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1. Molecular subtypes explain lupus epigenomic heterogeneity unveiling new regulatory genetic risk variants

Author

Castellini-Pérez, Olivia, Povedano, Elena, Barturen, Guillermo, Martínez-Bueno, Manuel, Iakovliev, Andrii, Kerick, Martin, López-Domínguez, Raúl, Marañón, Concepción, Martín, Javier, Ballestar, Esteban, Borghi, María Orietta, Qiu, Weiliang, Zhu, Cheng, Shankara, Srinivas, Spiliopoulou, Athina, de Rinaldis, Emanuele, Carnero-Montoro, Elena, and Alarcón-Riquelme, Marta E.

Published
2024
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2. A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

Author

Minnai, Francesca, Biscarini, Filippo, Esposito, Martina, Dragani, Tommaso A., Bujanda, Luis, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Bernardo, David, Carnero-Montoro, Elena, Buti, Maria, Zeberg, Hugo, Asselta, Rosanna, Romero-Gómez, Manuel, Fernandez-Cadenas, Israel, Fallerini, Chiara, Zguro, Kristina, Croci, Susanna, Baldassarri, Margherita, Bruttini, Mirella, Furini, Simone, Renieri, Alessandra, and Colombo, Francesca

Published
2024
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3. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Beretta, Lorenzo, Vigone, Barbara, Pers, Jacques-Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Alonso, Ricardo Blanco, Martínez, Alfonso Corrales, Cervera, Ricard, Rodríguez-Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, De Langhe, Ellen, Hunzelmann, Nicolas, Belz, Doreen, Witte, Torsten, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Moleón, Inmaculada Jiménez, de Ramon, Enrique, Quintero, Isabel Díaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Parodis, Ioannis, Lindblom, Julius, Toro-Domínguez, Daniel, Borghi, Maria O., Castillo, Jessica, Carnero-Montoro, Elena, Enman, Yvonne, Mohan, Chandra, Alarcón-Riquelme, Marta E., Barturen, Guillermo, and Nikolopoulos, Dionysis

Published
2024
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11. Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients

Author

Lanata, Cristina M, Nititham, Joanne, Taylor, Kimberly E, Chung, Sharon A, Torgerson, Dara G, Seldin, Michael F, Pons-Estel, Bernardo A, Tusié-Luna, Teresa, Tsao, Betty P, Morand, Eric F, Alarcón-Riquelme, Marta E, and Criswell, Lindsey A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lupus, Clinical Research, Human Genome, Autoimmune Disease, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Cohort Studies, Female, Humans, Lupus Nephritis, Male, Middle Aged, Models, Genetic, Polymorphism, Single Nucleotide, Risk Factors, General Science & Technology
Abstract

ObjectiveAfrican Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect.MethodsIn this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age.ResultsWe studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035).ConclusionDistinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups.

Published
2018

13. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Parodis, Ioannis, primary, Lindblom, Julius, additional, Toro-Domínguez, Daniel, additional, Beretta, Lorenzo, additional, Borghi, Maria O., additional, Castillo, Jessica, additional, Carnero-Montoro, Elena, additional, Enman, Yvonne, additional, Mohan, Chandra, additional, Alarcón-Riquelme, Marta E., additional, Barturen, Guillermo, additional, Nikolopoulos, Dionysis, additional, Vigone, Barbara, additional, Pers, Jacques-Olivier, additional, Saraux, Alain, additional, Devauchelle-Pensec, Valérie, additional, Cornec, Divi, additional, Jousse-Joulin, Sandrine, additional, Lauwerys, Bernard, additional, Ducreux, Julie, additional, Maudoux, Anne-Lise, additional, Vasconcelos, Carlos, additional, Tavares, Ana, additional, Neves, Esmeralda, additional, Faria, Raquel, additional, Brandão, Mariana, additional, Campar, Ana, additional, Marinho, António, additional, Farinha, Fátima, additional, Almeida, Isabel, additional, Gonzalez-Gay Mantecón, Miguel Angel, additional, Alonso, Ricardo Blanco, additional, Martínez, Alfonso Corrales, additional, Cervera, Ricard, additional, Rodríguez-Pintó, Ignasi, additional, Espinosa, Gerard, additional, Lories, Rik, additional, De Langhe, Ellen, additional, Hunzelmann, Nicolas, additional, Belz, Doreen, additional, Witte, Torsten, additional, Baerlecken, Niklas, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Lehner, Michaela, additional, Collantes, Eduardo, additional, Ortega-Castro, Rafaela, additional, Aguirre-Zamorano, Ma Angeles, additional, Escudero-Contreras, Alejandro, additional, Castro-Villegas, Ma Carmen, additional, Ortego, Norberto, additional, Fernández Roldán, María Concepción, additional, Raya, Enrique, additional, Moleón, Inmaculada Jiménez, additional, de Ramon, Enrique, additional, Quintero, Isabel Díaz, additional, Meroni, Pier Luigi, additional, Gerosa, Maria, additional, Schioppo, Tommaso, additional, Artusi, Carolina, additional, Chizzolini, Carlo, additional, Zuber, Aleksandra, additional, Wynar, Donatienne, additional, Kovács, Laszló, additional, Balog, Attila, additional, Deák, Magdolna, additional, Bocskai, Márta, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Hiepe, Falk, additional, Gerl, Velia, additional, Thiel, Silvia, additional, Maresca, Manuel Rodriguez, additional, López-Berrio, Antonio, additional, Aguilar-Quesada, Rocío, additional, and Navarro-Linares, Héctor, additional

Published
2024
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17. Molecular characterisation of lupus low disease activity state (LLDAS) and DORIS remission by whole-blood transcriptome-based pathways in a pan-European systemic lupus erythematosus cohort

Author

Parodis, Ioannis, Lindblom, Julius, Barturen, Guillermo, Ortega-Castro, Rafaela, Cervera, Ricard, Pers, Jacques-Olivier, Genre, Fernanda, Hiepe, Falk, Gerosa, Maria, Kovács, László, De Langhe, Ellen, Piantoni, Silvia, Stummvoll, Georg, Vasconcelos, Carlos, Vigone, Barbara, Witte, Torsten, Alarcón-Riquelme, Marta E., Beretta, Lorenzo, Parodis, Ioannis, Lindblom, Julius, Barturen, Guillermo, Ortega-Castro, Rafaela, Cervera, Ricard, Pers, Jacques-Olivier, Genre, Fernanda, Hiepe, Falk, Gerosa, Maria, Kovács, László, De Langhe, Ellen, Piantoni, Silvia, Stummvoll, Georg, Vasconcelos, Carlos, Vigone, Barbara, Witte, Torsten, Alarcón-Riquelme, Marta E., and Beretta, Lorenzo

Abstract

OBJECTIVES: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE). METHODS: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission. RESULTS: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway. CONCLUSIONS: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway dif, IP has received grants from the Swedish Rheumatism Association (R-969696), King Gustaf V’s 80-year Foundation (FAI-2020-0741), Swedish Society of Medicine (SLS-974449), Nyckelfonden (OLL-974804), Professor Nanna Svartz Foundation (2021-00436), Ulla and Roland Gustafsson Foundation (2021-26), Region Stockholm (FoUI-955483), and Karolinska Institute. This work was supported by EU/EFPIA/Innovative Medicines Initiative (IMI) Joint Undertaking (JU) PRECISESADS grant no. 115565 and IMI 2 JU (now HIH) 3TR grant no. 831434, and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy, EXC 2155, project no. 390874280.

Published
2024
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18. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Parodis, Ioannis, Lindblom, Julius, Toro-Domínguez, Daniel, Beretta, Lorenzo, Borghi, Maria O., Castillo, Jessica, Carnero-Montoro, Elena, Enman, Yvonne, Mohan, Chandra, Alarcón-Riquelme, Marta E., Barturen, Guillermo, Nikolopoulos, Dionysis, Parodis, Ioannis, Lindblom, Julius, Toro-Domínguez, Daniel, Beretta, Lorenzo, Borghi, Maria O., Castillo, Jessica, Carnero-Montoro, Elena, Enman, Yvonne, Mohan, Chandra, Alarcón-Riquelme, Marta E., Barturen, Guillermo, and Nikolopoulos, Dionysis

Abstract

INTRODUCTION: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. METHODS: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. RESULTS: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the "B cell" and "plasma cells/Ig" modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the "plasma cells/Ig" signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. CONCLUSION: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN., This work has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking (JU) for the PRECISESADS project (grant number 115565), as well as from the IMI 2 JU for the 3TR project (grant number 831434). The JU receives support from the EU Horizon 2020 research and innovation programme and EFPIA.

Published
2024
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19. A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

Author

Istituto Buddista Italiano Soka Gakkai, Banca Intesa Sanpaolo, Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Minnai, Francesca, Biscarini, Filippo, Esposito, Martina, Dragani, Tommaso A., Bujanda, Luis, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Bernardo, David, Carnero-Montoro, Elena, Buti, Maria, Zeberg, Hugo, Asselta, Rosanna, Romero-Gómez, Manuel, Fernandez-Cadenas, Israel, Fallerini, Chiara, Zguro, Kristina, Croci, Susanna, Baldassarri, Margherita, Bruttini, Mirella, Furini, Simone, Renieri, Alessandra, Colombo, Francesca, Istituto Buddista Italiano Soka Gakkai, Banca Intesa Sanpaolo, Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Minnai, Francesca, Biscarini, Filippo, Esposito, Martina, Dragani, Tommaso A., Bujanda, Luis, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Bernardo, David, Carnero-Montoro, Elena, Buti, Maria, Zeberg, Hugo, Asselta, Rosanna, Romero-Gómez, Manuel, Fernandez-Cadenas, Israel, Fallerini, Chiara, Zguro, Kristina, Croci, Susanna, Baldassarri, Margherita, Bruttini, Mirella, Furini, Simone, Renieri, Alessandra, and Colombo, Francesca

Abstract

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways.

Published
2024

22. Local ancestry at the MHC region is not a major contributor to disease heterogeneity in a multi‐ethnic lupus cohort

Author

Solomon, Olivia, primary, Lanata, Cristina M., additional, Adams, Cameron, additional, Nititham, Joanne, additional, Taylor, Kimberly E., additional, Chung, Sharon A., additional, Yazdany, Jinoos, additional, Dall'Era, Maria, additional, Pons‐Estel, Bernado A., additional, Tusie‐Luna, Tersa, additional, Tsao, Betty, additional, Morand, Eric, additional, Alarcón‐Riquelme, Marta E., additional, Barcellos, Lisa F., additional, and Criswell, Lindsey A., additional

Published
2023
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23. Response to the letter ‘testing the effectiveness of MyPROSLE in classifying patients with lupus nephritis’

Author

Toro-Domínguez, Daniel, primary, Martorell-Marugán, Jordi, additional, Martinez-Bueno, Manuel, additional, López-Domínguez, Raúl, additional, Carnero-Montoro, Elena, additional, Barturen, Guillermo, additional, Goldman, Daniel, additional, Petri, Michelle, additional, Carmona-Sáez, Pedro, additional, and Alarcón-Riquelme, Marta E, additional

Published
2023
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24. Corrigendum to ‘Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus’ [J. Autoimmun. 136 (April 2023) 103025]

Author

Lindblom, Julius, primary, Toro-Domínguez, Daniel, additional, Carnero-Montoro, Elena, additional, Beretta, Lorenzo, additional, Borghi, Maria Orietta, additional, Castillo, Jessica, additional, Enman, Yvonne, additional, Mohan, Chandra, additional, Alarcón-Riquelme, Marta E., additional, Barturen, Guillermo, additional, and Parodis, Ioannis, additional

Published
2023
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25. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Author

Teruel, María, Barturen, Guillermo, Martínez-Bueno, Manuel, Castellini-Pérez, Olivia, Barroso-Gil, Miguel, Povedano, Elena, Kerick, Martin, Català-Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Pers, Jacques-Olivier, Marañón, Concepción, Ballestar, Esteban, Martin, Javier, Carnero-Montoro, Elena, and Alarcón-Riquelme, Marta E.

Published
2021
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26. Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children

Author

Beckmann, Noam D., Comella, Phillip H., Cheng, Esther, Lepow, Lauren, Beckmann, Aviva G., Tyler, Scott R., Mouskas, Konstantinos, Simons, Nicole W., Hoffman, Gabriel E., Francoeur, Nancy J., Del Valle, Diane Marie, Kang, Gurpawan, Do, Anh, Moya, Emily, Wilkins, Lillian, Le Berichel, Jessica, Chang, Christie, Marvin, Robert, Calorossi, Sharlene, Lansky, Alona, Walker, Laura, Yi, Nancy, Yu, Alex, Chung, Jonathan, Hartnett, Matthew, Eaton, Melody, Hatem, Sandra, Jamal, Hajra, Akyatan, Alara, Tabachnikova, Alexandra, Liharska, Lora E., Cotter, Liam, Fennessy, Brian, Vaid, Akhil, Barturen, Guillermo, Shah, Hardik, Wang, Ying-chih, Sridhar, Shwetha Hara, Soto, Juan, Bose, Swaroop, Madrid, Kent, Ellis, Ethan, Merzier, Elyze, Vlachos, Konstantinos, Fishman, Nataly, Tin, Manying, Smith, Melissa, Xie, Hui, Patel, Manishkumar, Nie, Kai, Argueta, Kimberly, Harris, Jocelyn, Karekar, Neha, Batchelor, Craig, Lacunza, Jose, Yishak, Mahlet, Tuballes, Kevin, Scott, Ieisha, Kumar, Arvind, Jaladanki, Suraj, Agashe, Charuta, Thompson, Ryan, Clark, Evan, Losic, Bojan, Peters, Lauren, Roussos, Panagiotis, Zhu, Jun, Wang, Wenhui, Kasarskis, Andrew, Glicksberg, Benjamin S., Nadkarni, Girish, Bogunovic, Dusan, Elaiho, Cordelia, Gangadharan, Sandeep, Ofori-Amanfo, George, Alesso-Carra, Kasey, Onel, Kenan, Wilson, Karen M., Argmann, Carmen, Bunyavanich, Supinda, Alarcón-Riquelme, Marta E., Marron, Thomas U., Rahman, Adeeb, Kim-Schulze, Seunghee, Gnjatic, Sacha, Gelb, Bruce D., Merad, Miriam, Sebra, Robert, Schadt, Eric E., and Charney, Alexander W.

Published
2021
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27. A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Jamin, Christophe, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valérie, Boudjeniba, Cheïma, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovács, László, Witte, Torsten, Bettacchioli, Eléonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Borghi, Maria Orietta, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickaël, Moingeon, Philippe, Alarcón-Riquelme, Marta E., Laigle, Laurence, and Pers, Jacques-Olivier

Published
2021
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28. A comprehensive database for integrated analysis of omics data in autoimmune diseases

Author

Martorell-Marugán, Jordi, López-Domínguez, Raúl, García-Moreno, Adrián, Toro-Domínguez, Daniel, Villatoro-García, Juan Antonio, Barturen, Guillermo, Martín-Gómez, Adoración, Troule, Kevin, Gómez-López, Gonzalo, Al-Shahrour, Fátima, González-Rumayor, Víctor, Peña-Chilet, María, Dopazo, Joaquín, Sáez-Rodríguez, Julio, Alarcón-Riquelme, Marta E., and Carmona-Sáez, Pedro

Published
2021
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30. Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression

Author

Lu, Xiaoming, Zoller, Erin E, Weirauch, Matthew T, Wu, Zhiguo, Namjou, Bahram, Williams, Adrienne H, Ziegler, Julie T, Comeau, Mary E, Marion, Miranda C, Glenn, Stuart B, Adler, Adam, Shen, Nan, Nath, Swapan K, Stevens, Anne M, Freedman, Barry I, Tsao, Betty P, Jacob, Chaim O, Kamen, Diane L, Brown, Elizabeth E, Gilkeson, Gary S, Alarcón, Graciela S, Reveille, John D, Anaya, Juan-Manuel, James, Judith A, Sivils, Kathy L, Criswell, Lindsey A, Vilá, Luis M, Alarcón-Riquelme, Marta E, Petri, Michelle, Scofield, R Hal, Kimberly, Robert P, Ramsey-Goldman, Rosalind, Bin Joo, Young, Choi, Jeongim, Bae, Sang-Cheol, Boackle, Susan A, Graham, Deborah Cunninghame, Vyse, Timothy J, Guthridge, Joel M, Gaffney, Patrick M, Langefeld, Carl D, Kelly, Jennifer A, Greis, Kenneth D, Kaufman, Kenneth M, Harley, John B, and Kottyan, Leah C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biotechnology, Lupus, Autoimmune Disease, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Animals, Asian People, Bayes Theorem, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Mice, Protein Binding, Proto-Oncogene Protein c-ets-1, STAT1 Transcription Factor, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Published
2015

31. SMIM1 absence is associated with reduced energy expenditure and excess weight

Author

Banasik, Karina, Bay, Jakob, Boldsen, Jens Kjærgaard, Brodersen, Thorsten, Brunak, Søren, Burgdorf, Kristoffer, Chalmer, Mona Ameri, Didriksen, Maria, Dinh, Khoa Manh, Dowsett, Joseph, Erikstrup, Christian, Feenstra, Bjarke, Geller, Frank, Gudbjartsson, Daniel, Hansen, Thomas Folkmann, Hindhede, Lotte, Hjalgrim, Henrik, Jacobsen, Rikke Louise, Jemec, Gregor, Jensen, Bitten Aagaard, Kaspersen, Katrine, Kjerulff, Bertram Dalskov, Kogelman, Lisette, Hørup Larsen, Margit Anita, Louloudis, Ioannis, Lundgaard, Agnete, Susan, Mikkelsen, Christina, Nissen, Ioanna, Nyegaard, Mette, Ostrowski, Sisse Rye, Pedersen, Ole Birger, Henriksen, Alexander Pil, Rohde, Palle Duun, Rostgaard, Klaus, Schwinn, Michael, Stefansson, Kari, Stefánsson, Hreinn, Sørensen, Erik, þorsteinsdóttir, Unnur, Thørner, Lise Wegner, Bruun, Mie Topholm, Ullum, Henrik, Werge, Thomas, Westergaard, David, Chen, Ji, Spracklen, Cassandra N., Marenne, Gaëlle, Varshney, Arushi, Corbin, Laura J., Luan, Jian’an, Willems, Sara M., Wu, Ying, Zhang, Xiaoshuai, Horikoshi, Momoko, Boutin, Thibaud S., Mägi, Reedik, Waage, Johannes, Li-Gao, Ruifang, Katie Chan, Kei Hang, Yao, Jie, Anasanti, Mila D., Chu, Audrey Y., Claringbould, Annique, Heikkinen, Jani, Hong, Jaeyoung, Hottenga, Jouke-Jan, Huo, Shaofeng, Kaakinen, Marika A., Louie, Tin, März, Winfried, Moreno-Macias, Hortensia, Ndungu, Anne, Nelson, Sarah C., Nolte, Ilja M., North, Kari E., Raulerson, Chelsea K., Ray, Debashree, Rohde, Rebecca, Rybin, Denis, Schurmann, Claudia, Sim, Xueling, Southam, Loz, Stewart, Isobel D., Wang, Carol A., Wang, Yujie, Wu, Peitao, Zhang, Weihua, Ahluwalia, Tarunveer S., Appel, Emil V.R., Bielak, Lawrence F., Brody, Jennifer A., Burtt, Noël P., Cabrera, Claudia P., Cade, Brian E., Chai, Jin Fang, Chai, Xiaoran, Chang, Li-Ching, Chen, Chien-Hsiun, Chen, Brian H., Chitrala, Kumaraswamy Naidu, Chiu, Yen-Feng, de Haan, Hugoline G., Delgado, Graciela E., Demirkan, Ayse, Duan, Qing, Engmann, Jorgen, Fatumo, Segun A., Gayán, Javier, Giulianini, Franco, Gong, Jung Ho, Gustafsson, Stefan, Hai, Yang, Hartwig, Fernando P., He, Jing, Heianza, Yoriko, Huang, Tao, Huerta-Chagoya, Alicia, Hwang, Mi Yeong, Jensen, Richard A., Kawaguchi, Takahisa, Kentistou, Katherine A., Kim, Young Jin, Kleber, Marcus E., Kooner, Ishminder K., Lai, Shuiqing, Lange, Leslie A., Langefeld, Carl D., Lauzon, Marie, Li, Man, Ligthart, Symen, Liu, Jun, Loh, Marie, Long, Jirong, Lyssenko, Valeriya, Mangino, Massimo, Marzi, Carola, Montasser, May E., Nag, Abhishek, Nakatochi, Masahiro, Noce, Damia, Noordam, Raymond, Pistis, Giorgio, Preuss, Michael, Raffield, Laura, Rasmussen-Torvik, Laura J., Rich, Stephen S., Robertson, Neil R., Rueedi, Rico, Ryan, Kathleen, Sanna, Serena, Saxena, Richa, Schraut, Katharina E., Sennblad, Bengt, Setoh, Kazuya, Smith, Albert V., Southam, Lorraine, Sparsø, Thomas, Strawbridge, Rona J., Takeuchi, Fumihiko, Tan, Jingyi, Trompet, Stella, van den Akker, Erik, van der Most, Peter J., Verweij, Niek, Vogel, Mandy, Wang, Heming, Wang, Chaolong, Wang, Nan, Warren, Helen R., Wen, Wanqing, Wilsgaard, Tom, Wong, Andrew, Wood, Andrew R., Xie, Tian, Zafarmand, Mohammad Hadi, Zhao, Jing-Hua, Zhao, Wei, Amin, Najaf, Arzumanyan, Zorayr, Astrup, Arne, Bakker, Stephan J.L., Baldassarre, Damiano, Beekman, Marian, Bergman, Richard N., Bertoni, Alain, Blüher, Matthias, Bonnycastle, Lori L., Bornstein, Stefan R., Bowden, Donald W., Cai, Qiuyin, Campbell, Archie, Campbell, Harry, Chang, Yi Cheng, de Geus, Eco J.C., Dehghan, Abbas, Du, Shufa, Eiriksdottir, Gudny, Farmaki, Aliki Eleni, Frånberg, Mattias, Fuchsberger, Christian, Gao, Yutang, Gjesing, Anette P., Goel, Anuj, Han, Sohee, Hartman, Catharina A., Herder, Christian, Hicks, Andrew A., Hsieh, Chang-Hsun, Hsueh, Willa A., Ichihara, Sahoko, Igase, Michiya, Ikram, M. Arfan, Johnson, W. Craig, Jørgensen, Marit E., Joshi, Peter K., Kalyani, Rita R., Kandeel, Fouad R., Katsuya, Tomohiro, Khor, Chiea Chuen, Kiess, Wieland, Kolcic, Ivana, Kuulasmaa, Teemu, Kuusisto, Johanna, Läll, Kristi, Lam, Kelvin, Lawlor, Deborah A., Lee, Nanette R., Lemaitre, Rozenn N., Li, Honglan, Lin, Shih-Yi, Lindström, Jaana, Linneberg, Allan, Liu, Jianjun, Lorenzo, Carlos, Matsubara, Tatsuaki, Matsuda, Fumihiko, Mingrone, Geltrude, Mooijaart, Simon, Moon, Sanghoon, Nabika, Toru, Nadkarni, Girish N., Nadler, Jerry L., Nelis, Mari, Neville, Matt J., Norris, Jill M., Ohyagi, Yasumasa, Peters, Annette, Peyser, Patricia A., Polasek, Ozren, Qi, Qibin, Raven, Dennis, Reilly, Dermot F., Reiner, Alex, Rivideneira, Fernando, Roll, Kathryn, Rudan, Igor, Sabanayagam, Charumathi, Sandow, Kevin, Sattar, Naveed, Schürmann, Annette, Shi, Jinxiu, Stringham, Heather M., Taylor, Kent D., Teslovich, Tanya M., Thuesen, Betina, Timmers, Paul R.H.J., Tremoli, Elena, Tsai, Michael Y., Uitterlinden, Andre, van Dam, Rob M., van Heemst, Diana, van Hylckama Vlieg, Astrid, Van Vliet-Ostaptchouk, Jana V., Vangipurapu, Jagadish, Vestergaard, Henrik, Wang, Tao, Willems van Dijk, Ko, Zemunik, Tatijana, Abecasis, Goncalo R., Adair, Linda S., Aguilar-Salinas, Carlos Alberto, Alarcón-Riquelme, Marta E., An, Ping, Aviles-Santa, Larissa, Becker, Diane M., Beilin, Lawrence J., Bergmann, Sven, Bisgaard, Hans, Black, Corri, Boehnke, Michael, Boerwinkle, Eric, Böhm, Bernhard O., Bønnelykke, Klaus, Boomsma, D.I., Bottinger, Erwin P., Buchanan, Thomas A., Canouil, Mickaël, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Ida Chen, Yii-Der, Cheng, Ching-Yu, Collins, Francis S., Correa, Adolfo, Cucca, Francesco, Janaka de Silva, H., Dedoussis, George, Elmståhl, Sölve, Evans, Michele K., Ferrannini, Ele, Ferrucci, Luigi, Florez, Jose C., Franks, Paul W., Frayling, Timothy M., Froguel, Philippe, Gigante, Bruna, Goodarzi, Mark O., Gordon-Larsen, Penny, Grallert, Harald, Grarup, Niels, Grimsgaard, Sameline, Groop, Leif, Gudnason, Vilmundur, Guo, Xiuqing, Hamsten, Anders, Hansen, Torben, Hayward, Caroline, Heckbert, Susan R., Horta, Bernardo L., Huang, Wei, Ingelsson, Erik, James, Pankow S., Jarvelin, Marjo-Ritta, Jonas, Jost B., Jukema, J. Wouter, Kaleebu, Pontiano, Kaplan, Robert, Kardia, Sharon L.R., Kato, Norihiro, Keinanen-Kiukaanniemi, Sirkka M., Kim, Bong-Jo, Kivimaki, Mika, Koistinen, Heikki A., Kooner, Jaspal S., Körner, Antje, Kovacs, Peter, Kuh, Diana, Kumari, Meena, Kutalik, Zoltan, Laakso, Markku, Lakka, Timo A., Launer, Lenore J., Leander, Karin, Li, Huaixing, Lin, Xu, Lind, Lars, Lindgren, Cecilia, Liu, Simin, Loos, Ruth J.F., Magnusson, Patrik K.E., Mahajan, Anubha, Metspalu, Andres, Mook-Kanamori, Dennis O., Mori, Trevor A., Munroe, Patricia B., Njølstad, Inger, O'Connell, Jeffrey R., Oldehinkel, Albertine J., Ong, Ken K., Padmanabhan, Sandosh, Palmer, Colin N.A., Palmer, Nicholette D., Pedersen, Oluf, Pennell, Craig E., Porteous, David J., Pramstaller, Peter P., Province, Michael A., Psaty, Bruce M., Qi, Lu, Raffel, Leslie J., Rauramaa, Rainer, Redline, Susan, Ridker, Paul M., Rosendaal, Frits R., Saaristo, Timo E., Sandhu, Manjinder, Saramies, Jouko, Schneiderman, Neil, Schwarz, Peter, Scott, Laura J., Selvin, Elizabeth, Sever, Peter, Shu, Xiao-Ou, Slagboom, P. Eline, Small, Kerrin S., Smith, Blair H., Snieder, Harold, Sofer, Tamar, Sørensen, Thorkild I.A., Spector, Tim D., Stanton, Alice, Steves, Claire J., Stumvoll, Michael, Sun, Liang, Tabara, Yasuharu, Tai, E. Shyong, Timpson, Nicholas J., Tönjes, Anke, Tuomilehto, Jaakko, Tusie, Teresa, Uusitupa, Matti, van der Harst, Pim, van Duijn, Cornelia, Vitart, Veronique, Vollenweider, Peter, Vrijkotte, Tanja G.M., Wagenknecht, Lynne E., Walker, Mark, Wang, Ya X., Wareham, Nick J., Watanabe, Richard M., Watkins, Hugh, Wei, Wen B., Wickremasinghe, Ananda R., Willemsen, Gonneke, Wilson, James F., Wong, Tien-Yin, Wu, Jer-Yuarn, Xiang, Anny H., Yanek, Lisa R., Yengo, Loïc, Yokota, Mitsuhiro, Zeggini, Eleftheria, Zheng, Wei, Zonderman, Alan B., Rotter, Jerome I., Gloyn, Anna L., McCarthy, Mark I., Dupuis, Josée, Meigs, James B., Scott, Robert A., Prokopenko, Inga, Leong, Aaron, Liu, Ching-Ti, Parker, Stephen C.J., Mohlke, Karen L., Langenberg, Claudia, Wheeler, Eleanor, Morris, Andrew P., Barroso, Inês, Stefanucci, Luca, Moslemi, Camous, Tomé, Ana R., Virtue, Samuel, Bidault, Guillaume, Gleadall, Nicholas S., Watson, Laura P.E., Kwa, Jing E., Burden, Frances, Farrow, Samantha, Võsa, Urmo, Burling, Keith, Walker, Lindsay, Ord, John, Barker, Peter, Warner, James, Frary, Amy, Renhstrom, Karola, Ashford, Sofie E., Piper, Jo, Biggs, Gail, Erber, Wendy N., Hoffman, Gary J., Schoenmakers, Nadia, Rieneck, Klaus, Dziegiel, Morten H., Azzu, Vian, Vacca, Michele, Aparicio, Hugo Javier, Hui, Qin, Cho, Kelly, Sun, Yan V., Wilson, Peter W., Bayraktar, Omer A., Vidal-Puig, Antonio, Ostrowski, Sisse R., Astle, William J., Olsson, Martin L., Storry, Jill R., Pedersen, Ole B., Ouwehand, Willem H., Chatterjee, Krishna, Vuckovic, Dragana, and Frontini, Mattia

Published
2024
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32. Contributors

Author

Ahearn, Joseph M., primary, Alarcón-Riquelme, Marta E., additional, Almaani, Salem J., additional, Anolik, Jennifer H., additional, Aranow, Cynthia, additional, Bacalao, Maria A., additional, Barilla-LaBarca, Maria-Louise, additional, Barnas, Jennifer L., additional, Barturen, Guillermo, additional, Bermas, Bonnie L., additional, Bernatsky, Sasha, additional, Bruce, I.N., additional, Bucala, Richard, additional, Buyon, Jill P., additional, Carnero-Montoro, Elena, additional, Clarke, Ann E., additional, Clowse, Megan E.B., additional, Concha, Josef Symon S., additional, Dellaripa, Paul, additional, Diamond, Betty, additional, Doyle, Tracy J., additional, Fernando, Michelle M.A., additional, Fisk, John D., additional, Furie, Richard, additional, Gordon, Caroline, additional, Greiling, Teri M., additional, Han, Shuhong, additional, Hanly, John G., additional, Hile, Grace A., additional, Horowitz, Diane, additional, Isenberg, David, additional, Izmirly, Peter, additional, Jacobs, Barbara, additional, James, Judith A., additional, Kahlenberg, J. Michelle, additional, Kalunian, Kenneth C., additional, Kang, Insoo, additional, Kaplan, Mariana J., additional, Khamashta, Munther A., additional, Kim, Mimi, additional, Knight, Jason S., additional, Koumpouras, Fotios, additional, Kriegel, Martin A., additional, La Cava, Antonio, additional, Ladouceur, Alexandra, additional, Lahita, Robert G., additional, Lee, Iris Jung-Won, additional, Lessard, Christopher J., additional, Lewandowski, Laura B., additional, Liang, Yun, additional, Liu, Chau-Ching, additional, Mackay, Meggan, additional, Madaio, Michael P., additional, Marder, Galina, additional, Matteson, Eric L., additional, McCoy, Sara, additional, McMahon, Maureen, additional, Meffre, Eric, additional, Mejia-Vilet, Juan, additional, Merrill, Joan, additional, Morand, Eric F., additional, Moreira Pinto, Sara, additional, Nakabo, Shuichiro, additional, Northcott, Melissa, additional, Omisade, Antonina, additional, Ortel, Thomas L., additional, Perl, Andras, additional, Ramsey-Goldman, Rosalind, additional, Reeves, Westley H., additional, Reyes-Thomas, Joyce, additional, Reynolds, J.A., additional, Richardson, Bruce, additional, Rodriguez, Juan Vicente, additional, Rovin, Brad H., additional, Rudinskaya, Alla, additional, Ruiz-Irastorza, Guillermo, additional, Saxena, Amit, additional, Schanberg, Laura E., additional, Sharma, Tarun S., additional, Skaggs, Brian, additional, Somers, Emily C., additional, Stohl, William, additional, Talabi, Mehret Birru, additional, Tessneer, Kandice L., additional, Tsao, Betty P., additional, Ugarte, Amaia, additional, Volpe, Bruce T., additional, Vyse, Timothy J., additional, Wainwright, Benjamin J., additional, Ward, Michael M., additional, Wasko, Mary Chester M., additional, Werth, Victoria P., additional, Wise, Leanna, additional, Zhuang, Haoyang, additional, and Zuo, Yu, additional

Published
2021
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35. Two Functional Lupus-Associated BLK Promoter Variants Control Cell-Type- and Developmental-Stage-Specific Transcription

Author

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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Lupus, Autoimmune Disease, Clinical Research, Stem Cell Research, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Alleles, Chromosomes, Human, Pair 8, Electrophoretic Mobility Shift Assay, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription, Genetic, src-Family Kinases, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

Published
2014

36. Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.

Author

Solomon, Olivia, Lanata, Cristina M., Adams, Cameron, Nititham, Joanne, Taylor, Kimberly E., Chung, Sharon A., Yazdany, Jinoos, Dall'Era, Maria, Pons‐Estel, Bernado A., Tusié‐Luna, Teresa, Tsao, Betty, Morand, Eric, Alarcón‐Riquelme, Marta E., Barcellos, Lisa F., and Criswell, Lindsey A.

Subjects
MAJOR histocompatibility complex, SYSTEMIC lupus erythematosus, GENOTYPES
Abstract

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. Methods: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. Results: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. Conclusion: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations. [ABSTRACT FROM AUTHOR]

Published
2024
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37. Variable Association of Reactive Intermediate Genes with Systemic Lupus Erythematosus in Populations with Different African Ancestry

Author

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

Subjects
Autoimmune Disease, Lupus, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adult, Alleles, Black People, Electron Transport Complex I, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genotype, Glutathione Reductase, Haplotypes, Humans, Lupus Erythematosus, Systemic, NADH Dehydrogenase, Nitric Oxide Synthase Type I, Polymorphism, Single Nucleotide, SYSTEMIC LUPUS ERYTHEMATOSUS, AFRICAN AMERICANS, OXYGEN COMPOUNDS, GENETIC ASSOCIATION STUDIES, SINGLE-NUCLEOTIDE POLYMORPHISM, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
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

38. Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans

Author

Morris, David L, Taylor, Kimberly E, Fernando, Michelle MA, Nititham, Joanne, Alarcón-Riquelme, Marta E, Barcellos, Lisa F, Behrens, Timothy W, Cotsapas, Chris, Gaffney, Patrick M, Graham, Robert R, Pons-Estel, Bernardo A, Gregersen, Peter K, Harley, John B, Hauser, Stephen L, Hom, Geoffrey, Network, International MHC and Autoimmunity Genetics, Langefeld, Carl D, Noble, Janelle A, Rioux, John D, Seldin, Michael F, Consortium, Systemic Lupus Erythematosus Genetics, Criswell, Lindsey A, and Vyse, Timothy J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Immunology, Clinical Research, Autoimmune Disease, Lupus, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, HLA Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DQ alpha-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, White People, International MHC and Autoimmunity Genetics Network, Systemic Lupus Erythematosus Genetics Consortium, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

Published
2012

39. Association of two independent functional risk haplotypes in TNIP1 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, Networks, BIOLUPUS and GENLES, Alarcón, Graciela S, Anaya, Juan‐Manuel, Bae, Sang‐Cheol, Kim, Jae‐Hoon, Bin Joo, Young, 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, Martín, 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
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Human Genome, Lupus, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Adaptor Proteins, Signal Transducing, Black or African American, Asian, B-Lymphocytes, Cell Line, Transformed, DNA-Binding Proteins, Female, Genetic Markers, Genetic Predisposition to Disease, Haplotypes, Hispanic or Latino, Humans, Intracellular Signaling Peptides and Proteins, Lupus Erythematosus, Systemic, Male, Neoplasm Proteins, Polymorphism, Single Nucleotide, Risk Factors, United States, White People, BIOLUPUS and GENLES Networks, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 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.MethodsWe 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.ResultsWe 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.ConclusionOur 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

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

Author

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, La Torre, Ignacio García‐De, 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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Health Sciences, Genetics, Autoimmune Disease, Clinical Research, Lupus, Kidney Disease, American Indian or Alaska Native, Inflammatory and immune system, Adolescent, Adult, Child, Female, Genetic Predisposition to Disease, Genotype, Humans, Indians, North American, Indians, South American, Lupus Erythematosus, Systemic, Lupus Nephritis, Male, Middle Aged, Morbidity, Prevalence, Risk Factors, Socioeconomic Factors, White People, Young Adult, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
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

41. Evaluation of TRAF6 in a large multiancestral lupus cohort

Author

Namjou, Bahram, Choi, Chan‐Bum, Harley, Isaac TW, Alarcón‐Riquelme, Marta E, Network, BIOLUPUS, 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, 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, Network, Genoma en Lupus, 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

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Epidemiology, Health Sciences, Lupus, Clinical Research, Arthritis, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Alleles, Case-Control Studies, Cohort Studies, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lupus Erythematosus, Systemic, Male, Polymorphism, Single Nucleotide, TNF Receptor-Associated Factor 6, BIOLUPUS Network, Genoma en Lupus Network, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectiveSystemic 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.MethodsFifteen 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.ResultsEvidence 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.ConclusionOur 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

42. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap.

Author

Ramos, Paula S, Criswell, Lindsey A, Moser, Kathy L, Comeau, Mary E, Williams, Adrienne H, Pajewski, Nicholas M, Chung, Sharon A, Graham, Robert R, Zidovetzki, Raphael, Kelly, Jennifer A, Kaufman, Kenneth M, Jacob, Chaim O, Vyse, Timothy J, Tsao, Betty P, Kimberly, Robert P, Gaffney, Patrick M, Alarcón-Riquelme, Marta E, Harley, John B, Langefeld, Carl D, and International Consortium on the Genetics of Systemic Erythematosus

Subjects
International Consortium on the Genetics of Systemic Erythematosus, Humans, Arthritis, Rheumatoid, Colitis, Ulcerative, Crohn Disease, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Autoimmune Diseases, Genetic Predisposition to Disease, Receptors, Interleukin, Case-Control Studies, Cohort Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, OX40 Ligand, Interleukin-2 Receptor alpha Subunit, Genome-Wide Association Study, Genetic Pleiotropy, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Arthritis, Rheumatoid, Colitis, Ulcerative, Lupus Erythematosus, Systemic, Diabetes Mellitus, Type 1, Receptors, Interleukin, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

In spite of the well-known clustering of multiple autoimmune disorders in families, analyses of specific shared genes and polymorphisms between systemic lupus erythematosus (SLE) and other autoimmune diseases (ADs) have been limited. Therefore, we comprehensively tested autoimmune variants for association with SLE, aiming to identify pleiotropic genetic associations between these diseases. We compiled a list of 446 non-Major Histocompatibility Complex (MHC) variants identified in genome-wide association studies (GWAS) of populations of European ancestry across 17 ADs. We then tested these variants in our combined Caucasian SLE cohorts of 1,500 cases and 5,706 controls. We tested a subset of these polymorphisms in an independent Caucasian replication cohort of 2,085 SLE cases and 2,854 controls, allowing the computation of a meta-analysis between all cohorts. We have uncovered novel shared SLE loci that passed multiple comparisons adjustment, including the VTCN1 (rs12046117, P = 2.02×10(-06)) region. We observed that the loci shared among the most ADs include IL23R, OLIG3/TNFAIP3, and IL2RA. Given the lack of a universal autoimmune risk locus outside of the MHC and variable specificities for different diseases, our data suggests partial pleiotropy among ADs. Hierarchical clustering of ADs suggested that the most genetically related ADs appear to be type 1 diabetes with rheumatoid arthritis and Crohn's disease with ulcerative colitis. These findings support a relatively distinct genetic susceptibility for SLE. For many of the shared GWAS autoimmune loci, we found no evidence for association with SLE, including IL23R. Also, several established SLE loci are apparently not associated with other ADs, including the ITGAM-ITGAX and TNFSF4 regions. This study represents the most comprehensive evaluation of shared autoimmune loci to date, supports a relatively distinct non-MHC genetic susceptibility for SLE, provides further evidence for previously and newly identified shared genes in SLE, and highlights the value of studies of potentially pleiotropic genes in autoimmune diseases.

Published
2011

43. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production.

Author

Chung, Sharon A, Taylor, Kimberly E, Graham, Robert R, Nititham, Joanne, Lee, Annette T, Ortmann, Ward A, Jacob, Chaim O, Alarcón-Riquelme, Marta E, Tsao, Betty P, Harley, John B, Gaffney, Patrick M, Moser, Kathy L, SLEGEN, Petri, Michelle, Demirci, F Yesim, Kamboh, M Ilyas, Manzi, Susan, Gregersen, Peter K, Langefeld, Carl D, Behrens, Timothy W, and Criswell, Lindsey A

Subjects
SLEGEN, Humans, Lupus Erythematosus, Systemic, Genetic Predisposition to Disease, DNA, Autoantibodies, Case-Control Studies, Major Histocompatibility Complex, Polymorphism, Single Nucleotide, STAT4 Transcription Factor, Interferon Regulatory Factors, Genetic Variation, Genome-Wide Association Study, CD11b Antigen, Lupus Erythematosus, Systemic, Polymorphism, Single Nucleotide, Antigens, CD11b, Genetics, Developmental Biology
Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with p(heterogeneity)

Published
2011

45. Lack of strong innate immune reactivity renders macrophages alone unable to control productive Varicella-Zoster Virus infection in an isogenic human iPSC-derived neuronal co-culture model

Author

Van Breedam, Elise, primary, Buyle-Huybrecht, Tamariche, additional, Govaerts, Jonas, additional, Meysman, Pieter, additional, Bours, Andrea, additional, Boeren, Marlies, additional, Di Stefano, Julia, additional, Caers, Thalissa, additional, De Reu, Hans, additional, Dirkx, Laura, additional, Schippers, Jolien, additional, Bartholomeus, Esther, additional, Lebrun, Marielle, additional, Sadzot-Delvaux, Catherine, additional, Rybakowska, Paulina, additional, Alarcón-Riquelme, Marta E., additional, Marañón, Concepción, additional, Laukens, Kris, additional, Delputte, Peter, additional, Ogunjimi, Benson, additional, and Ponsaerts, Peter, additional

Published
2023
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47. Response to the letter 'testing the effectiveness of MyPROSLE in classifying patients with lupus nephritis'.

Author

Toro-Domínguez, Daniel, Martorell-Marugán, Jordi, Martinez-Bueno, Manuel, López-Domínguez, Raúl, Carnero-Montoro, Elena, Barturen, Guillermo, Goldman, Daniel, Petri, Michelle, Carmona-Sáez, Pedro, and Alarcón-Riquelme, Marta E

Subjects
LUPUS nephritis, MACHINE learning
Abstract

The article is a response to a letter discussing the effectiveness of a web application called MyPROSLE in classifying patients with lupus nephritis. The authors clarify that MyPROSLE is meant to provide additional information for clinical decisions, not replace standard diagnostic procedures. They address concerns raised in the letter and provide detailed explanations and analysis of MyPROSLE's performance. The authors also discuss the impact of incorporating healthy samples in the analysis and highlight the need for considering multiple performance metrics. They emphasize that MyPROSLE should only be used for research purposes and provide data availability and funding information. [Extracted from the article]

Published
2024
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48. Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus.

Author

Lindblom, Julius, Beretta, Lorenzo, Borghi, Maria Orietta, Alarcón-Riquelme, Marta E., and Parodis, Ioannis

Subjects
SYSTEMIC lupus erythematosus, AUTOIMMUNE diseases, AUTOANTIBODIES, DIAGNOSIS, IMMUNOASSAY
Abstract

Introduction: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs). Methods: Serum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays. Results: Of the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak. Discussion: Our findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE. [ABSTRACT FROM AUTHOR]

Published
2023
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49. Contributors

Author

Akhoon, Bashir Akhlaq, primary, Alarcón-Riquelme, Marta E., additional, Alberca, Lucas N., additional, Alice, Juan I., additional, Anuwongcharoen, Nuttapat, additional, Arga, Kazim Yalcin, additional, Belllera, Carolina L., additional, Berishvili, Vladimir P., additional, Bhardwaj, Anshu, additional, Bodiga, Vijaya Lakshmi, additional, Bodiga, Sreedhar, additional, Brylinski, Michal, additional, Carmona-Sáez, Pedro, additional, Chakraborti, Sohini, additional, Chaudhry, Vaishali, additional, Chen, Lixia, additional, Coumar, Mohane Selvaraj, additional, Toro-Domínguez, Daniel, additional, Dietis, Nikolas, additional, Douanne, Noelie, additional, Druzhilovskiy, Dmitry, additional, Eurídice Juárez-Mercado, K., additional, Fernández-Prada, Christopher, additional, Gautam, Pankaj, additional, Ghosh, Indira, additional, Mohan, C. Gopi, additional, Haider, Shozeb, additional, Hua, Li, additional, Iqbal, Jameel, additional, James, Nivya, additional, Jolly, Bani, additional, Kharkar, Prashant S., additional, Kim, Se-Min, additional, Kumar, Shivani, additional, Kumar, Suresh, additional, Kumar, Pawan, additional, Kurgan, Lukasz, additional, Lo, Yu-Chen, additional, López-López, Edgar, additional, Machhar, Janvhi S., additional, Manzoor, K., additional, Medina-Franco, José L., additional, Melge, Anu R., additional, Minadakis, George, additional, Minguez-Menendez, Aida, additional, Mitreva, Makedonka, additional, Monte-Neto, Rubens L., additional, Muneeswaran, Gurusamy, additional, Nagamani, Selvaraman, additional, Nair, Shantikumar V., additional, Nantasenamat, Chanin, additional, Sastry, G. Narahari, additional, Nargotra, Amit, additional, Nikitina, Anastasia A., additional, Orlov, Alexey A., additional, Osolodkin, Dmitry I., additional, Oulas, Anastasis, additional, Pal, Manoj Kumar, additional, Palyulin, Vladimir A., additional, Pandya, Ashma, additional, Passi, Anurag, additional, Pena, Joan, additional, Phanus-umporn, Chuleeporn, additional, Pires, Douglas E.V., additional, Poroikov, Vladimir, additional, Prieto-Martínez, Fernando D., additional, Radchenko, Eugene V., additional, Ramakrishnan, Gayatri, additional, Ramanathan, K., additional, Rosa, Bruce A., additional, Sahoo, Rosaleen, additional, Sahu, Niteshkumar U., additional, Sarica, Pemra Ozbek, additional, Sarvagalla, Sailu, additional, Savva, Kyriaki, additional, Sbaraglini, María L., additional, Schaduangrat, Nalini, additional, Serçinoğlu, Onur, additional, Shah, Chetan P., additional, Shanthi, V., additional, Sharma, Tina, additional, Sokratous, Kleitos, additional, Spyrou, George M., additional, Srinivasan, Narayanaswamy, additional, Sriwanichpoom, Nagaya, additional, Sun, Li, additional, Syed, Safiulla Basha, additional, Talevi, Alan, additional, Tiwari, Harshita, additional, Torres, Jorge Z., additional, Tunes, Luiza G., additional, Turanli, Beste, additional, Tyagi, Rahul, additional, Wang, Chen, additional, Wikberg, Jarl E.S., additional, Xia, Xuhua, additional, Yuen, Tony, additional, Zachariou, Margarita, additional, Zaidi, Neeha, additional, Zaidi, Samir, additional, Zaidi, Mone, additional, Zallone, Alberta, additional, and Zheng, Mengzhu, additional

Published
2019
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