor necrosis factor receptor associated factor 6, Genome-wide association study, Signal transduction, Cohort Studies, Genetic heterogeneity, Gene Frequency, immune system diseases, Ethnicity, Lupus Erythematosus, Systemic, Immunology and Allergy, Pharmacology (medical), skin and connective tissue diseases, Priority journal, education.field_of_study, Calculation, Gene linkage disequilibrium, Female, Human, Immunopathogenesis, Genotype, Immunology, Population, Single-nucleotide polymorphism, Major clinical study, Biology, Pedigree analysis, Polymorphism, Single Nucleotide, Article, Systemic lupus erythematosus, Rheumatology, Population based case control study, Humans, Genetic Predisposition to Disease, African american, Rheumatoid arthritis, Polymorphism, education, Alleles, Genetic Association Studies, Genetic association, TNF Receptor-Associated Factor 6, Lupus erythematosus, Immunity, Case-control study, Odds ratio, systemic, Thrombocytopenia, Single nucleotide polymorphism, Haplotypes, Case-Control Studies, Meta analysis (topic), Controlled study
Abstract

Objective Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. We undertook to study the role of TRAF6 as a candidate gene for SLE, since it plays a major role in several signaling pathways that are important for immunity and organ development. Methods Fifteen single-nucleotide polymorphisms (SNPs) across TRAF6 were evaluated in 7,490 SLE patients and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results Evidence of associations was detected in multiple SNPs. The best overall P values were obtained for SNPs rs5030437 and rs4755453 (P = 7.85 × 10 -5 and P = 4.73 × 10 -5, respectively) without significant heterogeneity among populations (P = 0.67 and P = 0.50, respectively, in Q statistic). In addition, SNP rs540386, which was previously reported to be associated with rheumatoid arthritis (RA), was found to be in linkage disequilibrium with these 2 SNPs (r 2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 × 10 -4, OR 0.89 [95% CI 0.83-0.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 × 10 -6, OR 0.57 [95% CI 0.45-0.72], for rs5030470). Finally, evidence of family-based association in 34 African American pedigrees with the presence of thrombocytopenia was detected in 1 available SNP (rs5030437) with a Z score magnitude of 2.28 (P = 0.02) under a dominant model. Conclusion Our data indicate the presence of association of TRAF6 with SLE, consistent with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity. Copyright © 2012 by the American College of Rheumatology.

Published
2012
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122. Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA

Author

Varela-Rosario, Noemí, primary, Arroyo-Ávila, Mariangelí, additional, Fred-Jiménez, Ruth M., additional, Díaz-Correa, Leyda M., additional, Pérez-Ríos, Naydi, additional, Rodríguez, Noelia, additional, Ríos, Grissel, additional, and Vilá, Luis M., additional

Published
2017
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123. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Graham, Deborah S. Cunninghame, Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., de la Torre, Ignacio García, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Graham, Deborah S. Cunninghame, Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., de la Torre, Ignacio García, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard, Li, Quan-Zhen, Maradiaga-Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., and Silverman, Earl D.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10-8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Published
2017

124. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

Langefeld, Carl D., Ainsworth, Hannah C., Cunninghame Graham, Deborah S., Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, De la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel Valerio, Jorge Antonio, Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan Zhen, Maradiaga Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar Salinas, Carlos Alberto, Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., Vyse, Timothy J., Langefeld, Carl D., Ainsworth, Hannah C., Cunninghame Graham, Deborah S., Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Brunner, Hermine I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, De la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel Valerio, Jorge Antonio, Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, Gary S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kottyan, Leah C., Kovács, László, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan Zhen, Maradiaga Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar Salinas, Carlos Alberto, Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann Christine, Rönnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., and Vyse, Timothy J.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 10 8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE

Published
2017

125. Transancestral mapping and genetic load in systemic lupus erythematosus

Author

National Institute for Health Research (UK), Arthritis Research UK, Alliance for Lupus Research, Junta de Andalucía, National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), National Institutes of Health (US), RILITE Foundation, Genentech Foundation, Langefeld, C. D., Ainsworth, H. C., Kelly, J. A., Comeau, M. E., Marion, M. C., Howard, T. D., Ramos, P. S., Croker, J. A., Morris, D. L., Sandling, J. K., Almlöf, J. C., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José Mario, Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjowall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusie-Luna, Teresa, Vasconcelos, C., Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvanen, Ann-Christine, Ronnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón-Riquelme, M. E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, P. M., Vyse, Timothy J., Acevedo-Vásquez, E. M., Alarcón, G. S., Babini, A. M., Baca, V., Bengtsson, A. A., Berbotto, G. A., Bij, l. M., Brown, E. E., Brunner, H.I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapaa, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rua Figueroa, Inigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emoke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, G. S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, D. L., Karp, David R., Kaufman, Kenneth M, Kottyan, Leah C., Kovacs, Laszlo, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Cecena, Marco A., Martín, J., McCune, Joseph M., McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, Jose F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, N., Petri, Michelle, Pineau, Christian A., National Institute for Health Research (UK), Arthritis Research UK, Alliance for Lupus Research, Junta de Andalucía, National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), National Institutes of Health (US), RILITE Foundation, Genentech Foundation, Langefeld, C. D., Ainsworth, H. C., Kelly, J. A., Comeau, M. E., Marion, M. C., Howard, T. D., Ramos, P. S., Croker, J. A., Morris, D. L., Sandling, J. K., Almlöf, J. C., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Ramsey-Goldman, Rosalind, Reveille, John D., Russell, Laurie P., Sabio, José Mario, Aguilar-Salinas, Carlos A., Scherbarth, Hugo R., Scorza, Raffaella, Seldin, Michael F., Sjowall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusie-Luna, Teresa, Vasconcelos, C., Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvanen, Ann-Christine, Ronnblom, Lars, Criswell, Lindsey A., Jacob, Chaim O., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón-Riquelme, M. E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, P. M., Vyse, Timothy J., Acevedo-Vásquez, E. M., Alarcón, G. S., Babini, A. M., Baca, V., Bengtsson, A. A., Berbotto, G. A., Bij, l. M., Brown, E. E., Brunner, H.I., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapaa, D'Alfonso, Sandra, Da Silva, Berta Martins, de la Rua Figueroa, Inigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emoke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., García de la Torre, Ignacio, Gilkeson, G. S., Gladman, Dafna D., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, D. L., Karp, David R., Kaufman, Kenneth M, Kottyan, Leah C., Kovacs, Laszlo, Laustrup, Helle, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Cecena, Marco A., Martín, J., McCune, Joseph M., McWilliams, David R, Merrill, Joan T, Miranda, Pedro, Moctezuma, Jose F., Nath, Swapan K., Niewold, Timothy B., Orozco, Lorena, Ortego-Centeno, N., Petri, Michelle, and Pineau, Christian A.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Published
2017

126. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

Author

Arroyo-Ávila, Mariangelí, Fred-Jiménez, Ruth M., and Vilá, Luis M.

Subjects
Article Subject, immune system diseases, hemic and lymphatic diseases
Abstract

Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) after the second weekly rituximab infusion (375 mg/m2 weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections.

Published
2015
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130. Association of soluble TREM-like transcript-1 with clinical features and patient reported outcomes in systemic lupus erythematosus.

Author

Vázquez-Otero, Ileana, Rodríguez-Navedo, Yerania, Vilá-Rivera, Karina, Nieves-Plaza, Mariely, Morales-Ortiz, Jessica, Washington, A. Valance, and Vilá, Luis M.

Abstract

Objective: The soluble triggering receptor expressed on myeloid cells (TREM-1)-like transcript 1 (sTLT- 1) has a modulatory effect on the activation of TREM-1. We compared plasma sTLT-1 levels between patients with systemic lupus erythematosus (SLE) and healthy individuals and determined the association between sTLT-1 levels and clinical features and patient-reported outcomes (PROs) among patients with lupus. Methods: An unmatched case-control study was conducted in 46 patients with SLE and 28 healthy subjects. sTLT-1 plasma levels were determined using enzyme-linked immunosorbent assay. Demographic factors, SLE manifestations, comorbidities, pharmacologic profile, disease activity (per SLAM-R), damage accrual, and PROs (as per Lupus Patient-Reported Outcome [LupusPRO]) were studied. Results: Patients with SLE were found to have lower sTLT-1 levels compared with healthy individuals (9.0±7.2 vs. 18.6±22.3 pg/mL, p=0.008). Among patients with SLE, higher sTLT-1 levels were found in those taking corticosteroids (11.1±8.8 vs. 6.9±4.6 pg/mL, p=0.014). Significant correlations were found for the cognition (r=-0.442, p=0.027) and desires/goals (r=0.435, p=0.030) domains of Lupus-PRO. A tendency was observed between sTLT-1 levels and the SLAM-R (r=-0.278, p=0.064) and the lupus symptoms (r=-0.388, p=0.055) and physical health (r=-0.382, p=0.060) domains of LupusPRO. Conclusion: Compared with healthy individuals, sTLT-1 levels were significantly lower in patients with SLE. Among patients with SLE, correlations were observed for some domains of LupusPRO. Given that sTLT-1 has anti-inflammatory properties, the deficiency of this protein could play an important role in the pathogenesis of SLE. [ABSTRACT FROM AUTHOR]

Published
2018
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131. Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Author

Sakurai, Daisuke, Zhao, Jian, Deng, Yun, Kelly, Jennifer A., Brown, Elizabeth E., Harley, John B., Bae, Sang Cheol, Alarcn-Riquelme, Marta E., Edberg, Jeffrey C., Kimberly, Robert P., Ramsey-Goldman, Rosalind, Petri, Michelle A., Reveille, John D., Vilá, Luis M., Alarcón, Graciela S., Kaufman, Kenneth M., Vyse, Timothy J., Jacob, Chaim O., Gaffney, Patrick M., Sivils, Kathy Moser, James, Judith A., Kamen, Diane L., Gilkeson, Gary S., Niewold, Timothy B., Merrill, Joan T., Scofield, R. Hal, Criswell, Lindsey A., Stevens, Anne M., Boackle, Susan A., Kim, Jae Hoon, Choi, Jiyoung, Pons-Estel, Bernardo A., Freedman, Barry I., Anaya, Juan Manuel, Martin, Javier, Yu, C. Yung, Chang, Deh Ming, Song, Yeong Wook, Langefeld, Carl D., Chen, Weiling, Grossman, Jennifer M., Cantor, Rita M., Hahn, Bevra H., Tsao, Betty P., Frostegård, Johan, Truedsson, Lennart, de Ramón, Enrique, Sabio, José M., Ortego-Centeno, Norberto, CAllejas, José Luis, González-Escribano, María F., Sánchez-Román, Julio, D'Alfonso, Sandra, Migliarese, Sergio, Sebastiani, Gian Domenico, Galeazzi, Mauro, Witte, Torsten, Lauwerys, Bernard R., Endreffy, Emoke, Kovács, László, Vasconcelos, Carlos, da Silva, Berta Martins, Scherbarth, Hugo R., Marino, Pilar C., Motta, Estela L., Gamron, Susana, Drenkard, Cristina, Menso, Emilia, Allievi, Alberto, Tate, Guillermo A., Presas, Jose L., Palatnik, Simon A., Abdala, Marcelo, Bearzotti, Mariela, Alvarellos, Alejandro, Caeiro, Francisco, Bertoli, Ana, Paira, Sergio, Roverano, Susana, Graf, Cesar E., Bertero, Estela, Caprarulo, Cesar, Buchanan, Griselda, Guillerón, Carolina, Grimaudo, Sebastian, Manni, Jorge, Catoggio, Luis J., Soriano, Enrique R., Santos, Carlos D., Prigione, Cristina, Ramos, Fernando A., Navarro, Sandra M., Berbotto, Guillermo A., Jorfen, Marisa, Romero, Elisa J., Garcia, Mercedes A., Marcos, Juan C., Marcos, Ana I., Perandones, Carlos E., Eimon, Alicia, Parque, Sanatorio, Battagliotti, Cristina G., Acevedo, Eduardo, Cucho, Mariano, de la Torre, Ignacio García, Ríos, Mario Cardiel, Moctezuma, José Francisco, and Ceceña, Marco Maradiaga

Subjects
Cancer Research, medicine.medical_treatment, Genome-wide association study, Gene, Disease predisposition, 0302 clinical medicine, Interleukin 10, immune system diseases, Lupus Erythematosus, Systemic, Disease activity, skin and connective tissue diseases, Genetics (clinical), Regulation of gene expression, 0303 health sciences, TGranscription factor Elk 1, Hispanic or Latino, Interleukin-10, Up-Regulation, 3. Good health, Cytokine, Research Article, Protein Binding, Genotype, lcsh:QH426-470, Inmunología, Single-nucleotide polymorphism, Down regulation, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Asian People, Enfermedades autoinmunes, Lupus eritematoso sistémico, Genetics, medicine, Humans, Genetic Predisposition to Disease, Electrophoretic mobility shift assay, Gene cluster, Allele, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, ets-Domain Protein Elk-1, 030304 developmental biology, Lupus erythematosus, medicine.disease, Enfermedades, Introns, lcsh:Genetics, Binding affinity, Gene Expression Regulation, Haplotypes, Immunology, Controlled study, Genome-Wide Association Study, 030215 immunology
Abstract

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.

Published
2013
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132. Two Independent Functional Risk Haplotypes in TNIP1 are Associated with Systemic Lupus Erythematosus

Author

Adrianto, Indra, Wang, Shaofeng, Wiley, Graham B., Lessard, Christopher J., Kelly, Jennifer A., Adler, Adam J., Glenn, Stuart B., Williams, Adrienne H., Ziegler, Julie T., Comeau, Mary E., Marion, Miranda C., Wakeland, Benjamin E., Liang, Chaoying, Kaufman, Kenneth M., Guthridge, Joel M., Alarcón-Riquelme, Marta E., Alarcón, Graciela S., Anaya, Juan-Manuel, Bae, Sang-Cheol, Kim, Jae-Hoon, Joo, Young Bin, Boackle, Susan A., Brown, Elizabeth E., Petri, Michelle A., Ramsey-Goldman, Rosalind, Reveille, John D., Vilá, Luis M., Criswell, Lindsey A., Edberg, Jeffrey C., Freedman, Barry I., Gilkeson, Gary S., Jacob, Chaim O., James, Judith A., Kamen, Diane L., Kimberly, Robert P., Martin, Javier, Merrill, Joan T., Niewold, Timothy B., Pons-Estel, Bernardo A., Scofield, R. Hal, Stevens, Anne M., Tsao, Betty P., Vyse, Timothy J., Langefeld, Carl D., Harley, John B., Wakeland, Edward K., Moser, Kathy L., Montgomery, Courtney G., and Gaffney, Patrick M.

Subjects
Genetic Markers, Male, B-Lymphocytes, Asian, Intracellular Signaling Peptides and Proteins, Hispanic or Latino, Polymorphism, Single Nucleotide, Article, United States, White People, Neoplasm Proteins, Black or African American, DNA-Binding Proteins, Haplotypes, Risk Factors, Humans, Lupus Erythematosus, Systemic, Female, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Cell Line, Transformed
Abstract

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 identified30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate 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 populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively.We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.Our results confirm 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.

Published
2012

134. Association of PPP2CA polymorphisms with SLE susceptibility in multiple ethnic groups

Author

Tan, Wenfeng, Sunahori, Katsue, Zhao, Jian, Deng, Yun, Kaufman, Kenneth M., Kelly, Jennifer A., Langefeld, Carl D., Williams, Adrienne H., Comeau, Mary E., Ziegler, Julie T., Marion, Miranda C., Bae, Sang-Cheol, Lee, Joo Hyun, Lee, Ji-Seon, Chang, Deh-Ming, Song, Yeong Wook, Yu, Chack-Yung, Kimberly, Robert P., Edberg, Jeffrey C., Brown, Elizabeth E., Petri, Michelle A., Ramsey-Goldman, Rosalind, Vilá, Luis M., Reveille, John D., Alarcón-Riquelme, Marta E., Harley, John B., Boackle, Susan A., Stevens, Anne M., Scofield, R. Hal, Merrill, Joan T., Freedman, Barry I., Anaya, Juan-Manuel, Criswell, Lindsey A., Jacob, Chaim O., Vyse, Timothy J., Niewold, Timothy B., Gaffney, Patrick M., Moser, Kathy L., Gilkeson, Gary S., Kamen, Diane L., James, Judith A., Grossman, Jennifer M., Hahn, Bevra H., Tsokos, George C., and Tsao, Betty P.

Subjects
Adult, Male, Polymorphism, Genetic, Adolescent, Genotype, T-Lymphocytes, Hispanic or Latino, Middle Aged, Article, White People, Asian People, Haplotypes, Humans, Interleukin-2, Lupus Erythematosus, Systemic, Female, Genetic Predisposition to Disease, Protein Phosphatase 2, Alleles, Genetic Association Studies
Abstract

T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction.A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007).Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians.

Published
2011

135. Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Author

Deng, Yun, primary, Zhao, Jian, additional, Sakurai, Daisuke, additional, Sestak, Andrea L, additional, Osadchiy, Vadim, additional, Langefeld, Carl D, additional, Kaufman, Kenneth M, additional, Kelly, Jennifer A, additional, James, Judith A, additional, Petri, Michelle A, additional, Bae, Sang-Cheol, additional, Alarcón-Riquelme, Marta E, additional, Alarcón, Graciela S, additional, Anaya, Juan-Manuel, additional, Criswell, Lindsey A, additional, Freedman, Barry I, additional, Kamen, Diane L, additional, Gilkeson, Gary S, additional, Jacob, Chaim O, additional, Merrill, Joan T, additional, Gaffney, Patrick M, additional, Sivils, Kathy Moser, additional, Niewold, Timothy B, additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D, additional, Scofield, R Hal, additional, Stevens, Anne M, additional, Boackle, Susan A, additional, Vilá, Luis M, additional, Sohn, I I Woong, additional, Lee, Seung, additional, Chang, Deh-Ming, additional, Song, Yeong Wook, additional, Vyse, Timothy J, additional, Harley, John B, additional, Brown, Elizabeth E, additional, Edberg, Jeffrey C, additional, Kimberly, Robert P, additional, Cantor, Rita M, additional, Hahn, Bevra H, additional, Grossman, Jennifer M, additional, and Tsao, Betty P, additional

Published
2016
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141. Possible Protective Effect of Hydroxychloroquine on Retarding the Occurrence of Integument Damage in Lupus: Data from LUMINA, a Multiethnic Cohort

Author

Pons-Estel, Guillermo J., Alarcón, Graciela S., González, Luis A., Zhang, Jie, Vilá, Luis M., Reveille, John D., and McGwin, Gerald

Subjects
Adult, Male, Hispanic or Latino, Kaplan-Meier Estimate, Skin Diseases, Article, White People, Black or African American, Young Adult, Antirheumatic Agents, Disease Progression, Humans, Lupus Erythematosus, Systemic, Female, Hydroxychloroquine
Abstract

To determine the features predictive of time to integument damage in patients with systemic lupus erythematosus (SLE) from a multiethnic cohort (LUpus in MInorities, NAture versus nurture [LUMINA]).LUMINA SLE patients (n = 580) ageor =16 years, with a disease duration ofor =5 years at baseline (T0), of African American, Hispanic, and Caucasian ethnicity were studied. Integument damage was defined per the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (scarring alopecia, extensive skin scarring, and skin ulcers lasting at least 6 months); factors associated with time to its occurrence were examined by Cox proportional univariable and multivariable (main model) hazards regression analyses. Two alternative models were also examined: in model 1, all patients, regardless of when integument damage occurred (n = 94), were included; in model 2, a time-varying approach (generalized estimating equation) was employed.Thirty-nine (6.7%) of 580 patients developed integument damage over a mean +/- SD total disease duration of 5.9 +/- 3.7 years, and were included in the main multivariable regression model. After adjusting for discoid rash, nailfold infarcts, photosensitivity, and Raynaud's phenomenon (significant in the univariable analyses), disease activity over time (hazard ratio [HR] 1.17, 95% confidence interval [95% CI] 1.09-1.26) was associated with a shorter time to integument damage, whereas hydroxychloroquine use (HR 0.23, 95% CI 0.12-0.47) and Texan-Hispanic (HR 0.35, 95% CI 0.14-0.87) and Caucasian ethnicities (HR 0.37, 95% CI 0.14-0.99) were associated with a longer time. Results of the alternative models were consistent with those of the main model, although in model 2, the association with hydroxychloroquine was not significant.Our data indicate that hydroxychloroquine use is possibly associated with a delay in integument damage development in patients with SLE.

Published
2010

143. Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study

Author

Lessard, Christopher J., Adrianto, Indra, Kelly, Jennifer A., Kaufman, Kenneth M., Grundahl, Kiely M., Adler, Adam, Williams, Adrienne H., Gallant, Caroline J., Anaya, Juan-Manuel, Bae, Sang-Cheol, Boackle, Susan A., Brown, Elizabeth E., Chang, Deh-Ming, Criswell, Lindsey A., Edberg, Jeffrey C., Freedman, Barry I., Gregersen, Peter K., Gilkeson, Gary S., Jacob, Chaim O., James, Judith A., Kamen, Diane L., Kimberly, Robert P., Martin, Javier, Merrill, Joan T., Niewold, Timothy B., Park, So-Yeon, Petri, Michelle A., Pons-Estel, Bernardo A., Ramsey-Goldman, Rosalind, Reveille, John D., Song, Yeong Wook, Stevens, Anne M., Tsao, Betty P., Vila, Luis M., Vyse, Timothy J., Yu, Chack-Yung, Guthridge, Joel M., Bruner, Gail R., Langefeld, Carl D., Montgomery, Courtney, Harley, John B., Scofield, R. Hal, Gaffney, Patrick M., and Moser, Kathy L.

Published
2011
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144. Brief Report: A Polymorphism in TLR2 Is Associated With Arterial Thrombosis in a Multiethnic Population of Patients With Systemic Lupus Erythematosus

Author

Kaiser, Rachel, primary, Tang, Ling Fung, additional, Taylor, Kimberly E., additional, Sterba, Kirsten, additional, Nititham, Joanne, additional, Brown, Elizabeth E., additional, Edberg, Jeffrey C., additional, McGwin, Gerald, additional, Alarcón, Graciela S., additional, Ramsey‐Goldman, Rosalind, additional, Reveille, John D., additional, Vilá, Luis M., additional, Petri, Michelle, additional, Rauch, Joyce, additional, Miller, Emily, additional, Mesznik, Kara, additional, Kwok, Pui‐Yan, additional, Kimberly, Robert P., additional, Salmon, Jane E., additional, and Criswell, Lindsey A., additional

Published
2014
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146. Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Author

Sakurai, D., Zhao, J., Deng, Y., Kelly, J. A., Brown, E. E., Harley, J. B., Bae, S. C., Alarcón-Riquelme, M. E., Edberg, J. C., Kimberly, R. P., Ramsey-Goldman, R., Caeiro, F., Soriano, E. R., Bertoli, A., Prigione, C., Ramos, F. A., Romero, E. J., Tsao, B. P., Chen, W., Truedsson, L., Yu, C. Y., Migliarese, S., García, M. A., Marcos, J. C., Eimon, A., Sánchez-Román, J., Battagliotti, C. G., Kaufman, K. M., Vyse, T. J., Jacob, C. O., Gaffney, P. M., Sebastiani, G. D., Ramón, Enrique de, Hahn, B. H., Song, Y. W., Grossman, J. M., Sivils, K. M., James, J. A., Kamen, D. L., Gilkeson, G. S., Niewold, T. B., D'Alfonso, Sandra, Merrill, J. T., Martín, J., Scofield, R. H., Chang, D. M., Criswell, L. A., Langefeld, C. D., Stevens, A. M., Cantor, R. M., Frostegård, Johan, Boackle, S. A., Kim, J. H., Choi, J., Pons-Estel, B. A., Freedman, Barry I., Sabio, José Mario, Anaya, J. M., Ortego-Centeno, N., Callejas-Rubio, J. L., González-Escribano, María Francisca, Buchanan, G., Graf, C. E., Paira, S., Galeazzi, M., Witte, Torsten, Lauwerys, B. R., Endreffy, E., Kovács, L., Vasconcelos, C., Silva, B. M. da, Scherbarth, H. R., Catoggio, L. J., Manni, J., Caprarulo, C., Guillerón, C., Marino, P. C., Motta, E. L., Gamron, S., Drenkard, C., Menso, E., Allievi, A., Roverano, S., Tate, G. A., Bertero, E., Presas, J. L., Navarro, S. M., Parque, S., Grimaudo, S., Palatnik, S. A., Abdala, M., Acevedo, E., Bearzotti, M., Santos, C. D., Alvarellos, A., Berbotto, G. A., Jorfen, M., Marcos, A. I., Perandones, C. E., Cucho, M., Torre, I. G. de la, Ríos, M. C., Moctezuma, J. F., Ceceña, M. M., Petri, M. A., Vilá, Luis M., Reveille, J. D., Alarcón, G. S., Sakurai, D., Zhao, J., Deng, Y., Kelly, J. A., Brown, E. E., Harley, J. B., Bae, S. C., Alarcón-Riquelme, M. E., Edberg, J. C., Kimberly, R. P., Ramsey-Goldman, R., Caeiro, F., Soriano, E. R., Bertoli, A., Prigione, C., Ramos, F. A., Romero, E. J., Tsao, B. P., Chen, W., Truedsson, L., Yu, C. Y., Migliarese, S., García, M. A., Marcos, J. C., Eimon, A., Sánchez-Román, J., Battagliotti, C. G., Kaufman, K. M., Vyse, T. J., Jacob, C. O., Gaffney, P. M., Sebastiani, G. D., Ramón, Enrique de, Hahn, B. H., Song, Y. W., Grossman, J. M., Sivils, K. M., James, J. A., Kamen, D. L., Gilkeson, G. S., Niewold, T. B., D'Alfonso, Sandra, Merrill, J. T., Martín, J., Scofield, R. H., Chang, D. M., Criswell, L. A., Langefeld, C. D., Stevens, A. M., Cantor, R. M., Frostegård, Johan, Boackle, S. A., Kim, J. H., Choi, J., Pons-Estel, B. A., Freedman, Barry I., Sabio, José Mario, Anaya, J. M., Ortego-Centeno, N., Callejas-Rubio, J. L., González-Escribano, María Francisca, Buchanan, G., Graf, C. E., Paira, S., Galeazzi, M., Witte, Torsten, Lauwerys, B. R., Endreffy, E., Kovács, L., Vasconcelos, C., Silva, B. M. da, Scherbarth, H. R., Catoggio, L. J., Manni, J., Caprarulo, C., Guillerón, C., Marino, P. C., Motta, E. L., Gamron, S., Drenkard, C., Menso, E., Allievi, A., Roverano, S., Tate, G. A., Bertero, E., Presas, J. L., Navarro, S. M., Parque, S., Grimaudo, S., Palatnik, S. A., Abdala, M., Acevedo, E., Bearzotti, M., Santos, C. D., Alvarellos, A., Berbotto, G. A., Jorfen, M., Marcos, A. I., Perandones, C. E., Cucho, M., Torre, I. G. de la, Ríos, M. C., Moctezuma, J. F., Ceceña, M. M., Petri, M. A., Vilá, Luis M., Reveille, J. D., and Alarcón, G. S.

Abstract

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 expressio

Published
2013

147. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

Author

UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de rhumatologie, Hughes, Travis, Adler, Adam, Merrill, Joan T, Kelly, Jennifer A, Kaufman, Kenneth M, Williams, Adrienne, Langefeld, Carl D, Gilkeson, Gary S, Sanchez, Elena, Martin, Javier, Boackle, Susan A, Stevens, Anne M, Alarcón, Graciela S, Niewold, Timothy B, Brown, Elizabeth E, Kimberly, Robert P, Edberg, Jeffrey C, Ramsey-Goldman, Rosalind, Petri, Michelle, Reveille, John D, Criswell, Lindsey A, Vilá, Luis M, Jacob, Chaim O, Gaffney, Patrick M, Moser, Kathy L, Vyse, Timothy J, Alarcón-Riquelme, Marta E, BIOLUPUS Network, James, Judith A, Tsao, Betty P, Scofield, R Hal, Harley, John B, Richardson, Bruce C, Sawalha, Amr H, Lauwerys, Bernard, UCL - SSS/DDUV - Institut de Duve, UCL - (SLuc) Service de rhumatologie, Hughes, Travis, Adler, Adam, Merrill, Joan T, Kelly, Jennifer A, Kaufman, Kenneth M, Williams, Adrienne, Langefeld, Carl D, Gilkeson, Gary S, Sanchez, Elena, Martin, Javier, Boackle, Susan A, Stevens, Anne M, Alarcón, Graciela S, Niewold, Timothy B, Brown, Elizabeth E, Kimberly, Robert P, Edberg, Jeffrey C, Ramsey-Goldman, Rosalind, Petri, Michelle, Reveille, John D, Criswell, Lindsey A, Vilá, Luis M, Jacob, Chaim O, Gaffney, Patrick M, Moser, Kathy L, Vyse, Timothy J, Alarcón-Riquelme, Marta E, BIOLUPUS Network, James, Judith A, Tsao, Betty P, Scofield, R Hal, Harley, John B, Richardson, Bruce C, Sawalha, Amr H, and Lauwerys, Bernard

Abstract

Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Published
2012

148. Genetic risk factors for thrombosis in systemic lupus erythematosus.

Author

Kaiser, Rachel, Kaiser, Rachel, Li, Yonghong, Chang, Monica, Catanese, Joseph, Begovich, Ann B, Brown, Elizabeth E, Edberg, Jeffrey C, McGwin, Gerald, Alarcón, Graciela S, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Petri, Michelle A, Kimberly, Robert P, Taylor, Kimberly E, Criswell, Lindsey A, Kaiser, Rachel, Kaiser, Rachel, Li, Yonghong, Chang, Monica, Catanese, Joseph, Begovich, Ann B, Brown, Elizabeth E, Edberg, Jeffrey C, McGwin, Gerald, Alarcón, Graciela S, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, Petri, Michelle A, Kimberly, Robert P, Taylor, Kimberly E, and Criswell, Lindsey A

Abstract

ObjectiveThrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.MethodsOur discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.ResultsIn the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.ConclusionOur results implicate specific genetic risk factors for thrombosis in patients with SLE and sugges

Published
2012

149. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations.

Author

Sánchez, Elena, Sánchez, Elena, Rasmussen, Astrid, Riba, Laura, Acevedo-Vasquez, Eduardo, Kelly, Jennifer A, Langefeld, Carl D, Williams, Adrianne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, García-De La Torre, Ignacio, Maradiaga-Ceceña, Marco A, Cardiel, Mario H, Esquivel-Valerio, Jorge A, Rodriguez-Amado, Jacqueline, Moctezuma, José Francisco, Miranda, Pedro, Perandones, Carlos E, Castel, Cecilia, Laborde, Hugo A, Alba, Paula, Musuruana, Jorge L, Goecke, I Annelise, Anaya, Juan-Manuel, Kaufman, Kenneth M, Adler, Adam, Glenn, Stuart B, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Vilá, Luis M, Criswell, Lindsey A, Gilkeson, Gary S, Niewold, Timothy B, Martín, Javier, Vyse, Timothy J, Boackle, Susan A, Ramsey-Goldman, Rosalind, Scofield, R Hal, Petri, Michelle, Merrill, Joan T, Reveille, John D, Tsao, Betty P, Orozco, Lorena, Baca, Vicente, Moser, Kathy L, Gaffney, Patrick M, James, Judith A, Harley, John B, Tusié-Luna, Teresa, Pons-Estel, Bernardo A, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Sánchez, Elena, Sánchez, Elena, Rasmussen, Astrid, Riba, Laura, Acevedo-Vasquez, Eduardo, Kelly, Jennifer A, Langefeld, Carl D, Williams, Adrianne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, García-De La Torre, Ignacio, Maradiaga-Ceceña, Marco A, Cardiel, Mario H, Esquivel-Valerio, Jorge A, Rodriguez-Amado, Jacqueline, Moctezuma, José Francisco, Miranda, Pedro, Perandones, Carlos E, Castel, Cecilia, Laborde, Hugo A, Alba, Paula, Musuruana, Jorge L, Goecke, I Annelise, Anaya, Juan-Manuel, Kaufman, Kenneth M, Adler, Adam, Glenn, Stuart B, Brown, Elizabeth E, Alarcón, Graciela S, Kimberly, Robert P, Edberg, Jeffrey C, Vilá, Luis M, Criswell, Lindsey A, Gilkeson, Gary S, Niewold, Timothy B, Martín, Javier, Vyse, Timothy J, Boackle, Susan A, Ramsey-Goldman, Rosalind, Scofield, R Hal, Petri, Michelle, Merrill, Joan T, Reveille, John D, Tsao, Betty P, Orozco, Lorena, Baca, Vicente, Moser, Kathy L, Gaffney, Patrick M, James, Judith A, Harley, John B, Tusié-Luna, Teresa, Pons-Estel, Bernardo A, Jacob, Chaim O, and Alarcón-Riquelme, Marta E

Abstract

ObjectiveAmerican Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients.MethodsA total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).ResultsThe average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian 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 for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement.ConclusionIn general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.

Published
2012

150. Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus

Author

Hughes, T., Adler, A. J., Merrill, J. T., Kelly, J. A., Kaufman, K. M., Williams, A. H., Langefeld, C. D., Gilkeson, G. S., Sánchez, Elena, Martín, J., Boackle, S. A., Stevens, A. M., Alarcón, G. S., Niewold, T. B., Brown, E. E., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., Petri, M., Reveille, J. D., Criswell, L. A., Vilá, Luis M., Jacob, C. O., Gaffney, P. M., Moser, K. L., Vyse, T. J., Alarcón-Riquelme, M. E., James, J. A., Tsao, B. P., Scofield, R. H., Harley, J. B., Richardson, B. C., Sawalha, A. H., Frostegård, Johan, Truedsson, L., Ramón, Enrique de, Sabio, José Mario, González-Escribano, María Francisca, Ortego-Centeno, N., Callejas-Rubio, J. L., Sánchez-Román, J., D'Alfonso, Sandra, Migliarese, S., Sebastiani, G. D., Galeazzi, M., Witte, Torsten, Lauwerys, B. R., Endreffy, E., Kovács, L., Vasconcelos, C., Silva, B. M. da, Hughes, T., Adler, A. J., Merrill, J. T., Kelly, J. A., Kaufman, K. M., Williams, A. H., Langefeld, C. D., Gilkeson, G. S., Sánchez, Elena, Martín, J., Boackle, S. A., Stevens, A. M., Alarcón, G. S., Niewold, T. B., Brown, E. E., Kimberly, R. P., Edberg, J. C., Ramsey-Goldman, R., Petri, M., Reveille, J. D., Criswell, L. A., Vilá, Luis M., Jacob, C. O., Gaffney, P. M., Moser, K. L., Vyse, T. J., Alarcón-Riquelme, M. E., James, J. A., Tsao, B. P., Scofield, R. H., Harley, J. B., Richardson, B. C., Sawalha, A. H., Frostegård, Johan, Truedsson, L., Ramón, Enrique de, Sabio, José Mario, González-Escribano, María Francisca, Ortego-Centeno, N., Callejas-Rubio, J. L., Sánchez-Román, J., D'Alfonso, Sandra, Migliarese, S., Sebastiani, G. D., Galeazzi, M., Witte, Torsten, Lauwerys, B. R., Endreffy, E., Kovács, L., Vasconcelos, C., and Silva, B. M. da

Abstract

Objectives: Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. Methods: A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. Results: A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10 -8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. Conclusions: The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Published
2012

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