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252. Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

Author

Guthridge, Joel M., primary, Lu, Rufei, additional, Sun, Harry, additional, Sun, Celi, additional, Wiley, Graham B., additional, Dominguez, Nicolas, additional, Macwana, Susan R., additional, Lessard, Christopher J., additional, Kim-Howard, Xana, additional, Cobb, Beth L., additional, Kaufman, Kenneth M., additional, Kelly, Jennifer A., additional, Langefeld, Carl D., additional, Adler, Adam J., additional, Harley, Isaac T.W., additional, Merrill, Joan T., additional, Gilkeson, Gary S., additional, Kamen, Diane L., additional, Niewold, Timothy B., additional, Brown, Elizabeth E., additional, Edberg, Jeffery C., additional, Petri, Michelle A., additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D., additional, Vilá, Luis M., additional, Kimberly, Robert P., additional, Freedman, Barry I., additional, Stevens, Anne M., additional, Boackle, Susan A., additional, Criswell, Lindsey A., additional, Vyse, Tim J., additional, Behrens, Timothy W., additional, Jacob, Chaim O., additional, Alarcón-Riquelme, Marta E., additional, Sivils, Kathy L., additional, Choi, Jiyoung, additional, Joo, Young Bin, additional, Bang, So-Young, additional, Lee, Hye-Soon, additional, Bae, Sang-Cheol, additional, Shen, Nan, additional, Qian, Xiaoxia, additional, Tsao, Betty P., additional, Scofield, R. Hal, additional, Harley, John B., additional, Webb, Carol F., additional, Wakeland, Edward K., additional, James, Judith A., additional, Nath, Swapan K., additional, Graham, Robert R., additional, and Gaffney, Patrick M., additional

Published
2014
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253. Impact of early disease factors on metabolic syndrome in systemic lupus erythematosus: data from an international inception cohort

Author

Parker, Ben, primary, Urowitz, Murray B, additional, Gladman, Dafna D, additional, Lunt, Mark, additional, Donn, Rachelle, additional, Bae, Sang-Cheol, additional, Sanchez-Guerrero, Jorge, additional, Romero-Diaz, Juanita, additional, Gordon, Caroline, additional, Wallace, Daniel J, additional, Clarke, Ann E, additional, Bernatsky, Sasha, additional, Ginzler, Ellen M, additional, Isenberg, David A, additional, Rahman, Anisur, additional, Merrill, Joan T, additional, Alarcón, Graciela S, additional, Fessler, Barri J, additional, Fortin, Paul R, additional, Hanly, John G, additional, Petri, Michelle, additional, Steinsson, Kristjan, additional, Dooley, Mary Anne, additional, Manzi, Susan, additional, Khamashta, Munther A, additional, Ramsey-Goldman, Rosalind, additional, Zoma, Asad A, additional, Sturfelt, Gunnar K, additional, Nived, Ola, additional, Aranow, Cynthia, additional, Mackay, Meggan, additional, Ramos-Casals, Manuel, additional, van Vollenhoven, Ronald F, additional, Kalunian, Kenneth C, additional, Ruiz-Irastorza, Guillermo, additional, Lim, S Sam, additional, Kamen, Diane L, additional, Peschken, Christine A, additional, Inanc, Murat, additional, and Bruce, Ian N, additional

Published
2014
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255. Cancer risk factors in systemic lupus erythematosus: multivariate regression analysis in 16,409 patients

Author

Bernatsky, Sasha, primary, Ramsey-Goldman, Rosalind, additional, Boivin, Jean-François, additional, Joseph, Lawrence, additional, Petri, Michelle A, additional, Zoma, Asad, additional, Manzi, Susan, additional, Urowitz, Murray B, additional, Gladman, Dafna D, additional, Fortin, Paul R, additional, Ginzler, Ellen M, additional, Yelin, Edward, additional, Bae, Sang-Cheol, additional, Wallace, Daniel J, additional, Edworthy, Steven M, additional, Jacobsen, Soren, additional, Gordon, Caroline, additional, Dooley, Mary A, additional, Peschken, Christine A, additional, Hanly, John G, additional, Alarcón, Graciela S, additional, Nived, Ola, additional, Ruiz-Irastorza, Guillermo, additional, Isenberg, David, additional, Rahman, Anisur, additional, Witte, Torsten, additional, Aranow, Cynthia, additional, Kamen, Diane L, additional, Steinsson, Kristján, additional, Askanase, Anca, additional, Barr, Susan G, additional, Criswell, Lindsey A, additional, Sturfelt, Gunnar, additional, Patel, Neha M, additional, Senécal, Jean-Luc, additional, Zummer, Michel, additional, Pope, Janet E, additional, Ensworth, Stephanie, additional, El-Gabalawy, Hani, additional, McCarthy, Timothy, additional, St Pierre, Yvan, additional, and Clarke, Anne E, additional

Published
2014
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256. Clinical response to belimumab in academic clinical practices

Author

Reddy, Arthi, primary, Li, XiaoQing, additional, Buyon, Jill P, additional, Franks, Andrew G, additional, Furie, Richard A, additional, Kamen, Diane L, additional, Manzi, Susan, additional, Petri, Michelle, additional, Ramsey-Goldman, Rosalind, additional, Tseng, Chung-E, additional, van Vollenhoven, Ronald F, additional, Wallace, Daniel J, additional, and Askanase, Anca D, additional

Published
2014
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258. Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry.

Author

Ramos, Paula S, Ramos, Paula S, Oates, James C, Kamen, Diane L, Williams, Adrienne H, Gaffney, Patrick M, Kelly, Jennifer A, Kaufman, Kenneth M, Kimberly, Robert P, Niewold, Timothy B, Jacob, Chaim O, Tsao, Betty P, Alarcón, Graciela S, Brown, Elizabeth E, Edberg, Jeffrey C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, James, Judith A, Guthridge, Joel M, Merrill, Joan T, Boackle, Susan A, Freedman, Barry I, Scofield, R Hal, Stevens, Anne M, Vyse, Timothy J, Criswell, Lindsey A, Moser, Kathy L, Alarcón-Riquelme, Marta E, Langefeld, Carl D, Harley, John B, Gilkeson, Gary S, Ramos, Paula S, Ramos, Paula S, Oates, James C, Kamen, Diane L, Williams, Adrienne H, Gaffney, Patrick M, Kelly, Jennifer A, Kaufman, Kenneth M, Kimberly, Robert P, Niewold, Timothy B, Jacob, Chaim O, Tsao, Betty P, Alarcón, Graciela S, Brown, Elizabeth E, Edberg, Jeffrey C, Petri, Michelle A, Ramsey-Goldman, Rosalind, Reveille, John D, Vilá, Luis M, James, Judith A, Guthridge, Joel M, Merrill, Joan T, Boackle, Susan A, Freedman, Barry I, Scofield, R Hal, Stevens, Anne M, Vyse, Timothy J, Criswell, Lindsey A, Moser, Kathy L, Alarcón-Riquelme, Marta E, Langefeld, Carl D, Harley, John B, and Gilkeson, Gary S

Abstract

ObjectiveLittle 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. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.MethodsA total of 244 single-nucleotide polymorphisms (SNP) 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). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.ResultsThe glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 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 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 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 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.ConclusionThese results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Published
2013

259. Headache in Systemic Lupus Erythematosus:Results From a Prospective, International Inception Cohort Study

Author

Hanly, John G, Urowitz, Murray B, O'Keeffe, Aidan G, Gordon, Caroline, Bae, Sang-Cheol, Sanchez-Guerrero, Jorge, Romero-Diaz, Juanita, Clarke, Ann E, Bernatsky, Sasha, Wallace, Daniel J, Ginzler, Ellen M, Isenberg, David A, Rahman, Anisur, Merrill, Joan T, Petri, Michelle, Fortin, Paul R, Gladman, Dafna D, Fessler, Barri J, Alarcón, Graciela S, Bruce, Ian N, Dooley, Mary Anne, Steinsson, Kristjan, Khamashta, Munther A, Ramsey-Goldman, Rosalind, Manzi, Susan, Sturfelt, Gunnar K, Nived, Ola, Zoma, Asad A, van Vollenhoven, Ronald F, Ramos-Casals, Manuel, Aranow, Cynthia, Mackay, Meggan, Ruiz-Irastorza, Guillermo, Kalunian, Kenneth C, Lim, S Sam, Inanc, Murat, Kamen, Diane L, Peschken, Christine A, Jacobsen, Soren, Theriault, Chris, Thompson, Kara, Farewell, Vernon, Hanly, John G, Urowitz, Murray B, O'Keeffe, Aidan G, Gordon, Caroline, Bae, Sang-Cheol, Sanchez-Guerrero, Jorge, Romero-Diaz, Juanita, Clarke, Ann E, Bernatsky, Sasha, Wallace, Daniel J, Ginzler, Ellen M, Isenberg, David A, Rahman, Anisur, Merrill, Joan T, Petri, Michelle, Fortin, Paul R, Gladman, Dafna D, Fessler, Barri J, Alarcón, Graciela S, Bruce, Ian N, Dooley, Mary Anne, Steinsson, Kristjan, Khamashta, Munther A, Ramsey-Goldman, Rosalind, Manzi, Susan, Sturfelt, Gunnar K, Nived, Ola, Zoma, Asad A, van Vollenhoven, Ronald F, Ramos-Casals, Manuel, Aranow, Cynthia, Mackay, Meggan, Ruiz-Irastorza, Guillermo, Kalunian, Kenneth C, Lim, S Sam, Inanc, Murat, Kamen, Diane L, Peschken, Christine A, Jacobsen, Soren, Theriault, Chris, Thompson, Kara, and Farewell, Vernon

Published
2013

260. Cancer risk in systemic lupus:An updated international multi-centre cohort study

Author

Bernatsky, Sasha, Ramsey-Goldman, Rosalind, Labrecque, Jeremy, Joseph, Lawrence, Boivin, Jean-Francois, Petri, Michelle, Zoma, Asad, Manzi, Susan, Urowitz, Murray B, Gladman, Dafna, Fortin, Paul R, Ginzler, Ellen, Yelin, Edward, Bae, Sang-Cheol, Wallace, Daniel J, Edworthy, Steven, Jacobsen, Soren, Gordon, Caroline, Dooley, Mary Anne, Peschken, Christine A, Hanly, John G, Alarcón, Graciela S, Nived, Ola, Ruiz-Irastorza, Guillermo, Isenberg, David, Rahman, Anisur, Witte, Torsten, Aranow, Cynthia, Kamen, Diane L, Steinsson, Kristjan, Askanase, Anca, Barr, Susan, Criswell, Lindsey A, Sturfelt, Gunnar, Patel, Neha M, Senécal, Jean-Luc, Zummer, Michel, Pope, Janet E, Ensworth, Stephanie, El-Gabalawy, Hani, McCarthy, Timothy, Dreyer, Lene, Sibley, John, St Pierre, Yvan, Clarke, Ann E, Bernatsky, Sasha, Ramsey-Goldman, Rosalind, Labrecque, Jeremy, Joseph, Lawrence, Boivin, Jean-Francois, Petri, Michelle, Zoma, Asad, Manzi, Susan, Urowitz, Murray B, Gladman, Dafna, Fortin, Paul R, Ginzler, Ellen, Yelin, Edward, Bae, Sang-Cheol, Wallace, Daniel J, Edworthy, Steven, Jacobsen, Soren, Gordon, Caroline, Dooley, Mary Anne, Peschken, Christine A, Hanly, John G, Alarcón, Graciela S, Nived, Ola, Ruiz-Irastorza, Guillermo, Isenberg, David, Rahman, Anisur, Witte, Torsten, Aranow, Cynthia, Kamen, Diane L, Steinsson, Kristjan, Askanase, Anca, Barr, Susan, Criswell, Lindsey A, Sturfelt, Gunnar, Patel, Neha M, Senécal, Jean-Luc, Zummer, Michel, Pope, Janet E, Ensworth, Stephanie, El-Gabalawy, Hani, McCarthy, Timothy, Dreyer, Lene, Sibley, John, St Pierre, Yvan, and Clarke, Ann E

Abstract

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.

Published
2013

261. Economic Evaluation of Lupus Nephritis in the Systemic Lupus International Collaborating Clinics Inception Cohort Using a Multistate Model Approach

Author

Barber, Megan R. W., Hanly, John G., Su, Li, Urowitz, Murray B., St. Pierre, Yvan, Romero‐Diaz, Juanita, Gordon, Caroline, Bae, Sang‐Cheol, Bernatsky, Sasha, Wallace, Daniel J., Isenberg, David A., Rahman, Anisur, Ginzler, Ellen M., Petri, Michelle, Bruce, Ian N., Fortin, Paul R., Gladman, Dafna D., Sanchez‐Guerrero, Jorge, Ramsey‐Goldman, Rosalind, Khamashta, Munther A., Aranow, Cynthia, Mackay, Meggan, Alarcón, Graciela S., Manzi, Susan, Nived, Ola, Jönsen, Andreas, Zoma, Asad A., Vollenhoven, Ronald F., Ramos‐Casals, Manuel, Ruiz‐Irastorza, Guillermo, Lim, S. Sam, Kalunian, Kenneth C., Inanc, Murat, Kamen, Diane L., Peschken, Christine A., Jacobsen, Soren, Askanase, Anca, Theriault, Chris, Farewell, Vernon, and Clarke, Ann E.

Abstract

Little is known about the long‐term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling. Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10‐year cumulative costs by multiplying annual costs associated with each renal state by the expected state duration. A total of 1,545 patients participated; 89.3% were women, the mean ± age at diagnosis was 35.2 ± 13.4 years, 49% were white, and the mean followup duration was 6.3 ± 3.3 years. LN developed in 39.4% of these patients by the end of followup. Ten‐year cumulative costs were greater in those with LN and an estimated glomerular filtration rate (GFR) <30 ml/minute ($310,579 2015 Canadian dollars versus $19,987 if no LN and estimated GFR >60 ml/minute) or with LN and estimated proteinuria >3 gm/day ($84,040 versus $20,499 if no LN and estimated proteinuria <0.25 gm/day). Patients with estimated GFR <30 ml/minute incurred 10‐year costs 15‐fold higher than those with normal estimated GFR. By estimating the expected duration in each renal state and incorporating associated annual costs, disease severity at presentation can be used to anticipate future health care costs. This is critical knowledge for cost‐effectiveness evaluations of novel therapies.

Published
2018
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262. ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Author

Caster, Dawn J., primary, Korte, Erik A., additional, Nanda, Sambit K., additional, McLeish, Kenneth R., additional, Oliver, Rebecca K., additional, G'Sell, Rachel T., additional, Sheehan, Ryan M., additional, Freeman, Darrell W., additional, Coventry, Susan C., additional, Kelly, Jennifer A., additional, Guthridge, Joel M., additional, James, Judith A., additional, Sivils, Kathy L., additional, Alarcon-Riquelme, Marta E., additional, Scofield, R. Hal, additional, Adrianto, Indra, additional, Gaffney, Patrick M., additional, Stevens, Anne M., additional, Freedman, Barry I., additional, Langefeld, Carl D., additional, Tsao, Betty P., additional, Pons-Estel, Bernardo A., additional, Jacob, Chaim O., additional, Kamen, Diane L., additional, Gilkeson, Gary S., additional, Brown, Elizabeth E., additional, Alarcon, Graciela S., additional, Edberg, Jeffrey C., additional, Kimberly, Robert P., additional, Martin, Javier, additional, Merrill, Joan T., additional, Harley, John B., additional, Kaufman, Kenneth M., additional, Reveille, John D., additional, Anaya, Juan-Manuel, additional, Criswell, Lindsey A., additional, Vila, Luis M., additional, Petri, Michelle, additional, Ramsey-Goldman, Rosalind, additional, Bae, Sang-Cheol, additional, Boackle, Susan A., additional, Vyse, Timothy J., additional, Niewold, Timothy B., additional, Cohen, Philip, additional, and Powell, David W., additional

Published
2013
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263. Evaluation of TRAF6 in a large multiancestral lupus cohort

Author

Namjou, Bahram, Choi, Chan-Bum, Harley, Isaac T. W., Alarcon-Riquelme, Marta E., Kelly, Jennifer A., Glenn, Stuart B., Ojwang, Joshua O., Adler, Adam, Kim, Kwangwoo, Gallant, Caroline J., Boackle, Susan A., Criswell, Lindsey A., Kimberly, Robert P., Brown, Elizabeth E., Edberg, Jeffrey, Alarcon, 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, Vila, 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, Namjou, Bahram, Choi, Chan-Bum, Harley, Isaac T. W., Alarcon-Riquelme, Marta E., Kelly, Jennifer A., Glenn, Stuart B., Ojwang, Joshua O., Adler, Adam, Kim, Kwangwoo, Gallant, Caroline J., Boackle, Susan A., Criswell, Lindsey A., Kimberly, Robert P., Brown, Elizabeth E., Edberg, Jeffrey, Alarcon, 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, Vila, 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., and Bae, Sang-Cheol

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 casecontrol 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 x 10(-5) and P = 4.73 x 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 (r2 = 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis P = 9.15 x 10(-4), OR 0.89 [95% CI 0.830.95]). The presence of thrombocytopenia improved the overall results in different populations (meta-analysis P = 1.99 x 10(-6), OR 0.57 [95% CI 0.450.72], 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.

Published
2012
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264. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Author

Adrianto, Indra, Wen, Feng, Templeton, Amanda, Wiley, Graham, King, Jarrod B., Lessard, Christopher J., Bates, Jared S., Hu, Yanqing, Kelly, Jennifer A., Kaufman, Kenneth M., Guthridge, Joel M., Alarcon-Riquelme, Marta E., Anaya, Juan-Manuel, Bae, Sang-Cheol, Bang, So-Young, Boackle, Susan A., Brown, Elizabeth E., Petri, Michelle A., Gallant, Caroline, Ramsey-Goldman, Rosalind, Reveille, John D., Vila, Luis M., 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, Pons-Estel, Bernardo A., Scofield, R. Hal, Stevens, Anne M., Tsao, Betty P., Vyse, Timothy J., Langefeld, Carl D., Harley, John B., Moser, Kathy L., Webb, Carol F., Humphrey, Mary Beth, Montgomery, Courtney Gray, Gaffney, Patrick M., Adrianto, Indra, Wen, Feng, Templeton, Amanda, Wiley, Graham, King, Jarrod B., Lessard, Christopher J., Bates, Jared S., Hu, Yanqing, Kelly, Jennifer A., Kaufman, Kenneth M., Guthridge, Joel M., Alarcon-Riquelme, Marta E., Anaya, Juan-Manuel, Bae, Sang-Cheol, Bang, So-Young, Boackle, Susan A., Brown, Elizabeth E., Petri, Michelle A., Gallant, Caroline, Ramsey-Goldman, Rosalind, Reveille, John D., Vila, Luis M., 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, Pons-Estel, Bernardo A., Scofield, R. Hal, Stevens, Anne M., Tsao, Betty P., Vyse, Timothy J., Langefeld, Carl D., Harley, John B., Moser, Kathy L., Webb, Carol F., Humphrey, Mary Beth, Montgomery, Courtney Gray, and Gaffney, Patrick M.

Abstract

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 x 10(-8), odds ratio = 1.70) and Korean (P = 8.33 x 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-kappa B subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

Published
2011
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265. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility

Author

Zhao, Jian, Wu, Hui, Khosravi, Melanie, Cui, Huijuan, Qian, Xiaoxia, Kelly, Jennifer A., Kaufman, Kenneth M., Langefeld, Carl D., Williams, Adrienne H., Comeau, Mary, Ziegler, Julie T., Marion, Miranda C., Adler, Adam, Glenn, Stuart B., Alarcón-Riquelme, Marta E., Pons-Estel, Bernardo A., Harley, John B., Bae, Sang-Cheol, Bang, So-Young, Cho, Soo-Kyung, Jacob, Chaim O., Vyse, Timothy J., Niewold, Timothy B., Gaffney, Patrick M., Moser, Kathy L., Kimberly, Robert P., Edberg, Jeffrey C., Brown, Elizabeth E., Alarcón, Graciela S., Petri, Michelle A., Ramsey-Goldman, Rosalind, Vilá, Luis M., Reveille, John D., James, Judith A., Gilkeson, Gary S., Kamen, Diane L., Freedman, Barry I., Anaya, Juan-Manuel, Merrill, Joan T., Criswell, Lindsey A., Scofield, Robert H., Stevens, Anne M., Guthridge, Joel M., Chang, Deh-Ming, Song, Yeong Wook, Park, Ji Ah, Young Lee, Eun, Boackle, Susan, Grossman, Jennifer M., Hahn, Bevra H., Goodship, Timothy H. J., Cantor, Rita M., Yu, Chack-Yung, Shen, Nan, Tsao, Betty P., Zhao, Jian, Wu, Hui, Khosravi, Melanie, Cui, Huijuan, Qian, Xiaoxia, Kelly, Jennifer A., Kaufman, Kenneth M., Langefeld, Carl D., Williams, Adrienne H., Comeau, Mary, Ziegler, Julie T., Marion, Miranda C., Adler, Adam, Glenn, Stuart B., Alarcón-Riquelme, Marta E., Pons-Estel, Bernardo A., Harley, John B., Bae, Sang-Cheol, Bang, So-Young, Cho, Soo-Kyung, Jacob, Chaim O., Vyse, Timothy J., Niewold, Timothy B., Gaffney, Patrick M., Moser, Kathy L., Kimberly, Robert P., Edberg, Jeffrey C., Brown, Elizabeth E., Alarcón, Graciela S., Petri, Michelle A., Ramsey-Goldman, Rosalind, Vilá, Luis M., Reveille, John D., James, Judith A., Gilkeson, Gary S., Kamen, Diane L., Freedman, Barry I., Anaya, Juan-Manuel, Merrill, Joan T., Criswell, Lindsey A., Scofield, Robert H., Stevens, Anne M., Guthridge, Joel M., Chang, Deh-Ming, Song, Yeong Wook, Park, Ji Ah, Young Lee, Eun, Boackle, Susan, Grossman, Jennifer M., Hahn, Bevra H., Goodship, Timothy H. J., Cantor, Rita M., Yu, Chack-Yung, Shen, Nan, and Tsao, Betty P.

Abstract

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, Pmeta = 6.6×10-8, OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, Pmeta = 2.9×10-7, OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (Pmeta = 3.2×10-7, OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (Pmeta = 3.5×10-4, OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.

Published
2011

267. Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

Author

Manku, Harinder, primary, Langefeld, Carl D., additional, Guerra, Sandra G., additional, Malik, Talat H., additional, Alarcon-Riquelme, Marta, additional, Anaya, Juan-Manuel, additional, Bae, Sang-Cheol, additional, Boackle, Susan A., additional, Brown, Elizabeth E., additional, Criswell, Lindsey A., additional, Freedman, Barry I., additional, Gaffney, Patrick M., additional, Gregersen, Peter A., additional, Guthridge, Joel M., additional, Han, Sang-Hoon, additional, Harley, John B., additional, Jacob, Chaim O., additional, James, Judith A., additional, Kamen, Diane L., additional, Kaufman, Kenneth M., additional, Kelly, Jennifer A., additional, Martin, Javier, additional, Merrill, Joan T., additional, Moser, Kathy L., additional, Niewold, Timothy B., additional, Park, So-Yeon, additional, Pons-Estel, Bernardo A., additional, Sawalha, Amr H., additional, Scofield, R. Hal, additional, Shen, Nan, additional, Stevens, Anne M., additional, Sun, Celi, additional, Gilkeson, Gary S., additional, Edberg, Jeff C., additional, Kimberly, Robert P., additional, Nath, Swapan K., additional, Tsao, Betty P., additional, and Vyse, Tim J., additional

Published
2013
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269. Variable Association of Reactive Intermediate Genes with Systemic Lupus Erythematosus in Populations with Different African Ancestry

Author

Ramos, Paula S., primary, Oates, James C., additional, Kamen, Diane L., additional, Williams, Adrienne H., additional, Gaffney, Patrick M., additional, Kelly, Jennifer A., additional, Kaufman, Kenneth M., additional, Kimberly, Robert P., additional, Niewold, Timothy B., additional, Jacob, Chaim O., additional, Tsao, Betty P., additional, Alarcón, Graciela S., additional, Brown, Elizabeth E., additional, Edberg, Jeffrey C., additional, Petri, Michelle A., additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D., additional, Vilá, Luis M., additional, James, Judith A., additional, Guthridge, Joel M., additional, Merrill, Joan T., additional, Boackle, Susan A., additional, Freedman, Barry I., additional, Scofield, R. Hal, additional, Stevens, Anne M., additional, Vyse, Timothy J., additional, Criswell, Lindsey A., additional, Moser, Kathy L., additional, Alarcón-Riquelme, Marta E., additional, Langefeld, Carl D., additional, Harley, John B., additional, and Gilkeson, Gary S., additional

Published
2013
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270. Cancer risk in systemic lupus: An updated international multi-centre cohort study

Author

Bernatsky, Sasha, primary, Ramsey-Goldman, Rosalind, additional, Labrecque, Jeremy, additional, Joseph, Lawrence, additional, Boivin, Jean-Francois, additional, Petri, Michelle, additional, Zoma, Asad, additional, Manzi, Susan, additional, Urowitz, Murray B., additional, Gladman, Dafna, additional, Fortin, Paul R., additional, Ginzler, Ellen, additional, Yelin, Edward, additional, Bae, Sang-Cheol, additional, Wallace, Daniel J., additional, Edworthy, Steven, additional, Jacobsen, Soren, additional, Gordon, Caroline, additional, Dooley, Mary Anne, additional, Peschken, Christine A., additional, Hanly, John G., additional, Alarcón, Graciela S., additional, Nived, Ola, additional, Ruiz-Irastorza, Guillermo, additional, Isenberg, David, additional, Rahman, Anisur, additional, Witte, Torsten, additional, Aranow, Cynthia, additional, Kamen, Diane L., additional, Steinsson, Kristjan, additional, Askanase, Anca, additional, Barr, Susan, additional, Criswell, Lindsey A., additional, Sturfelt, Gunnar, additional, Patel, Neha M., additional, Senécal, Jean-Luc, additional, Zummer, Michel, additional, Pope, Janet E., additional, Ensworth, Stephanie, additional, El-Gabalawy, Hani, additional, McCarthy, Timothy, additional, Dreyer, Lene, additional, Sibley, John, additional, St. Pierre, Yvan, additional, and Clarke, Ann E., additional

Published
2013
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271. Lymphoma risk in systemic lupus: effects of disease activity versus treatment

Author

Bernatsky, Sasha, primary, Ramsey-Goldman, Rosalind, additional, Joseph, Lawrence, additional, Boivin, Jean-Francois, additional, Costenbader, Karen H, additional, Urowitz, Murray B, additional, Gladman, Dafna D, additional, Fortin, Paul R, additional, Nived, Ola, additional, Petri, Michelle A, additional, Jacobsen, Soren, additional, Manzi, Susan, additional, Ginzler, Ellen M, additional, Isenberg, David, additional, Rahman, Anisur, additional, Gordon, Caroline, additional, Ruiz-Irastorza, Guillermo, additional, Yelin, Edward, additional, Bae, Sang-Cheol, additional, Wallace, Daniel J, additional, Peschken, Christine A, additional, Dooley, Mary Anne, additional, Edworthy, Steven M, additional, Aranow, Cynthia, additional, Kamen, Diane L, additional, Romero-Diaz, Juanita, additional, Askanase, Anca, additional, Witte, Torsten, additional, Barr, Susan G, additional, Criswell, Lindsey A, additional, Sturfelt, Gunnar K, additional, Blanco, Irene, additional, Feldman, Candace H, additional, Dreyer, Lene, additional, Patel, Neha M, additional, St Pierre, Yvan, additional, and Clarke, Ann E, additional

Published
2013
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275. Clinical associations of the metabolic syndrome in systemic lupus erythematosus: data from an international inception cohort

Author

Parker, Ben, primary, Urowitz, Murray B, additional, Gladman, Dafna D, additional, Lunt, Mark, additional, Bae, Sang-Cheol, additional, Sanchez-Guerrero, Jorge, additional, Romero-Diaz, Juanita, additional, Gordon, Caroline, additional, Wallace, Daniel J, additional, Clarke, Ann E, additional, Bernatsky, Sasha, additional, Ginzler, Ellen M, additional, Isenberg, David A, additional, Rahman, Anisur, additional, Merrill, Joan T, additional, Alarcón, Graciela S, additional, Fessler, Barri J, additional, Fortin, Paul R, additional, Hanly, John G, additional, Petri, Michelle, additional, Steinsson, Kristjan, additional, Dooley, Mary-Anne, additional, Manzi, Susan, additional, Khamashta, Munther A, additional, Ramsey-Goldman, Rosalind, additional, Zoma, Asad A, additional, Sturfelt, Gunnar K, additional, Nived, Ola, additional, Aranow, Cynthia, additional, Mackay, Meggan, additional, Ramos-Casals, Manuel, additional, van Vollenhoven, Raymond F, additional, Kalunian, Kenneth C, additional, Ruiz-Irastorza, Guillermo, additional, Lim, Sam, additional, Kamen, Diane L, additional, Peschken, Christine A, additional, Inanc, Murat, additional, and Bruce, Ian N, additional

Published
2012
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276. S-090

Author

Kamen, Diane L, primary, Stevens, Brandi E, additional, Peden-Adams, Margie M, additional, Vena, John E, additional, Gilkeson, Gary S, additional, Hulsey, Thomas C, additional, and Moultrie, Lee, additional

Published
2012
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278. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study

Author

Lessard, Christopher J., primary, Adrianto, Indra, additional, Ice, John A., additional, Wiley, Graham B., additional, Kelly, Jennifer A., additional, Glenn, Stuart B., additional, Adler, Adam J., additional, Li, He, additional, Rasmussen, Astrid, additional, Williams, Adrienne H., additional, Ziegler, Julie, additional, Comeau, Mary E., additional, Marion, Miranda, additional, Wakeland, Benjamin E., additional, Liang, Chaoying, additional, Ramos, Paula S., additional, Grundahl, Kiely M., additional, Gallant, Caroline J., additional, Alarcón, Graciela S., additional, Anaya, Juan-Manuel, additional, Bae, Sang-Cheol, additional, Boackle, Susan A., additional, Brown, Elizabeth E., additional, Chang, Deh-Ming, additional, Cho, Soo-Kyung, additional, Criswell, Lindsey A., additional, Edberg, Jeffrey C., additional, Freedman, Barry I., additional, Gilkeson, Gary S., additional, Jacob, Chaim O., additional, James, Judith A., additional, Kamen, Diane L., additional, Kimberly, Robert P., additional, Kim, Jae-Hoon, additional, Martin, Javier, additional, Merrill, Joan T., additional, Niewold, Timothy B., additional, Park, So-Yeon, additional, Petri, Michelle A., additional, Pons-Estel, Bernardo A., additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D., additional, Scofield, R. Hal, additional, Song, Yeong Wook, additional, Stevens, Anne M., additional, Tsao, Betty P., additional, Vila, Luis M., additional, Vyse, Timothy J., additional, Yu, Chack-Yung, additional, Guthridge, Joel M., additional, Kaufman, Kenneth M., additional, Harley, John B., additional, Wakeland, Edward K., additional, Langefeld, Carl D., additional, Gaffney, Patrick M., additional, Montgomery, Courtney G., additional, and Moser, Kathy L., additional

Published
2012
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280. Multiple Autoantibodies Display Association with Lymphopenia, Proteinuria, and Cellular Casts in a Large, Ethnically Diverse SLE Patient Cohort

Author

Lu, Rufei, primary, Robertson, Julie M., additional, Bruner, Benjamin F., additional, Guthridge, Joel M., additional, Neas, Barbara R., additional, Nath, Swapan K., additional, Kelly, Jennifer A., additional, Moser Sivils, Kathy L., additional, Chakravarty, Eliza F., additional, Kamen, Diane L., additional, Gilkeson, Gary S., additional, Wallace, Daniel J., additional, Weisman, Michael H., additional, Scofield, R. Hal, additional, Harley, John B., additional, and James, Judith A., additional

Published
2012
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281. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases

Author

Zhao, Jian, Ma, Jianyang, Deng, Yun, Kelly, Jennifer A, Kim, Kwangwoo, Bang, So-Young, Lee, Hye-Soon, Li, Quan-Zhen, Wakeland, Edward K, Qiu, Rong, Liu, Mengru, Guo, Jianping, Li, Zhanguo, Tan, Wenfeng, Rasmussen, Astrid, Lessard, Christopher J, Sivils, Kathy L, Hahn, Bevra H, Grossman, Jennifer M, Kamen, Diane L, Gilkeson, Gary S, Bae, Sang-Cheol, Gaffney, Patrick M, Shen, Nan, and Tsao, Betty P

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component characterized by autoantibody production and a type I interferon signature. Here we report a missense variant (g.74779296G>A; p.Arg90His) in NCF1, encoding the p47phoxsubunit of the phagocyte NADPH oxidase (NOX2), as the putative underlying causal variant that drives a strong SLE-associated signal detected by the Immunochip in the GTF2IRD1–GTF2I region at 7q11.23 with a complex genomic structure. We show that the p.Arg90His substitution, which is reported to cause reduced reactive oxygen species (ROS) production, predisposes to SLE (odds ratio (OR) = 3.47 in Asians (Pmeta= 3.1 × 10−104), OR = 2.61 in European Americans, OR = 2.02 in African Americans) and other autoimmune diseases, including primary Sjögren's syndrome (OR = 2.45 in Chinese, OR = 2.35 in European Americans) and rheumatoid arthritis (OR = 1.65 in Koreans). Additionally, decreased and increased copy numbers of NCF1 predispose to and protect against SLE, respectively. Our data highlight the pathogenic role of reduced NOX2-derived ROS levels in autoimmune diseases.

Published
2017
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282. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus

Author

Niewold, Timothy B, primary, Kelly, Jennifer A, additional, Kariuki, Silvia N, additional, Franek, Beverly S, additional, Kumar, Akaash A, additional, Kaufman, Kenneth M, additional, Thomas, Kenaz, additional, Walker, Daniel, additional, Kamp, Stan, additional, Frost, Jacqueline M, additional, Wong, Andrew K, additional, Merrill, Joan T, additional, Alarcón-Riquelme, Marta E, additional, Tikly, Mohammed, additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D, additional, Petri, Michelle A, additional, Edberg, Jeffrey C, additional, Kimberly, Robert P, additional, Alarcón, Graciela S, additional, Kamen, Diane L, additional, Gilkeson, Gary S, additional, Vyse, Timothy J, additional, James, Judith A, additional, Gaffney, Patrick M, additional, Moser, Kathy L, additional, Crow, Mary K, additional, and Harley, John B, additional

Published
2011
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285. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Author

Adrianto, Indra, primary, Wen, Feng, additional, Templeton, Amanda, additional, Wiley, Graham, additional, King, Jarrod B, additional, Lessard, Christopher J, additional, Bates, Jared S, additional, Hu, Yanqing, additional, Kelly, Jennifer A, additional, Kaufman, Kenneth M, additional, Guthridge, Joel M, additional, Alarcón-Riquelme, Marta E, additional, Anaya, Juan-Manuel, additional, Bae, Sang-Cheol, additional, Bang, So-Young, additional, Boackle, Susan A, additional, Brown, Elizabeth E, additional, Petri, Michelle A, additional, Gallant, Caroline, additional, Ramsey-Goldman, Rosalind, additional, Reveille, John D, additional, Vila, Luis M, additional, Criswell, Lindsey A, additional, Edberg, Jeffrey C, additional, Freedman, Barry I, additional, Gregersen, Peter K, additional, Gilkeson, Gary S, additional, Jacob, Chaim O, additional, James, Judith A, additional, Kamen, Diane L, additional, Kimberly, Robert P, additional, Martin, Javier, additional, Merrill, Joan T, additional, Niewold, Timothy B, additional, Park, So-Yeon, additional, Pons-Estel, Bernardo A, additional, Scofield, R Hal, additional, Stevens, Anne M, additional, Tsao, Betty P, additional, Vyse, Timothy J, additional, Langefeld, Carl D, additional, Harley, John B, additional, Moser, Kathy L, additional, Webb, Carol F, additional, Humphrey, Mary Beth, additional, Montgomery, Courtney Gray, additional, and Gaffney, Patrick M, additional

Published
2011
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286. Identification of a Systemic Lupus Erythematosus Susceptibility Locus at 11p13 between PDHX and CD44 in a Multiethnic Study

Author

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

Published
2011
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293. Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus.

Author

Aranow, Cynthia, Kamen, Diane L., Dall'Era, Maria, Massarotti, Elena M., Mackay, Meggan C., Koumpouras, Fotios, Coca, Andreea, Chatham, W. Winn, Clowse, Megan E. B., Criscione‐Schreiber, Lisa G., Callahan, Sherri, Goldmuntz, Ellen A., Keyes‐Elstein, Lynette, Oswald, Michaela, Gregersen, Peter K., and Diamond, Betty

Subjects
*SYSTEMIC lupus erythematosus treatment, *THERAPEUTIC use of vitamin D, *ANALYSIS of covariance, *ANALYSIS of variance, *STATISTICAL correlation, *FISHER exact test, *INTERFERONS, *PARATHYROID hormone, *PLACEBOS, *RESEARCH funding, *SAFETY, *T-test (Statistics), *VITAMIN D, *VITAMIN D deficiency, *GENOMICS, *RANDOMIZED controlled trials, *BLIND experiment, *DESCRIPTIVE statistics, *DISEASE complications
Abstract

Objective Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE. Methods SLE patients (n = 57) with stable, inactive disease, a serum 25-hydroxyvitamin D (25[OH]D) level ≤20 ng/ml, an elevated anti-double-stranded DNA antibody level, and an IFN signature (as determined by measuring the expression levels of 3 IFN response genes) were randomized into a 12-week double-blind, placebo-controlled trial of vitamin D3 at doses of 2,000 IU or 4,000 IU. An IFN signature response was defined as a 50% reduction in the expression of 1 of the 3 genes or a 25% reduction in the expression of 2 of the 3 genes. Disease activity, adverse events, and endocrine effects were assessed. Results Baseline characteristics of the patients in the 3 treatment groups (placebo, low-dose vitamin D3, or high-dose vitamin D3) were similar. Repletion of 25(OH)D (i.e., levels ≥30 ng/ml) was not observed in any of the patients who were receiving placebo, while repletion was observed in 16 of 33 patients receiving vitamin D3. The percentage of patients with an IFN signature response did not differ among the treatment groups. Moreover, there was no difference in the percentage of patients with an IFN signature response between those who remained vitamin D deficient and those who demonstrated repletion of vitamin D. Modular microarray analysis of a subset of patients (n = 40) did not reveal changes from baseline in any modules (including the IFN-inducible module) in any of the treatment groups, and no differences in expression were found between patients who demonstrated vitamin D repletion and patients who were persistently vitamin D deficient. Vitamin D3 was well tolerated, and there were no safety concerns. Conclusion Vitamin D3 supplementation up to 4,000 IU daily was safe and well-tolerated but failed to diminish the IFN signature in vitamin D-deficient SLE patients. Higher 25(OH)D levels sustained for a longer duration may be required to affect immunologic outcomes. [ABSTRACT FROM AUTHOR]

Published
2015
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294. In vitro evaluation of the effects of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) on IL-2 production in human T-cells.

Author

Midgett, Kristin, Peden‐Adams, Margie M., Gilkeson, Gary S., and Kamen, Diane L.

Subjects
PERFLUOROOCTANE sulfonate, PERFLUOROOCTANOIC acid, T cells, INTERLEUKIN-2, AUTOIMMUNE diseases, SYSTEMIC lupus erythematosus
Abstract

Perfluorinated compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)-2 production in the human Jurkat T-cell line and PFOS in healthy human primary T cells. Jurkat cells were stimulated with phytohemagglutinin (PHA)/phorbol myristate acetate (PMA), anti CD-3/anti CD-28, or anti CD-3, and dosed with 0, 0.05, 0.1, 0.5, 1, 5, 10, 50, 75, or 100 µg ml−1 PFOS or 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 µg ml−1 PFOA. Jurkat cells stimulated with PHA/PMA or anti CD-3 exhibited decreased IL-2 production beginning at 50 µg PFOS ml−1 and 5 µg PFOS ml−1 respectively, but stimulation with anti-CD3/anti-CD28 resulted in no changes compared with the control. Addition of the PPAR-alpha antagonist GW6471 to PFOS-dosed cells stimulated with PHA/PMA resulted in decreases in IL-2 production starting at 50 µg PFOS ml−1, which suggests PFOS affected T-cell IL-2 production via PPAR-alpha-independent mechanisms. Exposure to PFOA, PFOA + GW6471, or PFOS + PFOA in Jurkat cells resulted in no significant differences in IL-2 production. In vitro dosing studies using healthy primary human CD4+ T cells were consistent with the Jurkat results. These data demonstrated that PFOA did not impact IL-2 production, but PFOS suppressed IL-2 production in both a human cell line and human primary cells at dose levels within the high end of the human exposure range. A decrease in IL-2 production is characteristic of autoimmune diseases such as systemic lupus erythematosus and should be further investigated. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2015
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295. Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response

Author

Liu, Philip T., primary, Stenger, Steffen, additional, Li, Huiying, additional, Wenzel, Linda, additional, Tan, Belinda H., additional, Krutzik, Stephan R., additional, Ochoa, Maria Teresa, additional, Schauber, Jürgen, additional, Wu, Kent, additional, Meinken, Christoph, additional, Kamen, Diane L., additional, Wagner, Manfred, additional, Bals, Robert, additional, Steinmeyer, Andreas, additional, Zügel, Ulrich, additional, Gallo, Richard L., additional, Eisenberg, David, additional, Hewison, Martin, additional, Hollis, Bruce W., additional, Adams, John S., additional, Bloom, Barry R., additional, and Modlin, Robert L., additional

Published
2006
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298. Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4.

Author

Manku, Harinder, Langefeld, Carl D., Guerra, Sandra G., Malik, Talat H., Alarcon-Riquelme, Marta, Anaya, Juan-Manuel, Bae, Sang-Cheol, Boackle, Susan A., Brown, Elizabeth E., Criswell, Lindsey A., Freedman, Barry I., Gaffney, Patrick M., Gregersen, Peter A., Guthridge, Joel M., Han, Sang-Hoon, Harley, John B., Jacob, Chaim O., James, Judith A., Kamen, Diane L., and Kaufman, Kenneth M.

Subjects
AUTOIMMUNE diseases, LYMPHOCYTES, INFLAMMATION, ATHEROSCLEROSIS, ISCHEMIA
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2013
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299. MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus.

Author

Yun Deng, Jian Zhao, Sakurai, Daisuke, Kaufman, Kenneth M., Edberg, Jeffrey C., Kimberly, Robert P., Kamen, Diane L., Gilkeson, Gary S., Jacob, Chaim O., Scofield, R. Hal, Langefeld, Carl D., Kelly, Jennifer A., Ramsey-Goldman, Rosalind, Petri, Michelle A., Reveille, John D., Vilá, Luis M., Alarcón, Graciela S., Vyse, Timothy J., Pons-Estel, Bernardo A., and Freedman, Barry I.

Subjects
MICRORNA, COMPLEMENTATION (Genetics), GENE expression, SYSTEMIC lupus erythematosus, GENETICS of autoimmune diseases, GENETICS
Abstract

We previously reported that the G allele of rs3853839 at 3' untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5x10-10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5x10-11, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 39UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R² = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 39UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0x10-19, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148. [ABSTRACT FROM AUTHOR]

Published
2013
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